West Chester Hospital Opposition to Emergency Injunction re Ivermectin (Exhibit 27) — Apter v. HHS (S.D. Tex.)

Record facts

No. 3:22-cv-00184 · Doc. 12-27 · 2022-08-08 · Docket on CourtListener

Full text

Exhibit 27
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IN COMMON PLEAS COURT 
BUTLER COUNTY, OHIO 
JULIE SMITH, as Guardian of 
JEFFREY SMITH 
Plaintiff, 
v. 
WEST CHESTER HOSPITAL, LLC 
Defendant. 
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CASE NO. CV 2021 08 1206 
Judge Michael A. Oster, Jr. 
MEMORANDUM OF LAW 
FILED 
MARYL. SWAIN 
BUTLER COUNTY 
CLERK OF COURTS 
09/02/2021 03:56 PM 
CV 2021 08 1206 
IN OPPOSITION TO PLAINTIFF'S COMPLAINT FOR EMERGENCY MEDICAL 
DECLARATORY JUDGMENT AND EMERGENCY INJUNCTIVE 
RELIEF AND OBJECTION TO INJUNCTIVE RELIEF 
NOW COMES West Chester Hospital, by and through counsel, hereby requests the 
Court deny the injunctive relief sought by Plaintiff, Julie Smith, in her August 26, 2021, 
complaint seeking declaratory judgment and injunctive relief. Ohio law requires a 
particularized process through which a party may seek and obtain injunctive relief in an 
expedited manner. This process has not been followed by Plaintiff. Rather, Plaintiff has 
improperly circumvented the process through which expedited injunctive relief can be 
obtained, namely by failing to file a Motion for a Temporary Restraining Order ("TRO") 
seeking injunctive relief. Irrespective of Plaintiff's procedural short-comings, West Chester 
Hospital seeks to provide this Court with a response to Plaintiff's request of injunctive relief 
and presumed, yet absent, motion for TRO, which has been scheduled for an evidentiary 
hearing on Thursday, September 2, 2021, at 10:00 a.m. whereby this Court will determine the 
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appropriateness of a preliminary injunction. In opposition to Plaintiffs requested injunctive 
relief, West Chester Hospital states the following: 
INTRODUCTION & BACKGROUND 
On August 26, 2021, Plaintiff filed her Complaint for Emergency Medical 
Declaratory Judgment and Emergency Injunctive Relief seeking a declaratory judgment 
from this Court forcing West Chester Hospital to administer Ivermectin to Jeffrey Smith, 
Plaintiff's husband for which she is guardian of due to COVID-19 related illness and 
disability. 
On July 22, 2021, Mr. Smith was admitted for treatment of a COVID-19 infection. 
Since July 24, 2021, West Chester Hospital has provided Intensive Care Unit medical 
treatment to Mr. Smith, with Mr. Smith being on a ventilator since August 3, 2021. Mr. 
Smith was cleared of COVID-19 infection on or about August 10, 2021, and is presently 
diagnosed with, among other things, acute hypoxic respiratory failure due to severe acute 
respiratory distress syndrome. 
A Temporary Restraining Order ("TRO") was issued on August 26, 2021, directing 
West Chester Hospital to provide Ivermectin pursuant to the prescription written by Dr. Fred 
Wagshul. The TRO is set to expire on September 6, 2021, though a subsequent hearing for 
preliminary injunction has been scheduled for September 2, 2021 at 10 a.m. 
Although Plaintiff has never filed a motion for TRO, an evidentiary hearing for the 
Plaintiffs requested preliminary injunction has expeditiously been scheduled. Given the 
timeline between the filing of Plaintiffs complaint and the scheduled hearing, West Chester 
Hospital has promptly filed an answer in response to Plaintiff's allegations. 
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ARGUMENT 
In short, Plaintiffs request for preliminary injunctive relief disregards Ohio law, 
medical guidance and scientific information, and the facts and circumstances smTounding Mr. 
Smith's ongoing treatment at West Chester Hospital. Plaintiff's complaint seeking exceptional 
and extraordinary injunctive relief has improperly circumscribed the proper procedure for such 
a matter, limiting West Chester Hospital's ability to respond to Plaintiffs complaint and inform 
the Court of the realities of the instant matter. Further, Plaintiff relies on hearsay news articles 
in the form of assertions and limited studies purporting the efficacy and benefits of Ivermectin, 
while innumerable public health bodies, government agencies, and medical science generally 
provides directly contradictory guidance to not use Ivermectin for the treatment of COVID-19 
or the resulting acute respiratory distress syndrome ("ARDS") continuing once the infection 
has ceased. Finally, Plaintiff's requested administration of Ivermectin to treat post-infection 
ARDS is contraindicative to the facts and circumstances of Mr. Smith's present status and the 
medical expertise of his treating physicians at West Chester Hospital and may result in severe 
detrimental harm to his medical condition. 
I. 
Preliminary Injunction Standard. 
In general, "[t]he purpose of a preliminary injunction is to preserve a status between 
the parties pending a trial on the merits." Procter & Gamble Co. v. Stoneham (2000), 140 
Ohio App.3d 260, 267, 747 N.E.2d 268. "The right to an injunction must be clear and the 
proof thereof clear and convincing, and the right established by the strength of plaintiffs' own 
case rather than by any weakness of that of his adversary." White v. Long (1967), 12 Ohio 
App.2d 136, 140, 41 O.O.2d 200, 231 N.E.2d 337. In considering a preliminary injunction, 
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the court considers whether "(1) the movant has shown a strong or substantial likelihood or 
probability of success on the merits, (2) the movant has shown irreparable injury, (3) 
the preliminary injunction could harm third parties, and ( 4) the public interest would be 
served by issuing the preliminary injunction." Union Twp. v. Union Twp. Professional 
Firefighters' Local 3412 (Feb. 14, 2000), Clermont App. No. CA99-08-082, 2000 WL 
189959. 
As the Twelfth District Court of Appeals has stated, "[a] preliminary injunction is a 
provisional remedy, which is defined as a 'remedy other than a claim for relief.' " N. Fairfield 
Baptist Church v. Gl29, L.L.C., Butler App. No. CA2009-11-281, 2010-Ohio-2543, 2010 
WL 2252490,, 16, citing R.C. 2505.02(A)(3); State ex rel. Butler Cty. Children Servs. Bd. v. 
Sage (2002), 95 Ohio St.3d 23, 24, 764 N.E.2d 1027. 
II. 
Plaintiff Failed to Follow the Ohio Rules of Civil Procedure for the Requested 
Extraordinary Relief of a Temporary Restraining Order and Injunction. 
The improper and expeditious route by which Plaintiff has managed to obtain a TRO 
and evidentiary hearing for injunctive relief runs roughshod over West Chester Hospital's 
due process rights under the Ohio Rules of Civil Procedure. Plaintiff filed this action on a 
Friday afternoon, but did not notify undersigned counsel for West Chester Hospital until 
approximately thirty minutes before this Court held a hearing on the requested relief the 
following Monday. No copy of the complaint was provided - formally or informally - to 
West Chester Hospital until its counsel arrived at the Monday afternoon hearing. As the 
docket reflects, the clerk of courts issued its summons the same day the Judgment Entry was 
filed. 
This lack of notice was no doubt an effort at gamesmanship, meant to provide a 
strategic litigation advantage, given that Plaintiff's counsel and West Chester Hospital's 
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counsel both appeared at a hearing where Mrs. Smith's petition for guardianship was heard in 
the Butler County Probate Court, case no. PG21-08-0129. The Plaintiff filed this action 
shortly thereafter, yet did not alert counsel for West Chester Hospital until minutes before the 
August 23, 2021 hearing took place. 
Rule 65 allows a court to issue a TRO without notice only under limited and specific 
circumstances: "A temporary restraining order may be granted without written or oral notice 
to the adverse party or his attorney only if ... the applicant's attorney certifies to the court in 
writing the efforts, if any, which have been made to give notice and the reasons supporting his 
claim that notice should not be required." Civ.R. 65(A) ( emphasis added). The plaintiff's 
attorney failed to do any of that here. 
Despite that, the trial court issued a temporary 
restraining order without any meaningful notice to the hospital. This court should reverse the 
temporary restraining order couched in the Judgment Entry of August 23, 2021. 
As the Supreme Court of Ohio has observed: the "'elementary and fundamental 
requirement"' of due process "'in any proceeding ... is notice reasonably calculated, under 
all the circumstances, to apprise interested parties of the pendency of the action and afford 
them an opportunity to present their objections."' Ohio Valley Radiology Associates, Inc. v. 
Ohio Valley Hosp. Ass 'n, 28 Ohio St. 3d 118, 124-25, 502 N.E.2d 599 (I 986) ( quoting 
Mullane v. Central Hanover Bank & Trust Co. 339 U.S. 306, 314, 70 S.Ct. 652, 94 L.Ed. 865 
(1950)). The lack of notice-and the plaintiff's failure to explain why none was given or why 
Rule 65 was not otherwise obeyed-deprived West Chester Hospital of even the minimal 
process it was due under Ohio and federal law. 
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Rule 65's plain language provides mandatory requirements, not merely suggestions for 
notice. N. Elec. Co. v. United Steelworkers of America, 28 Ohio App.2d 253, 259, 277 
N.E.2d 59 (3d Dist.1971) ("We conclude that [the requirements of Rule 65(A)] are 
mandatory. To hold otherwise would give little meaning to the requirements that a temporary 
restraining order granted without notice must define the injury and state why it is irreparable 
and why the order was granted without notice.") (holding trial court erred in issuing 
injunction that failed to comply with rule's requirements regarding harm, irreparability, and 
notice). The Judgment Entry merely reiterated the plaintiff's demand for judgment and an 
order, the appearances of counsel for the parties, and ordered the hospital to administer the 
plaintiff's requested medication. It did none of the things Ohio law requires, such as explain 
why relief was granted without notice or why notice could not be provided. The Judgment 
Entry also failed to define the injury that would occur in its absence or explain why it was 
irreparable. In light of these deficiencies, the Judgment Entry of August 23, 2021 should be 
reversed. 
III. 
Temporary restraining order should only preserve the status quo, not compel 
affirmative relief. 
The trial court's order is also improper because it grants affirmative relief-in effect, 
it entered a judgment that accomplished the plaintiff's ultimate demand on mere minutes' 
notice to the opposing party and after a half-hour hearing. But "[p ]arties should rarely be able 
to obtain ex parte affirmative relief to accomplish the final object of their position in a 
dispute." Deluca v. BankOhio Nat'! Bank, Inc., 74 Ohio App.3d 233, 243, 598 N.E.2d 781 
(10th Dist.1991). The type of near-total relief the trial court ordered here is not within the 
province of Rule 65. As Deluca further observed, "the nature of Civ.R. 65(A) temporary 
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injunctive relief is to preserve the status quo ante," and so "is truly extraordinary and should 
be awarded only with the very greatest caution." Deluca v. BankOhio Nat'! Bank, Inc., 74 
Ohio App.3d 233, 598 N.E.2d 781 (10th Dist. 1991); see also CSIRW Westlake Indoor 
Storage, L.L.C. v. Russo, 2016-Ohio-2845, 64 N.E.3d 396, , 23 (8th Dist.) (citing Gries 
Sports Ents., Inc. v. Cleveland Browns Football Co., 26 Ohio St.3d 15, 496 N.E.2d 959 
(1986)) ("A court issues a temporary injunction when it is necessary to preserve the status quo 
of the case to prevent any actions of the parties from making null and unenforceable a final 
judgment.") The order here did not simply preserve the status quo. Rather, it ordered West 
Chester Hospital to undertake new, affirmative action at the request of Mr. Smith's wife and 
purported new doctor, and contrary to the clinical judgment of his current medical team. 
Even acknowledging for Mr. Smith's dire condition, Ohio law and procedure do not 
contemplate awarding the sort of complete relief and final judgment incorporated by the 
court's temporary restraining order, particularly absent the notice and process required by the 
Civil Rules. For this additional reason, the Judgment Entry should be reversed. 
IV. 
Plaintifrs Assertions Regarding the Efficacy and Dangers of lvermectin 
Disregard Guidance Provided by Public Health Bodies and the Broader Scientific 
Community 
The mandatory injunctive relief requested by Plaintiff from this Court rejects the 
reality of science and the medical community's current understanding of acceptable uses for 
Ivermectin. There is no doubt that the consensus of the medical science community in this 
country, and others, is that Ivermectin is neither safe nor effective to treat COVID-19 
infections, let alone the resulting damage once a COVID-19 infection is cleared. 
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Governmental Health Bodies Oppose the Use of Ivermectin for COVID-19 
Treatment 
Governmental health bodies across this country and around the world have provided 
clear and explicit guidance against the use Ivermectin for COVID-19 related treatment. Nearly 
the same day that Plaintiff filed her complaint, the federal authorities in the Food and Drug 
Administration ("FDA") announced: "You are not a horse. You are not a cow. Using the drug 
Ivermectin to treat COVID-19 can be dangerous and even lethal." See FDA Tweet attached 
hereto as Exhibit "A". 
The FDA has been forced to provide recurnng guidance against the use of 
Ivermectin to prevent or treat COVID-19. On April 10, 2021, the FDA issued an FDA Letter 
to Stakeholders: Do Not Use Ivermectin Intended for Animals as Treatment for COVID-19 
in Humans. This letter was one of the FDAs first attempts to address the vast amount of 
misinformation surrounding the medical administration of Ivermectin for COVID-19, which 
includes a research article relied upon by Plaintiffs experts. This FDA Letter is attached 
hereto as Exhibit B. 
Then on August 6, 2021, the FDA provided a frequently asked question ("FAQ") 
section in response to irregular usage of Ivermectin. A copy of the FDA FAQ: COVID-19 and 
Ivermectin Intended for Animals is attached hereto as Exhibit C. Within this FAQ the FDA 
states: (1) "[w]hile there are approved uses for Ivern1ectin in people and animals, it is not 
approved for the prevention or treatment of COVID-19"; (2) "[i]vermectin tablets are approved 
for use in humans for the treatment of some parasitic worms (intestinal strongyloidiasis and 
onchocerciasis) and Ivermectin topical formulations are approved for human use by 
prescription only for the treatment of external parasites such as headlice and for skin conditions 
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such as rosacea"; (3) "[a]ny use of Ivermectin for the prevention or treatment of COVID-19 
should be avoided as its benefits and safety for these purposes have not been established"; and 
(4), important to the instant matter, "[l]aboratory test abnormalities include decrease in white 
cell count and elevated liver tests". Id. (emphasis added). Also on August 21, 2021, the FDA 
distributed additional guidance via Twitter reiterating the information its previously provided. 
Within its publication, the FDA states that Ivermectin is not approved for use in treating or 
preventing COVID-19 and warned Ivermectin can negatively interact with other 
medications, like blood-thinners. 
The CDC and National Institute of Health, a part of the U.S. Department of Health and 
Human Services, have also issued guidance in opposition to any use of Ivermectin for 
COVID-19 treatment. See CDC Health Alert, Rapid Increase in Ivermectin Prescriptions and 
Reports of Severe Illness Associated with use of Product Containing lvermectin to Prevent or 
Treat COVID-19 (Aug. 26, 2021); NIH Publication, Antiviral Drugs That Are Approved or 
Under Evaluation for the Treatment of COVID-19 (last updated Jul. 8, 2021); copies of each 
are attached hereto as Exhibits D & E. This guidance opposing the use of Ive1mectin 
generally conforms with the guidance issued by the European Medicines Agency, the agency 
of the European Union in charge of the evaluation and supervision of medicinal products, and 
the World Health Organization regarding the use of Ivermectin for the prevention or treatment 
of COVID-19. See generally, European Medicines Agency Publication, EMA advises against 
the use of Ivermectin for the prevention or treatment or COVID-19 outside randomized 
clinical trials (March 22, 2021 ); World Health Organization, Living Guideline: Therapeutics 
and COVID-19, (July 6, 2021), copies of which are attached hereto as Exhibits F & G 
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respectively. 
This immense volume of public health guidance against the use of Ivermectin for the 
prevention and treatment of COVID-19 is consistent with the drug's FDA label describing its 
pharmacology and approved uses, attached hereto as Exhibit H. Additionally, Merck & Co., 
Inc., the initial patent holder for Ivermectin under the brand name STROMECTOL, has 
provided additional guidance reaffirming the proper use of Ivermectin and cautioning that 
"[n]o scientific basis for a potential therapeutic effect against COVID-19 from pre-clinical 
studies; [ n Jo meaningful evidence for clinical activity or clinical efficacy in patients with 
COVID-19 disease, and; [a] concerning lack of safety data in the majority of studies 
[supporting the use of Ivermectin for the treatment of COVID-19]." See Merck Statement on 
Ivermectin use During the COVID-19 Pandemic (Feb. 4, 2021), attached hereto as Exhibit 
I. 
V. 
Plaintifrs Cited Studies Fail to Show the Efficacy of Ivermectin. 
Finally, in contradiction to the voluminous guidance provided by public health 
authorities, the hearsay-laden studies and articles relied upon by Plaintiff are less than 
definitive and often limited to the laboratory setting. This past summer, the National Institute of 
Health ("NIH"), the United States agency responsible for medical research, examined many if 
not all of the studies relied upon by the Front Line COVID-19 Critical Care Alliance and 
Plaintiff ("FLCCC"). Through a detailed process, the NIH examined each study's design, 
methods, and results, issuing a statement on the limitations and interpretation of each. Again 
and again, the NIH found that: (1) the tested Ivermectin treatment "did not improve time to 
resolution"; (2) "the clinical efficacy of [Ivermectin] is unknown"; (3) "no reduction in 
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mortality was observed"; (4) "[Ivermectin] did not reduce risk of oxygen requirement, ICU 
admission, invasive mechanical ventilation, or death in hospitalized patients"; (5) "[Ivermectin] 
showed no effect on symptom resolution"; (6) "[Ivermectin] did not lead to faster recovery"; 
and (7) "no difference in viral clearance compared to those who received placebo", amongst 
interpretations. See NIH Ivermectin Clinical Data -
COVID-19 Treatment Guidelines (Jul. 19, 
2021), attached hereto as Exhibit J. The NIH was unable to verify the efficacy of Ivermectin 
for the treatment of COVID-19 related conditions, firmly contradicting the outlandish 
assertions advanced by the FLCCC. A private review of many of the same studies touted by 
FLCCC and Plaintiff came to the same conclusion, namely that it is uncertain whether 
Ivermectin is safe or effective to use to prevent or treat COVID-19. See Popp, M, Stegemann, 
M, Metzendm:f; M-1, Gould, S., Kranke, P., Meybohm, P., Skoetz, N, Weibel, S., Ivermectinfor 
preventing and treating COVID-19, Cochrane Database of Systematic Reviews 2021, Issue 
7. Art. No.: CD015017, attached hereto as Exhibit K. 
Beyond third-party disproval of Ivermectin treatment for COVID-19, studies that 
have been previously relied upon by Plaintiff have either been retracted or called into 
question by their own authors. Plaintiff's counsel has previously referenced the findings of 
Dr. Andrew Hill in support of the administration of Ivermectin. However, Dr. Hill, as 
recently as August 16, 2021, has expressed concern regarding the study, Meta-Analysis of 
Randomized Trials of Ivermectin to Treat SARS-Co V-3 Infection, that he along with others 
authored. Specifically, on August 16, Dr. Hill publicly retracted his study and tweeted that 
"[ o ]ur meta-analysis of survival for Ivermectin had to be retracted after one of the main 
studies was suspected of medical fraud." See Tweet of Dr. Andrew Hill (Aug. 16, 2021); 
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Expression of Concern: "Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-
Co V-2 Infection", published Jul 6, 2021, copies of which are attached as Exhibits L & M. 
Due to this, Dr. Hill concluded that "there is no statistically significant survival benefit for 
Ivermectin. So, the original version should not be quoted." Id. Dr. Hill's retracted study is 
included in Exhibit L to Plaintiff's complaint. This is precisely the same body of literature 
and studies that Plaintiff currently relies on. A study by Ahmed Elgazzar, also referenced 
within materials previously relied upon by Plaintiff, was withdrawn due to duplication of 
patient records, inconsistencies in raw data, and records indicating that some participating 
patients died before the study began. See Flawed Ivermectin preprint highlights challenges of 
COVID drug studies, Nature Portfolio (Aug. 2, 2021), attached hereto as Exhibit N. 
As previously stated, Plaintiffs asserted efficacy of Ivermectin disregards and 
contradicts scientific realities. West Chester Hospital is not aware of a single public health 
body in this nation in support of the use of Ivermectin to treat COVID-19 related conditions. 
Further, Plaintiffs own admissions and understanding regarding the efficacy of Ivermectin are 
inapplicable to the instant circumstances. Jeffrey Smith no longer has an active COVID-19 
infection. Rather, Mr. Smith is gradually overcoming ARDS since the infection has been 
cleared. 
VI. 
The Facts and Circumstances at Hand, Medical Expertise, and Mr. Smith's 
Current Conditions Contraindicate the Administration of Ivermectin 
Ohio law requires that West Chester Hospital establish and operate based on Medical 
Staff Bylaws and the policies, procedures, and protocols therein implemented. West Chester 
Hospital has established such Medical Staff Bylaws and operated pursuant to the same. 
Pursuant to these bylaws and in response to the COVID-19 pandemic, a clinical team at West 
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Chester Hospital composed of doctors and medical professionals of numerous specialties and 
backgrounds created West Chester Hospital's COVID-19 Protocol. The development of the 
COVID-19 Protocol has been through numerous iterative improvements as the clinical team 
strives to improve West Chester Hospital's COVID-19 care. To date, West Chester Hospital 
has followed its internal operating procedures and protocols and will continue to do so. The 
Judgment Entry of August 23, if maintained, would further force West Chester Hospital to 
act in conflict with its protocols and bylaws. 
In addition to West Chester Hospital's bylaws and thorough credentialing process, 
the Judgment Entry violated recently-enacted Ohio law protecting West Chester Hospital's 
right to decline to perform or participate in any health care service which violates the moral, 
ethical, or religious beliefs or principles held by it or its practitioners. See 134th G.A. Am. 
Sub. H.B. No. 110, enacting section 4743.10 of the Ohio Rev. Code. "Whenever a situation 
arises in which a requested course of treatment includes a particular health care service that 
conflicts with the moral, ethical, or religious beliefs or convictions of a medical practitioner, 
the medical practitioner shall be excused from participating in the particular health care 
service to which the practitioner has a conflict." Id. 
Pursuant to R.C. 4743.10, dispensing or administering a drug - such as Ivermectin -
constitutes a health care service. The ethical freedom granted therein extends not only to 
practitioners, but also health care institutions such as West Chester Hospital. 
Entities 
protected by this law enjoy immunity for civil actions where they exercise their right of 
conscience by declining to participate in a particular health care service. But not only does 
this immunity protect against civil liability - it shields from ""any other adverse action as a 
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result of declining to participate in or pay for a particular health care service on the basis of 
conscience. Moreover, a violation of West Chester Hospital's rights under this statute gives 
rise to an action for damages, injunctive relief, or any other appropriate relief. Id. 
Plaintiffs requested administration of Ivermectin to Mr. Smith via injunction violates 
Ohio law and directly conflicts with West Chester Hospital's policies and procedures, the 
medical expertise of his treating physicians, and the patient's present medical status. If the 
Judgment Entry is not reversed, the desired injunctive relief would violate the rights of West 
Chester Hospital and its attending physicians, and irreparably damage their ability to provide 
quality medical services to this community. Further, forcing a medical professional to 
administer a drug in opposition to their own medical expertise would require a physician to 
violate their Hippocratic Oath and jeopardize their medical license. Finally, administration 
of Ivermectin is contraindicative to Mr. Smith's medical status. 
VII. 
Granting Plaintifrs Requested Relief Would Violate Public Policy 
Plaintiffs Complaint and the relief sought therein would violate public policy if granted. 
What Plaintiff is seeking will open the floodgates of litigation, place the Courts in the position of 
making day to day medical decisions, and any type of general release of liability in exchange for 
contraindicative treatment is counter to the provision of safe and effective treatment. 
While Plaintiff alleges in her complaint, she is willing to sign a release in order for 
West Chester Hospital to administer this medication, such assurance does not advance the 
provision of safe and effective treatment and such a proposition violates public policy. When 
an individual sees her physician, she needs to rely upon the proposition that the physician is 
providing safe and effective treatment. To do a blanket release would invite a physician to 
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not provide safe and effective treatment and thereby violate her Hippocratic Oath. It is 
inviting a physician to do harm. What Plaintiff proposes is not protected by the rigorous 
safeguards of the FDA Drug Development Process, otherwise known as clinical trials. (See 
https:/ /www.fda.gov/patients/learn-abou t-drug-a nd-device-approvals/ dmg-developrnent-
process ). This is not something a physician can or should do. It is not something this Court 
should encourage. Public policy supports the safe and effective development of medications 
and medical practices, not the practice of mad science at the expense of patient safety. 
As pointed out throughout Plaintiffs complaint, her affidavit, and the various 
attachments thereto, Plaintiffs counsel was able to obtain the sought-after relief in Illinois 
State Court, specifically DuPage County case 2021-P-542. But that case was fraught with 
improper filings by Plaintiffs counsel, improper jurisdiction of the third-party hospital, and 
improper process, including the lack of an evidentiary hearing. Plaintiff states in her affidavit 
"Elmhurst Hospital appealed [the trial court's] Order and the Appellate Court recently 
dismissed the appeal in its entirety, but more importantly, upheld Judge Orel's original order." 
(Complaint, Exhibit A, Plaintiffs affidavit,, 36). What is notably missing from this assertion 
is how the Illinois Court of Appeals for the Second District actually ruled. The Second District 
ruled that the appeal was moot as the ward was no longer a patient at Elmhurst Hospital. See 
In re Estate of Nurije Fype, 2021 IL App (2d) 210259-U,, 38 (July 27, 2021). There is no 
proof or other legal support to be found in the Second District's order for approval of a 
mandatory injunction requiring a hospital to administer an unproven and disputed medication 
from a non-privileged physician ( or in the case of Elmhurst, allowing a non-privileged 
physician entry to administer said medication). The Second District's order of dismissal was 
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based on mootness, not the merits of the trial court's order. 
The Second District, in discussing exceptions to the mootness doctrine, disagreed with 
counsel for Elmhurst on the issues of the likelihood of recurrence of this type of suit. The 
Second District stated Elmhurst's counsel had "demonstrated, at best, no more than a handful of 
'similar' issues have arisen, not a 'flood' of cases." With all due respect to the Second District, 
the situation presented to this Court proves they were incorrect then, incorrect now, and in fact 
helped open the floodgates. Plaintiff devotes eight paragraphs of her affidavit and four 
additional exhibits to the Elmhurst Hospital case, beginning with her discussion of a Chicago 
Tribune article regarding the case. (Complaint, Exhibit A, Plaintiffs affidavit, Exhibits C-F.) 
News sources have reported on that particular case. Plaintiff also devoted four paragraphs of 
her affidavit, and two additional exhibits, to the case of an 80-year-old Buffalo woman. 
(Complaint, Exhibit A, Plaintiffs Affidavit, Exhibit G, and Exhibit H). Plaintiff fu1iher 
discusses the case of Glenna Dickinson in five paragraphs and two additional exhibits. 
(Complaint, Exhibit A, Plaintiffs Affidavit, Exhibit I, and Exhibit J). Plaintiff spends two 
paragraphs and one additional exhibit discussing Jeffery Smith. (Complaint, Exhibit A, 
Plaintiffs Affidavit, Exhibit M). In total, Plaintiff spends approximately one-third of her 
sixty-one-paragraph affidavit discussing other cases. These are not simply passing references 
to other cases; they are the reason this case was filed. If this Court follows down the path 
Plaintiff and Plaintiff's counsel wish it to, the snowball will gain momentum and there will 
continue to be more of these cases in this and other jurisdictions based on unsafe and 
ineffective science as discussed more fully below. Courts should not entertain this dubious 
invitation to practice pseudo-medicine. 
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Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 17 of 141

Since the filing of the instant complaint NewsChanne120, in Springfield, Illinois, ran a 
story the evening of August 27, 2021, that included interviews of Plaintiff's counsel. (See 
https://newschanne 120.com/news/local/family-of-auburn-man-hospital ized-with-covid-19-
takes-memorial-to-comi-to-get-Ivermectin to view video of Plaintiffs counsel). Plaintiffs 
counsel has described to this Court this type of litigation has been his life since the beginning 
of the year. He has described being in Court all over the country. Plaintiff's counsel has 
described to the Court his close association with the FLCCC. He advertises on their website 
for those seeking legal questions. (See https:/ /covidl9criticalcare.com/Ivermectin-in-covid-
19/faq-on-Ivennectin/ under a dropdown labelled "Can the FLCCC help with legal 
questions?"). He appeared on an FLCCC Expert Panel on May 6, 2021, describing his 
experience litigating cases like the one at bar, including stating he had "five successes, we 
have not had any failures." (See https://youtu.be/fWB4nDTr3wo). Plaintiff's counsel has also 
discussed in open court that he had a Zoom hearing in a similar case in the State of New 
Jersey. Plaintiff's counsel's website advertises various articles regarding his achievements in 
relation to Ive1mectin. Plaintiff's counsel uses this information as a badge of honor, but this 
Court should see warning signs instead. The floodgates are open in other areas of this State 
and Country, and this Court needs to close them. 
The idea of litigating day to day medical care should shock and frighten the Court. 
What Plaintiff, and future potential Plaintiffs, wish for this Court to do is change its J.D. into 
an M.D. and exchange its black robe for a white coat. Plaintiff wants this Court to decide it 
has the knowledge, experience, and know-how to make life or death medical decisions on a 
day-to-day basis. Public policy dictates this Court not do that. This Court cannot and should 
Page 17 of20 
EN00688.Public-00688 4848-3150-0025v2 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 18 of 141

not make day to day medical decisions for this patient or any patient. It has neither the 
training and experience to determine, proactively, which treatments are safe and effective, 
and which are not. As Plaintiff stated to Illinois Newschannel 20, "Let's just face it. When 
you're on death's door, and you have no other options, you'll grasp at whatever you can get." 
If a parent is faced with a severely ill child and disagrees with the trained medical 
professionals' opinions, it is understandable for that parent to want to take all options to help 
their child. But the Court should not be placed in a situation to order treatment that is not 
indicated, is unsafe, is ineffective, and has not been supported by any major public health 
body. These decisions are best left to the health care professionals on the front line of this or 
any other health issue. Even in the best of circumstances, it is understood that two similarly 
situated physicians with the same information could have differences of opinion on the 
proper course of action. It is not in the interest of the public generally, and the individuals 
specifically in this case, for the Court to be dragged into the situation and make a decision 
with no training, education, or experience in making these day-to-day decisions. It is neither 
safe nor effective. 
CONCLUSION 
Plaintiff has not articulated, let alone shown with conclusive evidence, that she is 
entitled to the extraordinary injunctive relief she seeks. This Comi need not wade into the 
highly contentious debate as to the medical efficacy of Ivermectin in treating COVID-19. 
Plaintiff's procedural deficiencies alone warrant denial of the requested injunction. There is 
no right to be treated by an unapproved medication, nor a duty of West Chester Hospital to 
administer the same. Should this Court decline to reverse the Judgment Entry, irreparable 
Page 18 of20 
EN00688.Public-00688 4848-3150-0025v2 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 19 of 141

harm to West Chester Hospital and its physicians will continue, and as a matter of public 
policy, the will of Ohio's General Assembly will be utterly disregarded. 
Defendant, West 
Chester Hospital, prays that this Honorable Court enter judgment for West Chester Hospital 
and against the Plaintiff and for such other and further relief as the Court deems just and 
proper. 
EN00688.Public-00688 4848-3150-0025v2 
Respectfully submitted, 
FROST BROWN TODD LLC 
By: 
/s/ Ch4-f:½ B. Cg..,L,y-u,y 
Bill J. Paliobeis (0066666) 
Charles B. Galvin (0091138) 
9277 Centre Pointe Drive, Suite No. 300 
West Chester, Ohio 45069 
(513) 870-8234 Direct Dial 
(513) 870-0999 Facsimile 
bpaliobeis@futlaw.com 
cgalvin(ZMbtlaw.corn 
Counsel for Defendant West Chester 
Hospital, LLC dba West Chester 
Hospital 
Page 19 of20 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 20 of 141

CERTIFICATE OF SERVICE 
I hereby certify that a copy of the foregoing Memorandum was served by Electronic 
Mail this 2nd day of September 2021 upon the following: 
Jonathan Davidson, Esq. 
DAVIDSON LAW OFFICE CO., LPA 
2 S. Third Street, Suite 301 
Hamilton, Ohio 45011 
j davi dson(a)da vidsonla w. org 
Jeffrey G. Stagnaro, Esq. 
Sharon J. Sobers, Esq. 
STAGNARO, SABA & PATTERSON CO., LP.A. 
73 73 Beechmont A venue 
Cincinnati, Ohio 45230 
jgs@D,sspfirm.com 
s i s@sspfirm. corn 
Ralph C. Lorigo, Esq. 
LAW OFFICE OF RALPH C. LO RIGO 
101 Slade Avenue 
West Seneca, New York 14224 
rlorigo(~lorigo.com 
Counsel for Plaintiff 
Julie Smith, Guardian of Jeffrey Smith 
EN00688.Public-00688 4848-3150-0025v2 
Charles B. Galvin (0091138) 
Page 20 of20 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 21 of 141

-E-
Thread 
# 
Explore 
U.S. FDA~ 
You are not a 11orSl:. You are not a cow. Sedous!y, 1/'ai:. Stop ft 
@ 
Settings 
V,tny Yrn.; Shou'd Not Use lve,mectin to Treat o, Prevent COV!D-19 
EXHIBIT A 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 22 of 141

FDA Letter to Stakeholders: Do Not Use lvermectin Intended 
for Animals as Treatment for COVID-19 in Humans 
Espanol ( /animal-vetetinazylproduct-saf ety-infQrruation/carta-de-la-fda-las-partes-
interesadas-nQ-use-iyermectina-d,estipada-aniruales-cgma-tratamiento-p..ru:a). 
April 10, 2020 
Dear Stakeholder, 
The FDA's Center for Veterinary Medicine has recently become aware of increased public 
visibility of the antiparasitic drug ivermectin after the announcement of a research article that 
described the effect ofivermectin on SARS-CoV-2 in a laboratory setting. The Antiviral 
Research pre-publication paper, "The EDA-approved drug ivermes;tin inhibits the re:glicat:iQn Qf 
SARS-Co V-2 in vitro (https: / /www.sciencedirect.com/science/artide{P.ii/SQ16635422o3rn1). 
E? Jhttp;L /www,fda.gov /about-f da/wcl;>site-policies/wcl;>site-Q.isc;laimer )," documents how 
SARS-CoV-2 (the virus that causes COVID-19) responded to ivermectin when exposed in a petri 
dish. This type of study is commonly used in the early stages of drug development. Ivermectin 
was not given to people or animals in this study. Additional testing is needed to determine 
whether ivermectin might be safe or effective to prevent or treat coronavirus or COVID-19. 
Ivermectin tablets are approved for use in people for the treatment of some parasitic worms 
(intestinal strongyloidiasis and onchocerciasis) and ivermectin topical formulations are 
approved for human use by prescription-only for the treatment of external parasites such as 
headlice and skin conditions such as rosacea. Ivermectin is FDA-approved for use in animals 
for prevention of heartworm disease in some small animal species, and for treatment of certain 
internal and external parasites in various animal species. 
FDA is concerned about the health of consumers who may self-medicate by taking ivermectin 
products intended for animals, thinking they can be a substitute for ivermectin intended for 
humans. People should never take animal drugs, as the FDA has only evaluated their safety and 
effectiveness in the particular animal species for which they are labeled. These animal drugs can 
cause serious harm in people. People should not take any form of ivermectin unless it has been 
prescribed to them by a licensed health care provider and is obtained through a legitimate 
source. 
Ivermectin is an important part of a parasite control program for certain species and should 
only be given to animals for approved uses or as prescribed by a veterinarian in compliance with 
the requirements for extra-label drug use. Due to potentially elevated interest in ivermectin 
EXHIBIT B 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 23 of 141

following the new research, some products may not be available. If you are having difficulty 
locating a particular ivermectin product for your animal(s), the FDA recommends that you 
consult with your veterinarian. 
The FDA has established a cross-agency task force dedicated to closely monitoring for 
fraudulent COVID-19 products that reaches out to major retailers to ask for their help in 
monitoring online marketplaces. Products that claim to prevent, diagnose, treat, or cure COVID-
19 are subject to FDA investigation and potential enforcement action if they have not 
demonstrated safety and effectiveness for that intended use. The task force has already worked 
with retailers to remove dozens of these types of product listings online. 
Please help us protect public health by alerting FDA of anyone claiming to have a product to 
prevent or cure COVID-19 and to help safeguard human and animal health by reporting any of 
these products to FDA-CQVID-19-Fraydulent-Produs;ts@fda,.hh~.gov (mailto:FDA-CQVID-19.:. 
Fraudulent-Product~@fda,hhs.gQY). or 1-888-InfoFDA (1-888-463-6332). 
We recognize this is a challenging time and urge you to continue practicing social distancing by 
sharing this information electronically. 
Thank you for your support. Please stay safe and healthy. 
Dr. Steven Solomon 
Director of FDA's Center for Veterinary Medicine 
Additional Information 
FAQ; CQYID-19 and Ivern;u,ctin Intended fQr Animals ( Lanimal-veterim1ryL12rodyct-safety_: 
informationLfag_-covid-19-and-ivermectin-intenged-animals). 
WhY. You Should Not :Use Ivermectin to Ireat Qr Prevent CQVID-19_( Lconsumers/consumer-
npdatesLwhy..:Y.ou-shoyld-not-use-ivermectin-treat-or-:grevent-covid-19). 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 24 of 141

FAQ: covm~ 19 and lvermectin Intended for Animals 
&mmw (lanimal-YlltetinaryJprndu1,1:-sa.fety-informatiqn/!IDlgy,n1&t;;-mi!§•cumune5-el::<;oyjd-19-y-la-i.Elrmectina-p~para-animales) 
Q: Should I take ivermectin to prevent or treat COVI0-19? 
A: No. While there are approved uses for ivermectin in people and animals, it is not approved for the prevention or treatment of COVID-19. You 
should not take any medicine to treat or prevent COVID-19 unless it has been prescribed to you by your health care provider and acquired from a 
legitimate source. 
A recently released resi;:auili amcie (https://pdf.scienC!:ilin:ctMllets,(;Qm/27w5LAJJ?Ll-s.2,P·S!U6'1354,~302011,/main pdf?X-Amz· 
Date-202004QQl'.215853Zll-Amz-Algw:itbm=-AWS4-HMAC:;SHA25Q&X-Am:.-
filgnat:yre=dfb8133954eQddo1au97.a.d.9zasf9.Q3~~5hlm.9_95fras;a,061bc7~07'7fe&X-Amz-
Credential-ASIAQ3mcm32VGY2LR%2Fw.ioo406%2E.Ys::east-1%;,;&3~4~~..!9.7.3--9.fu:2.:,H!5f::.954~ 
Q.2bc.9~~sh!~:z..4~7.f!49541.9~4~7..fulsQlllil.QgmI~54a22302011&X-Amz-Sign!¼IHeaders=hQSt&X-A.mz-Securitr-=-
Iqken=IQo.!IJ3,IpzgJuX2YjEKX%2F%2f%2f%2f%2F%2F%2F262F%2F%2&v.EaCXVzLWYhc3QtMSJHMfilJCIAI'J:ii2F6GH7KtlfhQG5MZJ;%glliCG7X!.fil 
~pire:,=3QQ&;hash-24d!3.99_e3!:Q.7.5!5cfarn.:8ai.283~9.9leddo39~9.cB.a3~393Wasl:.6.7.l C?_(http:f lwww,fda gqy/ahQy1-!<laLm~ite-
RQlii<iesfo:!:hsite-<fuclaimerl described the effect of ivermectin on SARS-Co V-2 in a laboratory setting. These types of laboratory studies are 
commonly used at an early stage of drug development. Additional testing is needed to determine whether ivermectin might be appropriate to prevent 
or treat coronavirus or COVID-19. 
Q: Is there an emergency use authorization for ivermectin in the U.S. to prevent or treat 
coronavirus or COVID-19? 
A: No. FDA has created a special emergency program for possible therapies, the CQronID'irnli T;rn,mnimt Acc;;elerati9!lhggram (L'.~g&/c9ronavirus-
~9.::.Q!Jlg§/s;orona:i(iru§-t;rnatment-a&1,;eleration-P.rogram-ctap) (CTAP). It uses every available method to move new treatments to patients as 
quickly as possible, while at the same time finding out whether they are helpful or harmfuL We continue to support clinical trials that are testing new 
treatments for COVJD so that we can gain valuable knowledge about their safety and effectiveness. 
Q: What is ivermectin approved for in the U.S.? 
A: Ivermectin tablets are approved for use in humans for the treatment of some parasitic worms (intestinal strongyloidiasis and onchocerciasis) and 
ivermectin topical formulations are approved for human use by prescription only for the treatment of external parasites such as headlice and for skin 
conditions such as rosacea. 
Ivermectin is FDA-approved for use in animals for prevention of heartworm disease in some small animal species, and for treatment of certain 
internal and external parasites in various animal species. People should never take animal drugs, as the FDA has only evaluated their safety and 
effectiveness in the particular species for which they are labeled. Using these products in humans could cause serious harm. 
Q: Is there any danger to humans taking ivermectin? 
A: There are approved uses for ivermectin in people and animals but it is not approved for the prevention or treatment of COVJD-19. You should not 
take any medicine to treat or prevent COVID-19 unless it has been prescribed to you by your health care provider and acquired from a legitimate 
source. 
Some of the side-effects that may be associated with ivermectin include skin rash, nausea, vomiting, diarrhea, stomach pain, facial or limb swelling, 
neurologic adverse events (dizziness, seizures, confusion), sudden drop in blood pressure, severe skin rash potentially requiring hospitalization and 
liver injury (hepatitis). Laboratory test abnormalities include decrease in white cell count and elevated liver tests. Any use of ivermcctin for the 
prevention or treatment of COVID-19 should be avoided as its benefits and safety for these purposes have not been established. Data from clinical 
trials are necessary for us to determine whether ivermectin is safe and effective in treating or preventing COVID-19. 
Q: What should I do if the ivermectin products I purchase for use in my animals are not available 
at my typical retailer? 
A: Ivermectin is an important part of a parasite control program for certain species and should only be given to animals for approved uses or as 
prescribed by a veterinarian in compliance with the requirements for extra-label drug use. Due to potentially elevated interest in ivermectin 
following the new research, some products may not be available. If you are having difficulty locating a particular ivermectin product for your 
animal(s), the FDA recommends that you consult with your veterinarian. 
Q: What is the FDA doing to protect people from fraudulent COVID-19 products? 
EXHIBIT C 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 25 of 141

A: We have established a cross-agency task force dedicated to closely monitoring for fraudulent COVID-19 products. We have reached out to major 
retailers to ask for their help in monitoring on!ine marketplaces for fraudulent COVID-19 products. Products sold are subject to FDA investigation 
and potential enforcement action if they claim to prevent, diagnose, treat, or cure COVID-19 and have not demonstrated safety and effectiveness for 
that intended use. The task force has already worked with retailers to remove dozens of these types of product listings online. 
The FDA and the Federal Trade Commission (FfC) issue warning letters to companies that violate federal law and pose significant risks to patient 
health by selling unapproved products with fraudulent claims to treat or prevent COVID-19. Yi~ the warning~(/consullli:!:§/health-fr1,1ud-
scmns/fraudulent-ooomilyirµ§::!iise!Wl-2Ql9~9~PIQQJJct'ifflaming l',&tter Table) for more information. 
Additional Information 
EPA Lcttcr 1Q Stakcl)Qlders; Do Nm Use Ivermeetin Intende<i for Animrus iw Treatment fQr CQYIQ-1q in Uumims Uanimal-veterinazyJ.~ 
~-informatiQn/fda-letter-stakehoJdet§•do-not-u§e-ivermeetin-intended-animaJ~-tteatmf.lnt-covid-1q~). 
filY- Y@ Sh®)d Nm Use Ivermeetin tQ Treat or fi;event CQY!D-19 ( /consumers/ cmisumer-update&/why.;yQJ1,:iill.gJJld-not-Ulle::ivenneetin-tu:at::ur-
Ptevimt -i;Qy!Q-191 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 26 of 141

Distributed via the CDC Health Alert Network 
August 26, 2021, 11 :40 AM ET 
CDCHAN-00449 
Rapid Increase in lvermectin Prescriptions and Reports of Severe 
mness Associated with Use of Products Containing lvermectin to 
Prevent or Treat COVID-19 
Summary 
lvermectin is a U.S. Food and Drug Administration (FDA)-approved prescription medication used to treat 
certain infections caused by internal and external parasites. When used as prescribed for approved 
indications, it is generally safe and well tolerated. 
During the COVID-19 pandemic, ivermectin dispensing by retail pharmacies has increased, as has use of 
veterinary formulations available over the counter but not intended for human use. FDA has cautioned 
about the potential risks of use for prevention or treatment of COVID-19. 
lvermectin is not authorized or approved by FDA for prevention or treatment of COVID-19. The National 
Institutes of Health's (NIH) COVID-19 Treatment Guidelines Panel has also determined that there are 
currently insufficient data to recommend ivermectin for treatment of COV!D-19. CHnica!Tria!s.gov has 
listings of ongoing clinical trials that might provide more information about these hypothesized uses in the 
future. 
Adverse effects associated with ivermectin misuse and overdose are increasing, as shown by a rise in 
calls to poison control centers reporting overdoses and more people experiencing adverse effects. 
Background 
The Centers for Disease Control and Prevention (CDC) confirmed with the American Association of 
Poison Control Centers (AAPCC) that human exposures and adverse effects associated with ivermectin 
reported to poison control centers have increased in 2021 compared to the pre~pandemic baseline. These 
reports inctude increased use of veterinary products not meant for human consumption. 
lvermectin is a medication that is approved by FDA in oral formulations to treat onchocerciasis (river 
blindness) and intestinal strongyloidiasis. Topical formulations are used to treat head lice and rosacea. 
lvermectin is also used in veterinary applications to prevent or treat internal and external parasitic 
infections in animals. When used in appropriate doses for approved indications, ivermectin is generally 
well tolerated. 
Clinical trials and observational studies to evaluate the use of ivermectin to prevent and treat COVID-19 
in humans have yielded insufficient evidence for the NIH COV!D-19 Treatment Guidelines Panel to 
recommend its use. Data from adequately sized, well-designed, and well-conducted clinical trials are 
needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of 
COVID-19. 
A recent study examining trends in ivermectin dispensing from outpatient retail pharmacies in the United 
States during the COVID-19 pandemic showed an increase from an average of 3,600 prescriptions per 
week at the pre-pandemic baseline (March 16, 2019-March 13, 2020) to a peak of 39,000 prescriptions in 
the week ending on January 8, 2021.1 Since early July 2021, outpatient ivermectin dispensing has again 
EXHIBIT D 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 27 of 141

.,, 
begun to rapidly increase, reaching more than 88,000 prescriptions in the week ending August 13, 2021. 
This represents a 24-fold increase from the pre-pandemic baseline. (figure) 
Figure: Estimated number of outpatient ivermectin prescriptions dispensed from retail 
pharmacies- United States, March 16, 2019--August 13, 2021* 
*Data are from the IQVIA National Prescription Audit Weekly (NPA Weekly) database. NPA Weekly 
collects data from a sample of approximately 48,900 U.S. retail pharmacies, representing 92% of all retail 
prescription activity. lvermectin dispensed by mail order and long-term care pharmacies, prescriptions by 
veterinarians, and non-oral formulations were not included. 
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In 2021, poison control centers across the U.S. received a three-fold increase in the number of calls for 
human exposures to ivermectin in January 2021 compared to the pre-pandemic baseline. 
In July 2021, ivermectin calls have continued to sharply increase, to a five-fold increase from baseline. 
These reports are also associated with increased frequency of adverse effects and emergency 
department/hospital visits. 
ln some cases, people have ingested ivermectin-containing products purchased without a prescription, 
including topical formulations and veterinary products. Veterinary formulations intended for use in large 
animals such as horses, sheep, and cattle (e.g., "sheep drench," injection formulations, and "pour-on" 
products for cattle) can be highly concentrated and result in overdoses when used by humans. Animal 
products may also contain inactive ingredients that have not been evaluated for use in humans. People 
who take inappropriately high doses of ivermectin above FDA-recommended dosing may experience 
toxic effects. 
Clinical effects of iverrnectin overdose include gastrointestinal symptoms such as nausea, vomiting, and 
diarrhea. Overdoses are associated with hypotension and neurologic effects such as decreased 
consciousness, confusion, hallucinations, seizures, coma, and death. lvermectin may potentiate the 
effects of other drugs that cause central nervous system depression such as benzodiazepines and 
barbiturates. 
Examples of recent significant adverse effects reported to U.S. poison control centers include the 
following: 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 28 of 141

., 
An adult drank an injectable ivermectin formulation intended for use in cattle in an attempt to 
prevent COVID-19 infection. This patient presented to a hospital with confusion, drowsiness, 
visual hallucinations, tachypnea, and tremors. The patient recovered after being hospitalized for 
nine days. 
• 
An adult patient presented with altered mental status after taking ivermectin tablets of unknown 
strength purchased on the internet. The patient reportedly took five tablets a day for five days to 
treat COVID-19. The patient was disoriented and had difficulty answering questions and following 
commands. Symptoms improved with discontinuation of ivermectin after hospital admission. 
Recommendations for Clinicians and Public Health Practitioners 
• 
Be aware that ivermectin is not currently authorized or approved by FDA for treatment of COVID-
19. NIH has also determined that there are currently insufficient data to recommend ivermectin for 
treatment of COV!D-19. 
• 
Educate patients about the risks of using ivermectin without a prescription, or ingesting ivermectin 
formulations that are meant for external use or ivermectin-containing products formulated for 
veterinary use . 
., 
Advise patients to immediately seek medical treatment if they have taken any ivermectin or 
ivermectin-containing products and are experiencing symptoms. Signs and symptoms of 
ivermectin toxicity include gastrointestinal effects (nausea, vomiting, abdominal pain, and 
diarrhea), headache, blurred vision, dizziness, tachycardia, hypotension, visual hallucinations, 
altered mental status, confusion, loss of coordination and balance, central nervous system 
depression, and seizures. !vermectin may increase sedative effects of other medications such as 
benzodiazepines and barbiturates. Call the poison control center hotline {1-800-222-1222) for 
medical management advice . 
., 
Educate patients and the public to get vaccinated against COVID-19. COVID-19 vaccination is 
safe and the most effective means to prevent infection and protect against severe disease and 
death from SARS-CoV-2, the virus that causes COVID-19, including the Delta variant. 
• 
Educate patients and the public to use COVID-19 prevention measures including wearing masks 
in indoor public places, physical distancing by staying at least six feet from other people who 
don't live in the same household, avoiding crowds and poorly ventilated spaces, and frequent 
handwashing and use of hand sanitizer that contains at least 60 percent alcohol. 
Recommendations for the Public 
., 
Be aware that currently, ivermectin has not been proven as a way to prevent or treat COVID-19. 
• 
Do not swallow ivermectin products that should be used on skin (e.g., lotions and creams) or are 
not meant for human use, such as veterinary ivermectln products. 
• 
Seek immediate medical attention or call the poison control center hotline (1-800-222-1222) for 
advice if you have taken ivermectin or a product that contains ivermectin and are having 
symptoms. Signs and symptoms include gastrointestinal effects (nausea, vomiting, abdominal 
pain, and diarrhea), headache, blurred vision, dizziness, fast heart rate, and low blood pressure. 
Other severe nervous system effects have been reported, including tremors, seizures, 
hallucinations, confusion, loss of coordination and balance, decreased alertness, and coma. 
• 
Get vaccinated against COVID-19. COVID-19 vaccination is approved by FDA and is the safest 
and most effective way to prevent getting sick and protect against severe disease and death from 
SARS-CoV-2, the virus that causes COVID-19, including the Delta variant. 
., 
Protect yourself and others from getting sick with COVID-19. In addition to vaccination, wear 
masks in indoor public places, practice staying at least six feet from other people who don't live in 
your household, avoid crowds and poorly ventilated spaces, and wash your hands often or use 
hand sanitizer that has at least 60 percent alcohol. 
For More Information 
NlH COViD-19 Treatment lvermectin Guidelines 
FDA Consumer Alert on Use of lvermectin to Treat or Prevent COVID-19 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 29 of 141

FDA Med\iyatch Adverse Eve0,_~QQ!:t\D_g_Q[Qg[_gm 
CDC Coronavirus (COVID-19) website 
U.S. Government Coronavirus (COVID-19) website 
American Association of Poison Control Centers 
Press Release: American College of Medical Toxicolog'.I{ RfiltQI1s Data on Adverse Effects and Toxicitx; 
from Unapproved Use of lvermectin for the Prevention or Treatment of COV!D-19 
Treatments Your Healthcare Provider Might Recommend if You Are Sick 
References 
1 Lind JN, Lovegrove MC, Geller Al, Uyeki TM, Datta SD, Budnitz OS. Increase in Outpatient !vermectin 
Dispensing in the US During the COVID-19 Pandemic: A Cross-Sectional Analysis. J Gen Intern Med. 
2021 Jun 18:1-3. doi: 10.1007/s11606-021-06948-6. 
The Centers for Disease Control and Prevention (CDC) protects people's health and safety by preventing 
and controlling diseases and injuries; enhances health decisions by providing credible information on 
critical health issues; and promotes healthy living through strong partnerships with local, national, and 
international organizations. 
Categories of Health Afert Network messages: 
Health Alert 
Requires immediate action or attention, highest level of importance 
Health Advisory May not require immediate action; provides important information for a specific incident or situation 
Health Update 
Unlikely to require immediate action; provides updated information regarding an incident or situation 
HAN Info Service Does not require immediate action; provides general public health information 
# #This message was distributed to state and local health officers, state and local epidemiologists, state 
and local laboratory directors, public information officers, HAN coordinators, and clinician 
organizations## 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 30 of 141

COVID-19 Treatment Guidelines 
Antiviral Drugs That Are Approved or Under 
Evaluation for the Treatment of COVID-19 
Last Updated: July 8, 2021 
Summary Recommendations 
Remdesivir is the only Food and Drug Administration-approved drug for the treatment 
of COV!D-19. In this section, the COVID-19 Treatment Guidelines Panel (the Panel) 
provides recommendations for using antiviral drugs to treat COV!D-19 based on the 
available data. As in the management of any disease, treatment decisions ultimately 
reside with the patient and their health care provider. For more information on these 
antiviral agents, see I»J,R~?@. 
Remdesivir 
• See ThefaPftUIBsM§nagemJlf)t oHfosojtaiized Ai;lutts.with CQVl0;:19 for 
recommendations on using remdesivir with or without dexamethasone. 
lvermectin 
• There is insufficient evidence for the Panel to recommend either for or against the use of 
ivermectin for the treatment of COVID-19. Results from adequately powered, well-
designed, and well-conducted clinical trials are needed to provide more specific, 
evidence-based guidance on the role of ivermectin in the treatment of COVID-19. 
Nitazoxanide 
• The Panel recommends against the use of nitazoxanide for the treatment of COVID-19, 
except in a clinical trial (Bila). 
Hydroxychloroquine or Chloroquine and/or Azithromycin 
• The Panel recommends against the use of chloroquine or hydroxychloroquine and/or 
azithromycin for the treatment of COVID-19 in hospitalized patients {Al) and in 
nonhospitalized patients (Alia). 
Lopinavir/Ritonavir and Other HIV Protease Inhibitors 
• The Panel recommends against the use of lopinavir/ritonavir and other HIV protease 
inhibitors for the treatment of COVID-19 in hospitalized patients {All and in 
nonhospitalized patients (Alli). 
Rating of Recommendations: A= Strong; B = Moderate; C = Optional 
Rating of Evidence: I= One or more randomized trials without major limitations; Ila= Other 
randomized trials or subgroup analyses of randomized trials; lib= Nonrandomized trials or 
observational cohort studies; Ill= Expert opinion 
EXHIBIT E 
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Antiviral Therapy 
Because SARS-CoV-2 replication leads to many of the clinical manifestations of COVID-
19, antiviral therapies are being investigated for the treatment of COVID-19. These drugs 
inhibit viral entry (via the angiotensin-converting enzyme 2 [ACE2] receptor and 
transmembrane serine protease 2 [TMPRSS21), viral membrane fusion and endocytosis, 
or the activity of the SARS-CoV-2 3-chymotrypsin-like protease (3Clpro) and the RNA-
dependent RNA polymerase.1 Because viral replication may be particularly active early in 
the course of COVID-19, antiviral therapy may have the greatest impact before the illness 
progresses to the hyperinflammatory state that can characterize the later stages of 
disease, including critical illness.2 For this reason, it is necessary to understand the role 
of antiviral medications in treating mild, moderate, severe, and critical illness in order to 
optimize treatment for people with COVID-19. 
The following sections describe the underlying rationale for using different antiviral 
medications, provide the COVID-19 Treatment Guidelines Panel's recommendations for 
using these medications to treat COVID-19, and summarize the existing clinical trial data. 
Additional antiviral therapies will be added to this section of the Guidelines as new 
evidence emerges. 
References 
www.covid19treatmentguidelines.nih.gov 
An official website of the N9!ign9l ln§titutes of He9lth 
+ 
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EUROPEAN MEDICINES AGENCY 
SCIENCE MEDICINES HEALTH 
EMA advises against use of ivermectin for 
the prevention or treatment of COVID-19 
outside randomised clinical trials 
News 22/03/2021 
EMA has reviewed the latest evidence on the use of ivermectin for the prevention and treatment 
of COVID-19 and concluded that the available data do not support its use for COVID-19 outside 
well-designed .~Jinical tr!~J~. 
In the EU, ivermectin tablets are approved for treating some parasitic worm infestations while 
ivermectin skin preparations are approved for treating skin conditions such as rosacea. 
Ivermectin is also authorised for veterinary use for a wide range of animal species for internal 
and external parasites. 
Ivermectin medicines are not authorised for use in COVID-19 in the EU, and EMA has not 
received any application for such use. 1 
Following recent media reports and publications on the use of ivermectin, EMA reviewed the 
latest published evidence from laboratory studies, observational studies, clinic::?1. triaJ? and meta-
analyses. laboratory studies found that ivermectin could block replication of SARS-CoV-2 (the 
virus that causes COVID-19), but at much higher ivermectin concentrations than those achieved 
with the currently authorised doses. Results from clinical studies were varied, with some studies 
showing no benefit and others reporting a potential benefit. Most studies EMA reviewed were 
small and had additional limitations, including different dosing regimens and use of concomitant 
medications. EMA therefore concluded that the currently available evidence is not sufficient to 
support the use of ivermectin in COVID-19 outside clinical trial§_. 
Although ivermectin is generally well tolerated at doses authorised for other indications, side 
effects could increase with the much higher doses that would be needed to obtain concentrations 
of ivermectin In the lungs that are effective against the virus. Toxicity when ivermectin is used at 
higher than approved doses therefore cannot be excluded. 
EMA therefore concluded that use of ivermectin for prevention or treatment of COVID-19 cannot 
currently be recommended outside controlled clinical trials. Further well-designed, randomised 
EXHIBIT F 
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studies are needed to draw conclusions as to whether the product is effective and safe in the 
prevention and treatment of COVID-19. 
This EMA public health statement has been endorsed by the COVID-19 EMA pandemic Task Force 
(COVID-ETF), in light of the ongoing discussions on the use of ivermectin in the prevention and 
treatment of COVID-19. 
1 Czechia e and 
e, have allowed the temporary use of the medicine for COVID-19 
within the remit of their national legislation. 
References 
1. 
E!gazzar, A., et al., Effi<:acy and safety of ivermectin for treatment and prophylaxis of 
COVID-19 pandemic. Research Square, 2020. 
2. 
Ahmed, S., et al., A five-day course of ivermectin for the treatment of COVID-19 may 
reduce the duration of illness. Int J Infect Dis, 2021. 103: p. 214-216. 
3. 
Alam, M.T., et al., Ivermectin as pre-exposure prophylaxis for COVID-19 among 
healthcare providers in a selected tertiary hospital in Dhaka - an observational study. European 
Journal of Medical Health and Sciences, 2020. 
4. 
Arevalo, A.P., et al., Ivermectin reduces coronavirus infection in vivo: a mouse 
experimental model. Biorxiv, 2020. 
5. 
Babaiola, O.E., et al., Ivermectin shows clinical benefits in mild to moderate COV!D19: a 
randomised controlled double-blind, dose-response study in Lagos. QJM, 2021. 
6. 
Behera, P., et al., Prophylactic role of ivermectin in SARS-CoV-2 infection among 
healthcare workers. Research Square, 2021. 
7. 
Bray, M., et al., Ivermectin and COVID-19: a report in antiviral research, widespread 
interest, an FDA warning, two letters to the editor and the authors' responses. Antiviral Res, 
2020. 178: p, 104805. 
8. 
Caly, L., et al., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 
in vitro. Antiviral Res, 2020. 178: p. 104787. 
9. 
Camprubf, D., et al., Lack of efficacy of standard doses of ivermectin in severe COVID-19 
patients. PloS One, 2020. 15(11): p. e0242184. 
10. 
Carvallo, H., et al., Safety and efficacy of the combined use of ivermectin, 
dexamethasone, enoxaparin and aspirin against COVID 19. MedRxiv, 2020. 
11. 
Carvallo, H., et al., Study of the efficacy and safety of topical ivermectin + iota-
carrageenan in the prophylaxis against COVID-19 in health personnel. Journal of Biomedical 
Research and Clinical Investigation, 2020. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 34 of 141

12. 
Castaf\eda-Sabogal, A., et al., Outcomes of ivermectin in the treatment of COVID-19: a 
systematic review and meta-analysis. Medrxiv, 2021. 
13. 
Chaccour, C., et al., Nebulized ivermectin for COVID-19 and other respiratory diseases, a 
proof of concept, dose-ranging study in rats. Sci Rep, 2020. 10(1): p. 17073. 
14. 
Chaccour, C., et a!., The effect of early treatment with ivermectin on viral load, symptoms 
and humoral response in patients with non-severe COVID-19: a pilot, double-blind, placebo-
controlled, randomized clinical trial. EC!inica!Medicine, 2021: p. 100720. 
15. 
Chachar, A.Z.K., et a!., Effectiveness of ivermectin in SARS-CoV-2/COVID-19 patients. 
International Journal of Sciences, 2020. 9(09): p. 31-35. 
16. 
Chowdhury, A.T.M.M., et al., A randomized trial of ivermectin-doxycyc!ine and 
hydroxychloroquine-azithromycin therapy on COVID19 patients. Research Square, 2020. 
17. 
de Melo, G.D., et al., Anti-COVID-19 efficacr.. of ivermectin in the golden hamster. 
BioRxiv, 2020. 
18. 
Elalfy, H., et al., Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus 
zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19. J Med Viral, 2021. 
19. 
Errecalde, J., et al., Safety and pharmacokinetic assessments of a novel ivermectin nasal 
spray formulation in a pig model. J Pharm Sci, 2021. 
20. 
Espitia-Hern, G., et al., Effects of ivermectin-azithromycin-cholecalciferol combined 
therapy on COVID-19 infected patients: A proof of concept study. Biomedical Research, 2020. 
21. 
Farmiga, F.R., et al., Ivermectin: an award-winning drug with expected antiviral activity 
against COVID-19. J Control Release, 2020. 
22. 
Gonzalez, J.LB., et al., Efficac:y and safety of ivermectin and hydroxychloroquine in 
patients with severe COVID-19. A randomized controlled trial. Medrxiv, 2021. 
23. 
Garia!, F.I., et al., Effectiveness of ivermectin as add-on therapy in COVID-19 
management (pilot trial). Medrxiv, 2020. 
24. 
Hashim, H.A., et al., Controlled randomized qinical trial on using ivermectin with 
doxycyc!ine for treating COVID-19 patients in Baghdad, Iraq. Medrxiv, 2020. 
25. 
Hellwig, M.D., and Maia, A., A COVID-19 prophylaxis? Lower incidence associated with 
prophylactic administration of ivermectin. Int J Antimicrob Agents, 2021. 57(1): p. 106248. 
26. 
Hill, A., et al., Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 
infection. Research Square, 2021. 
27. 
Jermain, B., et al., Development of a minimal physiologically-based pharmacokinetic 
model to simulate lung exposure in humans following oral administration of ivermectin for 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 35 of 141

COVID-19 drug repurposing. J Pharm Sci, 2020. 109(12}: p. 3574-3578. 
28. 
Kalfas, S., et al., The therapeutic potential of ivermectin for covid-19: a systematic 
review of mechanisms and evidence. Medrxiv, 2020. 
29. 
Khan, M.S.I., et al., Ivermectin treatment may improve the prognosis of patients with 
COVID-19. Arch Bronconeumol, 2020. 56(12): p. 828-830. 
30. 
Kim, M .S., et al., Comparative efficacx and safety of pharmacological interventions for 
the treatment of COVID-19: a systematic review and network meta-analysts. PloS Med, 2020. 
17(12): p. e1003501. 
31. 
Kory, P., et al., Review of the emerging evidence demonstrating the efficacy of ivermectin 
in the prophylaxis and treatment of COVID-19. FICCC.net, 2021. 
32. 
Krolewiecki, A., Antiviral effect of high-dose ivermectin in adults with COVID-19: a pilot 
randomised✓ controlled/ open label, multicentre trial. Lancet preprint, 2020. 
33. 
Lehrer, S., and Rheinstein, P.H., Ivermectin docks to the SARS-CoV-2 spike receptor-
binding domain attached to ACE2. In Vivo, 2020. 34(5): p. 3023-3026. 
34. 
Lima-Morales, R., et al., Effectiveness of a multidrug therapy consisting of ivermectin, 
azithromycin, montelukast and acetylsalicylic acid to prevent hospitalization and death among 
ambulatory COVID-19 cases in Tlaxcala, Mexico. Int J Infect Dis, 2021. 
35. 
Lopez-Medina, E., et al., Effect of ivermectin on time to resolution of symptoms among 
adults with mild COVID-19: a randomized clinical trii},.[. JAMA, 2021. 
36. 
Mittal, N. and Mittal, R., Inhaled route and anti-inflammatory action of ivermectin: Do 
they hold promise in fighting against COVJD-19? Med Hypotheses, 2021. 146: p. 110364. 
37. 
Mohan, A., et al., Ivermectin in mild and moderate COVID-19 (RIVET-COV): a 
randomized, placebo-controlled trial. Research Square, 2021. 
38. 
Niaee, M.S., Ivermectin as an adjunct treatment for hospitalized adult COVID-19 
patients: a randomized multi-center clinical trial. Research Square, 2020. 
39. 
Okumu§, N., et al., Evaluation of the effectiveness and safety of adding ivermectin to 
treatment in severe COVID-19 Patients. Research Square, 2021. 
40. 
Patel, A., Desai, S., et al, RETRACTED, Ivermectin in COVID-19 related critical illness. 
2020. 
41. 
Podder, C.S., et al., Outcome of ivermectin treated mild to moderate COVID-19 cases: a 
single-centre, open-label, randomised controlled study. IMC J Med Sci, 2020. 
42. 
Rajter, J.C., et al., Use of ivermectin is associated with lower mortality in hospitalized 
patients with coronavirus disease 2019: the ivermectin in covid nineteen study. Chest, 2021. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 36 of 141

159(1): p. 85-92. 
43. 
Ravikirti, R., et al., Ivermectin as a potential treatment for mild to moderate COVID-19 -
a double blind randomized placebo-controlled trial. Medrxiv, 2021. 
44. 
Bukhari, S.K.H.S., et al., Efficacy of ivermectin in COVID-19 patients with mild to 
moderate disease. Medrxiv, 2021. 
45. 
Soto-Becerra, P., et al., Real-world effectiveness of hydroxychloroquine, azfthromycin, 
and ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using 
observational data from a nationwide healthcare system in Peru. Medrxiv, 2020. 
46. 
Spoorthi, V,, and Surapaneni, S., Utility of ivermectin and doxycycline combination for the 
treatment of SARS-CoV-2. International Archives of Integrated Medicine, 2020. 
Related content 
• Coronavirus disease (COVID-19) 
• COVID-19: latest updates 
• Public-health advice during COVID-19 pandemic 
External links 
• Trial Site News: Slovakia Becomes the First EU Nation to Formally Approve Ivermectin for 
Both Prophylaxis and Treatment for COVID-19 Patients~ 
• Statnf ustav pro kontro!u leciv; Informace o povolenf pou:zivan[ neregistrovaneho !eciveho 
HUMEVEC (ivermektin) C 
Contact point 
EMA press offic:::e 
Tei. +31 (0)88 781 8427 
E-mail: press@ema.europa,eu 
Follow us on Twitter @EMA_News E: 
CONTACT 
European Medicines Agency 
Domenico Scarlattilaan 6 
1083 HS Amsterdam 
The Netherlands 
Tel: +31 (0)88 781 6000 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 37 of 141

For delivery address, see: 
How to find us 
© 1995-2021 European Medicines Agency 
European Union agencies network 
An agency of the European Union 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 38 of 141

Th 
Ii 
1111 I 
World Health 
Organization 
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EXHIBITG 
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Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 40 of 141

[ : : 
J 
Overview 
The WHO Therapeutics and COVID-19: living guideline contains the Organization's most up-to-date 
recommendations for the use of therapeutics in the treatment of COVID-19. The latest version of 
this living guideline is available in gdf format (via the 'Download' button) and via an online Qlatform, 
and is updated regularly as new evidence emerges. 
This fifth version of the WHO guideline now contains seven recommendations, including a new 
recommendation regarding interleukin-6 (IL-6) receptor blockers, including both tocilizumab and 
sarilumab. This latest update was initiated in response to publication of the RECOVERY and 
REMAP-CAP trials addressing IL-6 receptor blockers as a potential treatment for COVID-19. No 
further updates to the previous existing recommendations were made in this latest version. 
CORR!OErsQUM 
The WHO Therapeutics and COVID-19: living guideline currently includes a: 
• **NEW** strongsecomme)1AAtion wusellc<Lrecep59Lbfoc~(tocilizumabop,arilumab) in 
patients with severe or critical COVID-19 (published 6 July 2021); 
• recommendation not to use ivermectin in patients with COVID-19 except in the context of a clinical 
trial (published 31 March 2021); 
• strong r~£Qmmeudatign ag~ydroxy£hloroij_uine in patients with COVID-19 of any severity 
(published 17 December 2020); 
• strong recommendation ag;!,inst loJ.f n 
·rL · 
· in patients with COVID-19 of any severity 
(published 17 December 2020); 
• tonditional recommendation ~gi!inst remdesivir in hospitalized patients with COVID-19 (published 20 
November 2020); 
• strong recommendation for systemic corticosteroids in patients with severe and critical COVID-19 
(published 2 September 2020); 
• conditional rc£,ommcndation i.lgainst SY.Stemic corticosteroids in patients with non-severe COVID-19 
(published 2 September 2020). 
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Other COVID-19 therapeutics that are currently under consideration by WHO include colchicine, 
monoclonal antibodies and anticoagulants. This guideline will be updated if/when sufficient new 
evidence warrants this. 
Guidelines regarding the use of drugs to prevent (rather than treat) COVID-19 are included in a 
separate document, WHO Living guideline: Drugs to prevent COVID-19, that can be accessed via 
an onlioe glatforru and in gdf format (or click 'PDF' in top right comer of online platform). 
Guidelines regarding the clinical management of COVID-19 patients are included in a further 
document, COVID-19 Clinical management: Living guideline, that can be accessed via an online 
pJatfQrm and in_Qdf format (or click 'PDF' in top right corner of online platform). 
To view previous (now outdated) versions of this guideline, please see the links below: 
• First version, published 2 September 2020 (accessible as :r-df only) 
• Second version, published 20 November 2020 (access as pdf or via 9J:ilin,1Lp.latfQrm) 
• Third version, published 17 December 2020 (access as t2df or via Q.nli.ne_rilatform) 
• Fourth version, published 31 March 2021 (access as t2df or via online lili!.tfotm) 
This document was updated on 6 July 2021 
\'{1HO Hcadyuartcrs (HQ) 
\Vorld Ht:altl1 Organizarion 
REFERENCE NUMBERS 
WHO REFERENCE NUMBER: \X HO/2019-nCoV/therapeutics/2021.'.2 
COPYRIGHT 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 42 of 141

Drugs.com 
Kn{ff\' 
Be 
lvermectin Tablets 
Dosage form: tablet 
Drug class: Anthelmintics 
Medically reviewed by Drugs.com. Last updated on February 19, 2021. 
On This Page 
Description 
Clinical Pharmacology 
Clinical Studies 
Indications and Usage 
Contraindications 
Warnings 
Precautions 
Expand 
lvermectin Tablets Description 
lvermectin is a semisynthetic, anthelmintic agent for oral administration. lvermectin is derived from 
the avermectins, a class of highly active broad-spectrum, anti-parasitic agents isolated from the 
fermentation products of Streptomyces avermitilis. lvermectin is a mixture containing at least 90% 5-
O-demethyl-22,23-dihydroavermectin A1a and less than 10% 5-O-demethyl-25-de(1-
methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a, generally referred to as 22,23-
dihydroavermectin 818 and B1b, or H2B1a and H2B1b, respectively. The respective empirical formulas 
are C48H74O14 and C47H72O14, with molecular weights of 875.10 and 861.07, respectively. The 
structural formulas are: 
EXHIBITH 
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lvermectin is a white to yellowish-white, nonhygroscopic, crystalline powder with a melting point of 
about 155"C. It is insoluble In water but is freely soluble in methanol and soluble in 95% ethanol. 
lvermectin Tablets are available as 3-mg tablets containing the following inactive ingredients: 
colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, 
and prege!atinized starch. 
lvermectin Tablets .. Clinical Pharmacology 
Pharmacokinetics 
Following oral administration of ivermectin, plasma concentrations are approximately proportional to 
the dose. In two studies, after single 12-mg doses of ivermectin in fasting healthy volunteers 
(representing a mean dose of 165 mcg/kg), the mean peak plasma concentrations of the major 
component (H2B13} were 46.6 (±21.9) (range: 16.4 to 101.1) and 30.6 (±15.6) (range: 13.9 to 68.4) 
ng/mL, respectivefy, at approximately 4 hours after dosing. lvermectin is metabolized in the liver, 
and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 
12 days, with less than 1% of the administered dose excreted in the urine. The plasma half-life of 
ivermectin in man is approximately 18 hours following oral administration. 
The safety and pharmacokinetic properties of ivermectin were further assessed in a multiple-dose 
clinical pharmacokinetic study Involving healthy volunteers. Subjects received oral doses of 30 to 
120 mg (333 to 2000 mcg/kg) ivermectin in a fasted state or 30 mg (333 to 600 mcg/kg) ivermectin 
following a standard high-fat (48.6 g of fat) meal. Administration of 30 mg ivermectin following a 
high-fat meal resulted in an approximate 2.5-fold increase in bioavailability relative to administration 
of 30 mg ivermectin in the fasted state. 
In vitro studies using human liver microsomes and recombinant CYP450 enzymes have shown that 
ivermectin is primarily metabolized by CYP3A4. Depending on the in vitro method used, CYP2O6 
and CYP2E1 were also shown to be involved in the metabolism of ivermectin but to a significantly 
lower extent compared to CYP3A4. The findings of in vitro studies using human liver microsomes 
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suggest that clinically relevant concentrations of ivermectin do not significantly inhibit the 
metabolizing activities of CYP3A4, CYP2O6, CYP2C9, CYP1A2, and CYP2E1. 
Microbiology 
lvermectin is a member of the avermectin class of broad-spectrum antiparasitic agents which have 
a unique mode of action. Compounds of the class bind selectively and with high affinity to 
glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This 
leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization 
of the nerve or muscle cell, resulting in paralysis and death of the parasite. Compounds of this class 
may also interact with other ligand-gated chloride channels, such as those gated by the 
neurotransmitter gamma-aminobutyric acid (GABA). 
The selective activity of compounds of this class is attributable to the facts that some mammals do 
not have glutamate-gated chloride channels and that the avermectins have a low affinity for 
mammalian ligand-gated chloride channels. In addition, ivermectin does not readily cross the blood-
brain barrier in humans. 
lvermectin is active against various life-cycle stages of many but not all nematodes. It is active 
against the tissue microfilariae of Onchocerca volvulus but not against the adult form. Its activity 
against Strongyloides stercoralis is limited to the intestinal stages. 
Clinical Studies 
Stongyloidiasis 
Two controlled clinical studies using albendazole as the comparative agent were carried out in 
international sites where albendazole is approved for the treatment of strongyloidiasis of the 
gastrointestinal tract, and three controlled studies were carried out in the U.S. and internationally 
using thiabendazole as the comparative agent. Efficacy, as measured by cure rate, was defined as 
the absence of larvae in at least two follow-up stool examinations 3 to 4 weeks post-therapy. Based 
on this criterion, efficacy was significantly greater for ivermectin (a single dose of 170 to 200 
mcg/kg) than for albendazole (200 mg b.i.d. for 3 days). lvermectin administered as a single dose of 
200 mcg/kg for 1 day was as efficacious as thiabendazole administered at 25 mg/kg b.i.d. for 3 
days. 
Summary of Cure Rates for lvermectin Versus Comparative Agents in the Treatment of Strongyloidiasis 
Cure Rate• (%) 
*Number and % of evaluable patients 
t170 to 200 mcg/kg 
;t200 mg b.i.d. for 3 days 
lvermectint 
Comparative Agent 
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§25 mg/kg b.i.d. for 3 days 
Albendazole::f: Comparative 
International Study 
WHO Study 
Thiabendazole§ Comparative 
International Study 
US Studies 
24/26 (92) 
126/152 (83) 
9/14 (64) 
14/14 (100) 
12/22 (55) 
67/149 (45) 
13/15 (87) 
16/17 (94) 
In one study conducted in France, a non-endemic area where there was no possibility of reinfection, 
several patients were observed to have recrudescence of Strongyloides larvae in their stool as long 
as 106 days following ivermectin therapy. Therefore, at least three stool examinations should be 
conducted over the three months following treatment to ensure eradication. If recrudescence of 
larvae is observed, retreatment with ivermectin is indicated. Concentration techniques (such as 
using a Baermann apparatus) should be employed when performing these stool examinations, as 
the number of Strongyfoides larvae per gram of feces may be very low. 
Onchocerciasis 
The evaluation of ivermectin in the treatment of onchocerciasis is based on the results of clinical 
studies involving 1278 patients. In a double-blind, placebo-controlled study involving adult patients 
with moderate to severe onchocercal infection, patients who received a single dose of 150 mcg/kg 
ivermectin experienced an 83.2% and 99.5% decrease in skin microfilariae count (geometric mean) 
3 days and 3 months after the dose, respectively. A marked reduction of >90% was maintained for 
up to 12 months after the single dose. As with other microfilaricidal drugs, there was an increase in 
the microfilariae count in the anterior chamber of the eye at day 3 after treatment in some patients. 
However, at 3 and 6 months after the dose, a significantly greater percentage of patients treated 
with ivermectin had decreases in microfilariae count in the anterior chamber than patients treated 
with placebo. 
In a separate open study involving pediatric patients ages 6 to 13 (n=103; weight range: 17 to 41 
kg), similar decreases in skin microfilariae counts were observed for up to 12 months after dosing. 
Indications and Usage for lvermectin Tablets 
lvermectin is indicated for the treatment of the following infections: 
Strongyloidiasis of the intestinal tract 
lvermectin is indicated for the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to 
the nematode parasite Strongyloides stercoralis. This indication is based on clinical studies of both 
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comparative and open--iabel designs, in which 64-100% of infected patients were cured foflowing a 
single 200-mcg/kg dose of ivermectin (See CLINICAL PHARMACOLOGY, Clinical Studies). 
Onchocerciasis 
lvermectin is indicated for the treatment of onchocerciasis due to the nematode parasite 
Onchocerca volvulus. 
This indication is based on randomized, doubte-bUnd, placebo-controlled and comparative studies 
conducted in 1427 patients in onchocerciasis-endemic areas of West Africa. The comparative 
studies used diethylcarbamazine citrate (DEC-C). 
NOTE: lvermectin has no activity against adult Onchocerca volvulus parasites. The adult parasites 
reside in subcutaneous nodules which are infrequently palpable. Surgical excision of these nodules 
(nodulectomy) may be considered in the management of patients with onchocerciasis, since this 
procedure will eliminate the microfilariae-producing adult parasites, 
Contraindications 
lvermectin Tablets are contraindicated in patients who are hypersensitive to any component of this 
product 
Warnings 
Historical data have shown that microfilaricidal drugs, such as diethylcarbamazine citrate (DEC-C), 
might cause cutaneous and/or systemic reactions of varying severity (the Mazzotti reaction) and 
ophthalmological reactions in patients with onchocerciasis. These reactions are probably due to 
allergic and inflammatory responses to the death of microfilariae. Patients treated with ivermectin for 
onchocerciasis may experience these reactions in addition to clinical adverse reactions possibly, 
probably, or definitely related to the drug itself (See ADVERSE REACTIONS, Onchocerciasis). 
The treatment of severe Mazzotti reactions has not been subjected to controlled clinical trials. Oral 
hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been 
used to treat postural hypotension. Antihistamines and/or aspirin have been used for most mild to 
moderate cases. 
Precautions 
General 
After treatment with microfilaricida! drugs, patients with hyperreactive onchodermatitis {sowda) may 
be more likely than others to experience severe adverse reactions, especially edema and 
aggravation of onchodermatitis. 
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Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a 
serious or even fatal encephalopathy either spontaneously or following treatment with an effective 
microtHaricide. In these patients, the following adverse experiences have also been reported: pain 
(including neck and back pain), red eye, conjunctiva! hemorrhage, dyspnea, urinary and/or fecal 
incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, 
seizures, or coma. This syndrome has been seen very rarely following the use of ivermectin. In 
individuals who warrant treatment with ivermectin for any reason and have had significant exposure 
to Loa lea-endemic areas of West or Central Africa, pretreatment assessment for loiasis and careful 
posttreatment follow-up should be implemented. 
Information for Patients 
ivermectin Tablets should be taken on an empty stomach with water (See CLINICAL 
PHARMACOLOGY, Pharmacokinetics). 
Strongyloidiasis 
The patient should be reminded of the need for repeated stool examinations to document clearance 
of infection with Strongyloides stercoralis. 
Onchocerciasis 
The patient should be reminded that treatment with ivermectin does not kill the adult Onchocerca 
parasites, and therefore repeated follow-up and retreatment is usually required. 
Drug Interactions 
Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported 
when ivermectin was coadministered with warfarin. 
Carcinogenesis, Mutagenesis, Impairment of Fertmty 
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of 
ivermectin. 
fvermectin was not genotoxic in vitro in the Ames microbial mutagenicity assay of Salmonella 
typhimurium strains TA1535, TA1537, TA98, and TA100 with and without rat liver enzyme activation, 
the Mouse Lymphoma Cell Line L5178Y (cytotoxicity and mutagenicity) assays, or the unscheduled 
ONA synthesis assay in human fibroblasts. 
tvermectin had no adverse effects on the fertility in rats in studies at repeated doses of up to 3 times 
the maximum recommended human dose of 200 mcg/kg (on a mg/m2/day basis). 
Pregnancy 
Teratogenic Effects 
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Pregnancy Category C 
lvermectin has been shown to be teratogenic in mice, rats, and rabbits when given in repeated 
doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively (on a 
mg/m2/day basis). Teratogenicity was characterized in the three species tested by cleft palate; 
clubbed forepaws were additionally observed in rabbits. These developmental effects were found 
only at or near doses that were maternotoxic to the pregnant female. Therefore, ivermectin does not 
appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and 
well-controlled studies in pregnant women. lvermectin should not be used during pregnancy since 
safety in pregnancy has not been established. 
Nursing Mothers 
lvermectin is excreted in human milk in low concentrations. Treatment of mothers who intend to 
breast-feed should only be undertaken when the risk of delayed treatment to the mother outweighs 
the possible risk to the newborn. 
Pediatric Use 
Safety and effectiveness in pediatric patients weighing less than 15 kg have not been established. 
Geriatric Use 
Clinical studies of ivermectin did not include sufficient numbers of subjects aged 65 and over to 
determine whether they respond differently from younger subjects. Other reported clinical 
experience has not identified differences in responses between the elderly and younger patients. In 
general, treatment of an elderly patient should be cautious, reflecting the greater frequency of 
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 
Strcmgyloidiasis in lmmunocompromised Hosts 
In immunocompromised (including HIV-infected) patients being treated for intestinal strongyloidiasis, 
repeated courses of therapy may be required. Adequate and well-controlled clinical studies have not 
been conducted in such patients to determine the optimal dosing regimen. Several treatments, i.e., 
at 2-week intervals, may be required, and cure may not be achievable. Control of extra-intestinal 
strongyloidiasis in these patients is difficult, and suppressive therapy, i.e., once per month, may be 
helpful. 
Adverse Reactions 
Strongyloidiasis 
In four clinical studies involving a total of 109 patients given either one or two doses of 170 to 200 
mcg/kg of ivermectin, the following adverse reactions were reported as possibly, probably, or 
definitely related to ivermectin: 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 49 of 141

Body as a Whole: asthenia/fatigue (0.9%), abdominal pain (0.9%) 
Gastrointestinal: anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea {1.8%), vomiting 
(0.9%) 
Nervous System/Psychiatric: dizziness (2.8%}, somnolence (0.9%), vertigo (0.9%), tremor (0.9%) 
Skin: pruritus (2.8%), rash (0.9%), and urticaria (0.9%). 
In comparative trials, patients treated with ivermectin experienced more abdominal distention and 
chest discomfort than patients treated with albendazole. However, ivermectin was better tolerated 
than thiabendazole in comparative studies involving 37 patients treated with thiabendazole. 
The Mazzotti-type and ophthalmologic reactions associated with the treatment of onchocerciasis or 
the disease itself would not be expected to occur in strongyloidiasis patients treated with ivermectin 
(See ADVERSE REACTIONS, Onchocerciasis). 
Laboratory Test Findings 
In clinical trials involving 109 patients given either one or two doses of 170 to 200 mcg/kg 
ivermectin, the following laboratory abnormalities were seen regardless of drug relationship: 
elevation in ALT and/or AST (2% ), decrease in leukocyte count (3% ). Leukopenia and anemia were 
seen in one patient. 
Onchocerciasis 
In clinical trials involving 963 adult patients treated with 100 to 200 mcg/kg ivermectin, worsening of 
the following Mazzotti reactions during the first 4 days post-treatment were reported: 
arthralgia/synovitis (9.3%), axillary lymph node enlargement and tenderness (11.0% and 4.4%, 
respectively), cervical lymph node enlargement and tenderness {5.3% and 1.2%, respectively), 
inguinal lymph node enlargement and tenderness (12.6% and 13.9%, respectively), other lymph 
node enlargement and tenderness (3.0% and 1.9%, respectively), pruritus (27.5%), skin 
involvement including edema, papular and pustular or frank urticaria! rash (22.7%), and fever 
(22.6%) (See WARNINGS). 
In clinical trials, ophthalmological conditions were examined in 963 adult patients before treatment, 
at day 3, and months 3 and 6 after treat~ent with 100 to 200 mcg/kg ivermectin. Changes observed 
were primarily deterioration from baseline 3 days post-treatment. Most changes either returned to 
baseline condition or improved over baseline severity at the month 3 and 6 visits. The percentages 
of patients with worsening of the following conditions at day 3, month 3 and 6, respectively, were: 
limbitis: 5.5%, 4.8%, and 3.5% and punctate opacity: 1.8%, 1.8%, and 1.4%. The corresponding 
percentages for patients treated with placebo were: limbitis: 6.2%, 9.9%, and 9.4% and punctate 
opacity: 2.0%, 6.4%, and 7 .2% (See WARNINGS). 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 50 of 141

In clinical trials involving 963 adult patients who received 100 to 200 mcg/kg ivermectin, the 
following clinical adverse reactions were reported as possibly, probably, or definitely related to the 
drug in ~1 % of the patients: facial edema (1.2%), peripheral edema (3.2%), orthostatic hypotension 
(1.1%}, and tachycardia (3.5%), Drug-related headache and myalgia occurred in <1% of patients 
(0.2% and 0.4%, respectively). However, these were the most common adverse experiences 
reported overall during these trials regardless of causality (22.3% and 19. 7%, respectively). 
A similar safety profile was observed in an open study in pediatric patients ages 6 to 13. 
The following ophthalmological side effects do occur due to the disease itself but have also been 
reported after treatment with ivermectin: abnormal sensation in the eyes, eyelid edema, anterior 
uveitis, conjunctivitis, limbitis, keratitis, and chorioretinitis or choroiditis. These have rarely been 
severe or associated with loss of vision and have generally resolved without corticosteroid 
treatment. 
laboratory Test Findings 
In controlled clinical trials, the following laboratory adverse experiences were reported as possibly, 
probably, or definitety related to the drug in ~ 1 % of the patients: eosinophilia (3%) and hemoglobin 
increase ( 1 % ). 
Post-Marketing Experience 
The following adverse reactions have been reported since the drug was registered overseas: 
Onchocerciasis 
Conjunctiva! hemorrhage 
AH Indications 
Hypotension (mainly orthostatic hypotension), worsening of bronchial asthma, toxic epidermal 
necrolysis, Stevens~Johnson syndrome, seizures, hepatitis, elevation of liver enzymes, and 
elevation of bilirubin. 
Overdosage 
Significant lethality was observed in mice and rats after single oral doses of 25 to 50 mg/kg and 40 
to 50 mg/kg, respectively. No significant lethality was observed in dogs after single oral doses of up 
to 10 mg/kg. At these doses, the treatment-related signs that were observed in these animals 
include ataxia, bradypnea, tremors, ptosis, decreased activity, emesis, and mydriasis. 
In accidental intoxication with, or significant exposure to, unknown quantities of veterinary 
formulations of ivermectin in humans, either by ingestion, inhalation, injection, or exposure to body 
surfaces, the following adverse effects have been reported most frequently: rash, edema, 
headache, dizziness, asthenia, nausea, vomiting, and diarrhea. Other adverse effects that have 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 51 of 141

been reported include: seizure, ataxia, dyspnea, abdominal pain, paresthesia, urticaria, and contact 
dermatitis. 
In case of accidental poisoning, supportive therapy, if indicated, should include parenteral fluids and 
electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor 
agents if clinically significant hypotension is present. Induction of emesis and/or gastric lavage as 
soon as possible, followed by purgatives and other routine anti-poison measures, may be indicated 
if needed to prevent absorption of ingested material. 
lvermectin Tablets Dosage and Administration 
Strongyloidiasis 
The recommended dosage of lvermectin Tablets for the treatment of strongyloidiasis is a single oral 
dose designed to provide approximately 200 mcg of ivermectin per kg of body weight. See Table 1 
for dosage guidelines. Patients should take tablets on an empty stomach with water (See CLINICAL 
PHARMACOLOGY, Pharmacokinetics). In general, additional doses are not necessary. However, 
follow-up stool examinations should be performed to verify eradication of infection (See CLINICAL 
PHARMACOLOGY, Clinical Studies). 
Table 1: Dosage Guidelines for lvermectin Tablets for Strongyloidiasis 
Body Weight (kg} 
15 to 24 
25 to 35 
36 to 50 
51 to 65 
66 to 79 
Onchocerciasis 
Single Oral Dose 
Number of 3-mg Tablets 
1 tablet 
2 tablets 
3 tablets 
4 tablets 
5 tablets 
200 mcg/kg 
The recommended dosage of !vermectin Tablets for the treatment of onchocerciasis is a single oral 
dose designed to provide approximately 150 mcg of ivermectin per kg of body weight See Table 2 
for dosage guidelines. Patients should take tablets on an empty stomach with water (See CLINICAL 
PHARMACOLOGY, Pharmacokinetics). In mass distribution campaigns in international treatment 
programs, the most commonly used dose interval is 12 months. For the treatment of individual 
patients, retreatment may be considered at intervals as short as 3 months. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 52 of 141

Table 2: Dosage Guidelines for lvermectin Tablets for Onchocerciasis 
Body Weight (kg} 
15 to 25 
26 to 44 
45 to 64 
65 to 84 
How is lvermectin Tablets Supplied 
Single Oral Dose 
Number of 3-mg Tablets 
1 tablet 
2 tablets 
3 tablets 
4tablets 
150 mcg/kg 
lvermectin Tablets USP, 3 mg are white, round, flat, bevel-edged tablets debossed with "806" on 
one side and plain on the other side. They are supplied as follows: 
NOC 42799-806-01 unit dose packages of 20. 
Storage 
Store at temperatures below 30°C (86°F). 
Manufactured for: 
Edenbridge Pharmaceuticals, LLC 
Parsippany, NJ 07054 
Rev. 01/14 
PRINCIPAL DISPLAY PANEL .. 3 mg Tablet Carton 
NOC 42799-806-01 
lvermectin 
Tablets USP 
3mg 
20 Tablets 
{2 Foil Strips of 10 tablets each) 
Rx Only 
Edenbridge 
Pharmaceuticals 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 53 of 141

IVERMECTIN 
ivermectin tablet 
Product Information 
Product Type 
HUMAN PRESCRIPTION 
DRUG LABEL 
Item Code (Source) 
Route of Administration 
Active Ingredient/Active Moiety 
Ingredient Name 
IVERMECTIN (IVERMECTIN) 
Inactive Ingredients 
Ingredient Name 
ORAL 
SILICON DIOXIDE 
CROSCARIIIIELLOSE SODIUM 
MAGNESIUM STEA.RATE 
MICROCRYSTALUNE CELLULOSE 
STARCH, CORN 
Product Characteristics 
Color 
Shape 
Flavor 
Contains 
Packaging 
# 
Item Code 
WHITE 
ROUND 
DEA Schedule 
Basis of Strength 
IVERMECTIN 
Score 
Size 
Imprint Code 
Package Description 
NDC:42799-
806 
Strength 
3mg 
Strength 
no score 
6mm 
806 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 54 of 141

1 
NDC:42799~806-01 
1 
2 BLISTER PACK in 1 CARTON 
10 TABLET in 1 BLISTER PACK 
Marketing Information 
Marketing 
Category 
ANDA 
Application Number or Monograph 
Citation 
ANDA204154 
labeler - Edenbridge Pharmaceuticals, LLC (948715060) 
Edenbridge Pharmaceuticals, LLC 
Frequently asked questions 
" Can lvermectin be used to treat COVtD-19? 
Marketing Start 
Date 
11/15/2014 
Marketing End 
Date 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 55 of 141

MERCK 
Media > Company statements > Company statement 
Merck Statement on lvermectin use During the COVID-19 
Pandemic 
February 4, 202111:45 am ET 
Save 
KENILWORTH, N.J., Feb. 4, 2021- Merck (NYSE: MRK), known as MSD outside the United States 
and Canada, today affirmed its position regarding use of ivermectin during the COVID-19 pandemic. 
Company scientists continue to carefully examine the findings of all available and emerging studies 
of ivermectin for the treatment of COVID-19 for evidence of efficacy and safety. It is important to 
note that, to-date, our analysis has identified: 
No scientific basis for a potential therapeutic effect against COVID-19 from pre-clinical studies; 
No meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19 
disease, and; 
A concerning lack of safety data in the majority of studies. 
We do not believe that the data available support the safety and efficacy of ivermectin beyond the 
doses and populations indicated in the regulatory agency-approved prescribing information. 
Indications and Usage for STROMECTOl ® (ivermectin) 
lvermectin is approved in the United States under the brand name STROMECTOL STROMECTOL is 
indicated for the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the 
nematode parasite Strongyloides stercoralis and for the treatment of onchocerciasis due to the 
nematode parasite Onchocerca volvulus. 
STROMECTOL has no activity against adult Onchocerca volvulus parasites. 
SELECTED SAFETY INFORMATION FOR STROMECTOL ® (ivermectin) 
Contraindications 
STROMECTOL is contraindicated in patients who are hypersensitive to any component of this 
product. 
EXHIBIT I 
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Warnings and Precautions 
Patients treated with STROMECTOL for onchocerciasis may experience cutaneous and/or systemic 
reactions of varying severity (the Mazzetti reaction) and ophthalmological reactions. 
After treatment with microfilaricidal drugs, patients with hyperreactive onchodermatitis (sowda) 
may be more likely than others to experience severe adverse reactions, especially edema and 
aggravation of onchodermatitis. 
Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a serious 
or even fatal encephalopathy either spontaneously or following treatment with an effective 
microfilaricide. In these patients, the following adverse experiences have also been reported: pain 
(including neck and back pain), red eye, conjunctiva! hemorrhage, dyspnea, urinary and/or fecal 
incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, 
seizures, or coma. ln individuals who warrant treatment with ivermectin for any reason and have 
had significant exposure to Loa Joa-endemic areas of West or Central Africa, pretreatment 
assessment for loiasis and careful post-treatment follow-up should be implemented. 
STROMECTOL should be taken on an empty stomach with water. 
Strongyloidiasis: The patient should be reminded of the need for repeated stool examinations to 
document clearance of infection with Strongyloides stercorafis. 
Onchocerciasis: The patient should be reminded that treatment with STROMECTOL does not kill 
the adult Onchocerca parasites, and therefore repeated follow-up and retreatment is usually 
required. 
Adverse Reactions 
Strongyloidiasis 
In four clinical studies involving a total of 109 patients given either one or two doses of 170 to 200 
mcg/kg of STROMECTOL, the following adverse reactions were reported as possibly, probably, or 
definitely related to STROMECTOL: Body as a Whole: asthenia/fatigue (0.9%), abdominal pain 
(0.9%); Gastrointestinal: anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea (1.8%), 
vomiting (0.9%); Nervous System/Psychiatric: dizziness (2.8%), somnolence (0.9%), vertigo 
(0.9%), tremor (0.9%); Skin: pruritus (2.8%), rash (0.9%), and urticaria (0.9%). 
Onchocerciasis 
In clinical trials involving 963 adult patients treated with 100 to 200 mcg/kg STROMECTOL, 
worsening of the following Mazzotti reactions during the first 4 days post-treatment were reported: 
arthralgia/synovitis (9.3%), axillary lymph node enlargement and tenderness (11.0% and 4.4%, 
respectively), cervical lymph node enlargement and tenderness (5.3% and 1.2%, respectively), 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 57 of 141

inguinal lymph node enlargement and tenderness (12.6% and 13.9%, respectively), other lymph 
node enlargement and tenderness (3.0% and 1.9%, respectively), pruritus (27.5%), skin involvement 
including edema, papular and pustular or frank urticaria I rash (22. 7%), and fever (22.6%). 
In clinical trials, ophthalmological conditions were examined in 963 adult patients before treatment, 
at day 3, and months 3 and 6 after treatment with 100 to 200 mcg/kg STROMECTOL Changes 
observed were primarily deterioration from baseline 3 days post-treatment. Most changes either 
returned to baseline condition or improved over baseline severity at the month 3 and 6 visits. The 
percentages of patients with worsening of the following conditions at day 3, month 3 and 6, 
respectively, were: limbitis: 5.5%, 4.8%, and 3.5% and punctate opacity: 1.8%, 1.8%, and 1.4%. The 
corresponding percentages for patients treated with placebo were: limbitis: 6.2%, 9.9%, and 9.4% 
and punctate opacity: 2.0%, 6.4%, and 7.2%. 
In clinical trials involving 963 adult patients who received 100 to 200 mcg/kg STROMECTOL, the 
following clinical adverse reactions were reported as possibly, probably, or definitely related to the 
drug in 
31% of the patients: facial edema (1.2%), peripheral edema (3.2%), orthostatic hypotension 
{1.1%), and tachycardia (3.5%). Drug-related headache and myalgia occurred in <1% of patients 
(0.2% and 0.4% respectively). 
The following ophthalmological side effects do occur due to the disease itself but have also been 
reported after treatment with STROMECTOL: abnormal sensation in the eyes, eyelid edema, 
anterior uveitis1 conjunctivitis, limbitis, keratitis, and chorioretinitis or choroiditis. These have rarely 
been severe or associated with loss of vision and have generally resolved without corticosteroid 
treatment. 
Drug Interactions 
Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported 
when ivermectin was co-administered with warfarin. 
Use in Specific Populations 
lvermectin should not be used during pregnancy since safety in pregnancy has not been established. 
lvermectin is excreted in human milk in low concentrations.Treatment of mothers who intend to 
breast-feed should only be undertaken when the risk of delayed treatment to the mother outweighs 
the possible risk to the newborn. 
Safety and effectiveness in pediatric patients weighing less than 15 kg have not been established. 
Clinical studies of STROMECTOL did not include sufficient numbers of subjects aged 65 and over to 
determine whether they respond differently from younger subjects. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 58 of 141

In immunocompromised (including HIV-infected) patients being treated for intestinal 
strongyloidiasis, repeated courses of therapy may be required. Adequate and well-controlled clinical 
studies have not been conducted in such patients to determine the optimal dosing regimen. 
About Merck 
For 130 years, Merck, known as MSD outside of the United States and Canada, has been inventing 
for life, bringing forward medicines and vaccines for many of the world's most challenging diseases 
in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients 
and population health by increasing access to health care through far-reaching policies, programs 
and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat 
diseases that threaten people and animals - including cancer, infectious diseases such as HIV and 
Ebola, and emerging animal diseases - as we aspire to be the premier research-intensive 
biopharmaceutical company in the world. For more information, visit 
with us on Twitter, Facebook, !nstagram, You Tube and Unked!n. 
Forward·looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA 
and connect 
This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the "company") includes "forward-
looking statements" within the meaning of the safe harbor provisions of the U.S. Private Securities 
Litigation Reform Act of 1995. These statements are based upon the current beliefs and 
expectations of the company's management and are subject to significant risks and uncertainties. If 
underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may 
differ materially from those set forth in the forward-looking statements. 
Risks and uncertainties include but are not limited to, general industry conditions and competition; 
general economic factors, including interest rate and currency exchange rate fluctuations; the 
impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of 
pharmaceutical industry regulation and health care legislation in the United States and 
internationally; global trends toward health care cost containment; technological advances, new 
products and patents attained by competitors; challenges inherent in new product development, 
including obtaining regulatory approval; the company's ability to accurately predict future market 
conditions; manufacturing difficulties or delays; financial instability of international economies and 
sovereign risk; dependence on the effectiveness of the company's patents and other protections for 
innovative products; and the exposure to litigation, including patent litigation, and/or regulatory 
actions. 
The company undertakes no obligation to publicly update any forward-looking statement, whether 
as a result of new information, future events or otherwise. Additional factors that could cause 
results to differ materially from those described in the forward-looking statements can be found in 
the company's 2019 Annual Report on Form 10-K and the company's other filings with the Securities 
and Exchange Commission (SEC) available at the SEC's Internet site (www,sec.gov). 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 59 of 141

Please see Prescribing Information for STROMECTOl at 
https://www.merck.com/product/usa/pi_circufars/s/stromecto!/stromectol_pi.pdf. 
Media Contact: 
Patrick Ryan 973 275-7075 
Investor Contact: 
Peter Dannenbaum 908 740-1037 
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Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 62 of 141

Table 2c. lvermectin: Selected Clinical Data 
Last Updated: July 19, 2021 
The Panel has reviewed other clinical studies of !VM for the treatment of COVID-19.1•16 However. those studies have limitations that make 
them less definitive and informative than the studies discussed here. The studies summarized below are those that have had the greatest 
impact on the Panel's recommendations. 
Study Design 
Methods 
Results 
lvermectin Versus Placebo for Treatment of Mild COVID-1917 
Randomized, 
double-blind, 
placebo-controlled 
trial in Cali, 
Colombia (n = 476) 
Key Inclusion Criteria: 
• Positive SARS-CoV-2 PCR 
result or positive antigen test 
result 
• Symptoms began s7 days 
prior to randomization 
• Mild disease (defined as 
receiving outpatient or 
inpatient care, but not 
receiving HFNC oxygen or 
mechanical ventilation) 
Key Exclusion Criteria: 
• Asymptomatic disease 
• Severe pneumonia 
• Receipt of IVM within 
previous 5 days 
• Hepatic 
dysfunction/abnormal liver 
function tests 
Interventions: 
• Oral IVM 300 µg/kg per day in 
solution for 5 days, taken 
primarily on an empty 
stomach 
• Placebo 
Primary Endpoints: 
• Time from randomization to 
resolution of symptoms 
within the 21-day follow-up 
period. Resolution of 
symptoms was defined as the 
first day a patient reported a 
score of O (no clinical 
evidence of infection) on an 
8-point ordinal scale. 
Number of Participants: 
• IVM (n = 200) and placebo (n = 
198) in primary analysis 
Participant Characteristics: 
• Median age was 37 years; 4% of 
patients in lVM arm and 8% in 
placebo arm were aged l::65 
years. 
• 39% of patients in IVM arm and 
45% in placebo arm were male. 
• 79% of patients had no known 
comorbidities; median BMI in 
both arms was 26. 
• Median time from symptom 
onset to randomization was 5 
days {IQR 4-6 days). 
• 62% of patients in IVM arm and 
55% in placebo arm were not 
hospitalized and had no 
limitations of activities at 
baseline {ordinal scale 1); 38% 
and 44% were not hospitalized 
but had some limitations on 
activities. or they were 
receiving oxygen at home, or 
both (ordinal scale 2). 
• 1% of patients in both arms 
were hospitalized at baseline. 
Primary Outcomes: 
• No difference in time to 
resolution of symptoms (median 
10 days in IVM arm vs. 12 days in 
placebo arm; HR 1.07; 95% Cl, 
0.87-1.32; P = 0.53) 
• Symptoms resolved in 82% of 
patients in IVM arm and 79% in 
placebo arm by Day 21. 
Other Outcomes: 
Limitations and Interpretation 
Key Limitations: 
• Relatively small sample size 
• Primary endpoint was modified 
during the trial due to lower than 
expected event rates. 
• The first 65 patients received a 
placebo that smelled and tasted 
different from IVM. 
• The study enrolled a younger. 
healthier demographic than those 
who typically experience more 
serious cases of COVID-19. 
• Study included 4 hospitalized 
patients (out of 398). 
• The IVM dose used in this study was 
higher than the dose that is usually 
administered (IVM 200 µg/kg per 
day). 
Interpretation: 
• A 5-day course of IVM did not 
improve time to resolution of 
symptoms in patients with mild 
COVto-19. 
EXHIBIT J 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 63 of 141

Study Design 
Methods 
Results 
• No significant difference 
between arms in proportion of 
patients who showed clinical 
deterioration of 2'!2 points on the 
ordinal scale (3.5% in IVM arm 
vs. 2.0% in placebo arm; 
absolute difference -1.5%; 95% 
Cl, -4.8% to 1.7%) 
• No significant difference 
between arms in the odds of 
improvement in ordinal scale 
score and the proportion of 
patients who sought medical 
care or required escalation in 
care. 
• 8% of patients in IVM arm and 
3% in placebo arm discontinued 
treatment due to an AE. None of 
the reported SAEs were 
considered to be related to 
study interventions. 
lvermectin Versus lvermectin Plus Doxycycline Versus Placebo for Treatment of COVID-1918 
Limitations and Interpretation 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 64 of 141

Study Design 
Randomized, 
double-blind, 
placebo-controlled 
trial of hospitalized 
adults in Dhaka, 
Bangladesh (n = 72) 
Methods 
Key Inclusion Criteria: 
• Aged 18-65 years 
• Laboratory-confirmed SARS-
CoV-2 infection with fever, 
cough, or sore throat 
• Admitted to hospital within 
previous 7 days 
Key Exclusion Criteria: 
• Chronic cardiac, renal, or liver 
disease 
Interventions: 
• IVM 12 mg PO once daily for 5 
days 
• Single dose of IVM 12 mg PO 
plus DOX 200 mg PO on Day 
1, then DOX 100 mg every 12 
hours for 4 days 
• Placebo 
Primary Endpoints: 
• Time to virologic clearance, 
measured by obtaining an NP 
swab for SARS-CoV-2 PCR on 
Days 3, 7, and 14, then weekly 
until PCR result was negative 
• Resolution of fever and cough 
within 7 days 
Results 
Number of Participants: 
• IVM (n = 24; 2 withdrew). IVM 
plus DOX {n = 24; 1 withdrew), 
and placebo {n = 24; 1 withdrew) 
Participant Characteristics: 
• Mean age was 42 years. 
• 54% of patients were female. 
• Mean time from symptom onset 
to assessment was 3.83 days. 
• No patients required 
supplemental oxygen. 
Primary Outcomes: 
• Shorter mean time to virologic 
clearance with IVM than 
placebo (9.7 days vs. 12.7 days; 
P = 0.02), but not with IVM plus 
DOX (11.5 days; P = 0.27). 
• Rates of virologic clearance 
were greater in IVM arm at Day 
7 (HR 4.1; 95% Cl, 1.1-14.7; P = 
0.03) and at Day 14 (HR 2.7; 
95% Cl, 1.2-6.0; P = 0.02) 
compared to placebo, but not in 
the IVM plus DOX arm (HR 2.3; 
95% Cl, 0.6-9.0; P = 0.22 and 
HR 1.7; 95% Cl, 0.8-4.0; P= 
0.19). 
• No statistically significant 
difference in time to resolution 
of fever, cough, or sore throat 
between IVM and placebo arms 
(P= 0.35, P= 0.18, and P= 0.35, 
respectively) or IVM plus DOX 
and placebo arms (P = 0.09, P = 
0.23, and P = 0.09, respectively). 
Other Outcomes: 
• Mean values of CRP, LOH, 
procalcitonin, and ferritin 
declined in all arms from 
baseline to Day 7, but there 
were no between-arm 
comparisons of the changes. 
• No between-arm differences in 
duration of hospitalization (P= 
0.93). 
• No SAEs recorded. 
limitations and Interpretation 
Key limitations: 
• Small sample size 
• Unclear whether both IVM and DOX 
placebos were used. 
• Excluded patients with chronic 
diseases. 
• Disease appears to have been mild in 
all patients; thus. the reason for 
hospitalization is unclear. 
• Absolute changes in inflammatory 
markers were not presented, but 
were reportedly significant. 
• PCR results are not a validated 
surrogate marker for clinical efficacy. 
Interpretation: 
• A 5-day course of IVM resulted in 
faster virologic clearance than 
placebo, but not a faster time to 
resolution of symptoms (fever, cough, 
and sore throat). Because time to 
virologic clearance is not a validated 
surrogate marker for clinical 
efficacy, the clinical efficacy of IVM 
is unknown. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 65 of 141

Study Design 
Methods 
Results 
Llmitations and Interpretation 
Effectiveness and Safety of Adding lvermectin to Treatment in Patients With Severe COVI0-1919 
Randomized, single-
blind trial of 
hospitalized adults 
in Turkey (n" 66) 
Key Inclusion Criteria: 
• Hospitalized with PCR-
confirmed SARS-CoV-2 
infection 
• ;;,1 of the following severity 
criteria: 
o Tachypnea (::e30 
breaths/min), Sp02 <90% 
on RA, or Pa02/Fi02 <300 
mm Hg in patients who 
were receiving oxygen 
o Presence of "specific" 
radiologic findings 
o Mechanical ventilation 
o Acute organ dysfunction 
Key Exclusion Criteria: 
• Aged <18 years 
• Pregnant or breast feeding 
• Autoimmune disease 
• Chronic liver or kidney 
disease 
• lmmunosuppression 
• SNP mutation in 
MDR1/ABC81 gene and/or 
haplotypes and mutations of 
the CYP3A4 gene (affects 
IVM metabolism and toxicity) 
Interventions: 
• IVM 200 µg/kg per day for 5 
days plus SOC (HCQ plus 
favipiravir plus AZM} 
• SOCalone 
Primary Endpoint: 
• "Clinical response" at Day 5: 
extubation (in mechanically 
ventilated patients}, 
respiratory rate <26 
breaths/min, Sp02 >90% on 
RA, Pa02/Fi02 >300 mm Hg 
(if patient was receiving 
oxygen), presence of ~2 of 
the 2-point reduction criteria 
in SOFA 
Key Secondary Endpoints: 
Number of Participants: 
• IVM (n = 36) and SOC (n = 30) 
• 6 participants in IVM arm were 
excluded after genotyping. 
Participant Characteristics: 
• Mean age was 58 years in IVM 
arm and 66 years in SOC arm. 
• 70% of patients were male in 
IVM arm and 63% were male in 
SOC arm. 
• Comorbidities (IVM vs. SOC): 
OM (30% vs. 33%), HTN (50% 
vs. 40%), CAD (17% vs. 27%) 
Primary Outcome: 
• Clinical improvement at Day 5: 
14 of 30 patients (46.7%) in IVM 
arm, 11 of 30 (36.7%) in SOC 
arm (P = 0.43) 
Secondary Outcomes: 
Between-Arm Comparisons at Day 
10: 
• Clinical improvement: 73.3% in 
IVM arm, 53.3% in SOC arm (P 
=0.10) 
• IVM vs. SOC arm SOFA score at 
Day 10: P= 0.50 
• Mean SpOi 95.4% in IVM arm, 
93.0% in SOC arm (P = 0.032) 
• Mean Pa02/Fi02: 236.3 mm Hg 
in IVM arm, 220.8 mm Hg in 
SOC arm (P = 0.39) 
• Serum CRP, ferritin, and D-
dimer levels were lower in IVM 
arm than in SOC arm (P= 0.02, 
P= 0.005, and P"' 0.03, 
respectively). 
Within-Group Changes from 
Baseline: 
• Change in SOFA score to Day 
10; P = 0.009 in IVM arm, P = 
0.88 in SOC arm 
• Mean changes in Sp02 to Day 5: 
89.9% to 93.5% (P = 0.005) in 
IVM arm, 89.7% to 93.0% (P = 
0.003) in SOC arm 
Key Limitations: 
• Small sample size 
• Time from symptom onset to 
intervention was not reported. 
• Study used nonstandard severity 
classification for COVID-19. 
• Primary endpoint was difficult to 
characterize; it was presented in the 
Methods section as a composite 
endpoint, but each component was 
analyzed separately. 
• Power analysis performed for 
virologic endpoint, not primary 
endpoint. 
• Only 57% of patients in IVM arm and 
27% in SOC arm were evaluated for 
VLchanges. 
Interpretation: 
• A 5-day course of !VM in hospitalized 
patients with severe COVID-19 did 
not result in clinical improvement at 
the end of treatment, and no 
reduction in mortality was observed. 
• Faster improvement of oxygenation 
and more pronounced reduction in 
inflammatory markers were observed 
in IVMarm. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 66 of 141

Study Design 
Methods 
• Clinical response at Day 10: 
respiratory rate 22 to 24 
breaths/min, Sp02 >95% on 
RA, absence of oxygen 
requirement, and no need for 
intensive care 
• Changes in Sp02, Pa02/Fi02, 
and levels of CRP, ferritin, 
and D-dimer 
• Mortality 
Mortality Durwls~i'Jjpw-Up Period: 
• 6 patients {20%) in IVM arm and 
9 {30%) in SOC arm (P = 0.37). 
• Average length of follow-up 
was 3 months. 
Chloroquine, Hydroxychloroquine, or lvermectin in Patients With Severe COV!D-1920 
Randomized, 
double-blind, Phase 
2 trial of 
hospitalized adults 
in Brazil (n = 168) 
Key inclusion Criteria: 
• Hospitalized with laboratory-
confirmed SARS-CoV-2 
infection (PCR or lgM 
positive} 
• -,1 of the following severity 
criteria: 
o Dyspnea 
o Tachypnea (>30 
breaths/min) 
o Sp02 <93% 
o Pa02/Fi02 <300 mm Hg 
o Involvement of >50% of 
lungs on CXR or CT 
Key Exclusion Criteria: 
• Aged <18 years old 
• Cardiac arrhythmia, including 
prolonged QT interval 
• Previous use of CQ, HCQ, or 
IVM for >24 hours 
Interventions: 
• CQ 450 mg twice daily on 
Day 0, then CQ 450 mg once 
daily for 4 days 
• HCQ 400 mg twice daily on 
Day 0, then HCQ 400 mg 
once daily for 4 days 
• IVM 14 mg once daily for 3 
days followed by placebo for 
2days 
Endpoints: 
• Need for supplemental 
oxygen, invasive mechanical 
ventilation, or ICU admission 
• Mortality 
Number of Participants: 
• CQ (n = 61), HCQ (n = 54), and 
IVM (n=53) 
Participant Characteristics: 
• Mean age was 53.4±15.6 years. 
• 58.2% of patients were male. 
• 78.9% of patients were 
Hispanic. 
• 37.5% of patients had a BMI 
>30. 
• Most common comorbidities 
were HTN (43.4% of patients) 
and DM (28.1%). 
• On admission, 76.5% of 
patients had respiratory failure, 
and 42.5% had "pneumonic 
syndrome." 
Outcomes: 
• No differences between arms in 
proportion of patients who 
required supplemental oxygen 
(88.5% in CQ arm, 90.2% in 
HCQ arm, and 88.4% in IVM 
arm) or mean number of days of 
supplemental oxygenation (7.9 
vs. 7.8 vs. 8.1 days) 
• No differences between arms in 
proportion of patients admitted 
to the ICU (22.4% in CQ arm, 
21.1% in HCQ arm, and 28.0% in 
IVM arm) or proportion of 
patients who received invasive 
mechanical ventilation (20.6% 
vs. 21.1% vs. 23.5%) 
• No differences between arms in 
proportion of patients who were 
limitations and Interpretation 
Key limitations: 
• Small sample size 
• No placebo control 
• No clear primary endpoint 
Interpretation: 
• Use of IVM did not reduce risk of 
oxygen requirement, ICU admission, 
invasive mechanical ventilation, or 
death in hospitalized patients with 
severe COVID-19. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 67 of 141

Study Design 
Methods 
Results 
receiving concomitant 
medications, including steroids 
and anticoagulants 
• No differences between arms in 
death due to COVID-19 
complications (21.3% in CQ arm, 
22.2% in HCQ arm, and 23.0% 
inlVMarmj 
• Baseline characteristics that 
were associated with mortality 
included age >60 years (HR 
2.44; 95% Cl, 1.40-4.30), DM 
(HR 1.87; 95% Cl, 1.02-2.59), 
BMl >33 (HR 1.95; 95% Cl, 1.07-
3.09), and Sp02 <90% (HR 5.79; 
95% Cl, 2.63-12.7). 
• No difference in rates of A Es 
between arms 
lvermectin Versus Placebo for Outpatients With Mild COVID-1921 
Open-label RCT of 
adult outpatients in 
Lahore. Pakistan (n 
::50) 
Key Inclusion Criteria: 
• SARS-CoV-2 PCR positive 
• Mild disease 
Key Exclusion Criteria: 
• Severe symptoms likely 
related to cytokine storm 
• Malignancy, chronic kidney 
disease, or cirrhosis 
• Pregnancy 
Interventions: 
• IVM 12 mg PO immediately, 
followed by 12 mg doses at 12 
and 24 hours, plus 
symptomatic treatment 
• Symptomatic treatment 
Primary Endpoint: 
• Symptoms reported on Day 7. 
Patients were stratified as 
asymptomatic or 
symptomatic. 
lvermectin in Patients With Mild to Moderate COVI0-1922 
Number of Participants: 
• lVM (n = 25) and control (n = 25) 
Participant Characteristics: 
• Mean age was 40.6 years. 
• 62% of patients were male. 
• 40% of patients had diabetes, 
30% were smokers, 26% had 
hypertension, 8% had 
cardiovascular disease, and 
12% had obesity. 
Outcomes: 
• Proportion of asymptomatic 
patients at Day 7 was similar in 
IVM and control arms (64% vs. 
60%; P = 0.500). 
• AEs were attributed to IVM in 8 
patients (32%). 
Limitations and Interpretation 
Key limitations: 
• Small sample size 
• Open-label study 
• Authors reported the proportions of 
patients with certain symptoms and 
comorbidities but did not provide 
objective assessment of disease 
severity. This precludes the ability to 
compare outcomes between arms. 
• Study classified outcomes at Day 7 
as "symptomatic" and 
"asymptomatic," but did not account 
for symptom worsening or 
improvement. 
Interpretation: 
• IVM showed no effect on symptom 
resolution in patients with mild 
COVID-19. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 68 of 141

Study Design 
Open-label, single-
center, RCT of 
outpatients with 
laboratory-
confirmed SARS-
CoV-2 infection in 
Bangladesh (n = 62) 
Methods 
Key Inclusion Criteria: 
• Aged ;?18 years 
• Laboratory-confirmed SARS-
CoV-2 infection 
• s7 days of symptoms 
• Mild or moderate disease 
Results 
Number of Participants: 
• !VM (n = 32) and SOC (n = 30) 
Participant Characteristics: 
• 71% of patients were male. 
• Mean age was 39.2 years (SD 
12.1 years). 
Key Exclusion Criteria: 
• 81% of patients had mild 
• Hypersensitivity to IVM 
disease and 19% had moderate 
• Pregnancy or breastfeeding 
disease. 
• Use of HCQ or ·other 
• Study provided no information 
antimicrobials" 
on comorbidities. 
Interventions: 
Outcomes: 
• Single dose of IVM 200 µg/kg 
• Mean overall recovery time was 
• soc 
Primary Endpoint: 
• Full recovery from all 
symptoms 
Secondary Endpoint 
• Conversion to negative RT-
PCR at DaylO 
5.3 days (SD 2.5 days) in IVM 
arm and 6.3 days (SD 4.2 days) 
in SOC arm. The difference was 
not statistically significant. 
Time to resolution of fever, 
shortness of breath, and fatigue 
were no shorter in IVM arm. 
• Negative SARS-CoV-2 PCR 
result at Day 10: 18 of 20 
patients (90%) in IVM arm, 19 of 
20 {95%) in SOC arm. 
Limitations and Interpretation 
Key Limitations: 
• Open-label study 
• Small study 
• Study enrolled young patients with 
mild disease who were unlikely to 
progress to severe COVlD-19. 
Interpretation: 
• Compared to SOC, use of IVM did not 
lead to faster recovery from mild to 
moderate COVID-19. 
• The small sample size and large 
number of comparisons make it 
difficult to assess the clinical 
efficacy of IVM in this population. 
lvermectin Plus Doxycycline Versus Hyclroxychloroquine Plus Azithromycin for Asymptomatic Patients and Patients With Mild to 
Moderate COVI0-1923 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 69 of 141

Study Design 
RCT of outpatients 
with SARS-CoV-2 
infection with or 
without symptoms 
in Bangladesh (n = 
116) 
This is a preliminary 
report that has not 
yet been peer 
reviewed. 
Methods 
Key Inclusion Criteria: 
• Laboratory-confirmed SARS-
CoV-2 infection by RT-PCR 
• SpOz.!95% 
• Normal or near-normal CXR 
• No unstable comorbidities 
Interventions 
Group A: 
• A single dose of IVM 200 
µg/kg plus DOX 100 mg twice 
daily for 10 days 
GroupB: 
• HCQ 400 mg on Day 1, then 
HCQ 200 mg twice daily for 9 
days plus AZM 500 mg once 
daily for 5 days 
Primary Endpoints: 
• Time to negative PCR result. 
Asymptomatic patients were 
tested starting on Day 5, then 
every other day until a 
negative result occurred. 
Symptomatic patients were 
tested on their second 
symptom-free day, then every 
other day until a negative 
result occurred. 
• Time to resolution of 
symptoms 
Results 
Number of Participants: 
• Group A (n = 60) and Group 8 (n 
::56) 
Participant Characteristics: 
• Mean age was 33.9 years. 
• 78% of patients were male. 
• 91 of 116 patients (78.5%) were 
symptomatic. 
Outcomes: 
• PCR became negative in 60 of 
60 patients (100%) in Group A 
and in 54 of 56 patients (96.4%) 
in Group 8. 
• Mean time to negative PCR 
result: 8.93 days (range 8-13 
days) in Group A, 9.33 days 
(range 5-15 days) in Group B (P 
=0.2314). 
• Mean time to symptom 
recovery: 5.93 days (range 5-10 
days) in Group A, 6.99 days 
(range 4-12 days) in Group B (P 
=0.071). 
• In a subgroup analysis of 
patients who were symptomatic 
at baseline, the mean time to 
negative PCR result for Groups 
A and 8 were 9.06 days and 
9.74 days, respectively (P" 
0.0714). 
• Patients who received IVM plus 
DOX had fewer AEs than those 
who received HCQ plus AZM 
(31.7% VS, 46.4%) in the 
subgroup analysis. 
Antiviral Effect of High-Dose lvermectin in Adults with COVID-1924 
Multicenter, 
randomized, open• 
label, blinded trial 
of hospitalized 
adults with mild to 
moderate COVID-19 
in Argentina (n = 45) 
Key Inclusion Criteria: 
• Laboratory-confirmed SARS-
CoV-2 infection 
• Hospitalized 
• S5 days of symptoms 
Key Exclusion Criteria: 
• Use of immunomodulators or 
any agent with potential anti-
SARS-CoV-2 activity prior to 
enrollment 
Number of Participants: 
• IVM {n = 30) and SOC (n = 15) 
• After excluding patients with 
poor sample quality, those 
without a detectable VL at 
baseline, and those who 
withdrew, 32 patients (20 IVM, 
12 SOC) were included in the 
viral efficacy analysis 
population. 
Limitations and Interpretation 
Key Limitations: 
• Small sample size 
• Open-label study 
• No SOC alone group 
• Study enrolled young patients 
without major risk factors for disease 
progression. 
• None of the comparative outcome 
measures were statistically 
significant. 
Interpretation: 
• In this small study with a young 
population, the authors suggested 
that IVM plus DOX was superior to 
HCQ plus AZM despite no 
statistically significant difference in 
time from recovery to negative PCR 
result and symptom recovery 
between patients who received IVM 
plus DOX and those who received 
HCQ plus AZM. 
Key Limitations: 
• Small sample size 
• No clinical response data reported. 
• The Cmax level of 160 ng/mL used in 
the analysis appears to be arbitrary. 
Interpretation: 
• Concentration-dependent virologic 
response was seen when using a 
higher-than-usual dose of IVM (600 
µg/kg vs. 200 or 400 µg/kg once 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 70 of 141

Study Design 
Methods 
• Poorly controlled 
comorbidlties 
Interventions: 
• IVM 600 µg/kg once daily 
plus SOC for 5 days 
• soc 
Primary Endpaint: 
• VL reduction at Day 5. VL was 
quantified by NP swab at 
baseline, then at 24, 48, and 
72 hours and Day 5. 
PK Sampling: 
• Performed 4 hours after dose 
on Days 1, 2, 3, 5, and 7 to 
assess elimination 
Results 
Participant Characteristics: 
• Mean age was 42.3±12.8 years 
in IVM arm and 38.1±11.7 years 
in SOC arm. 
• 50% of patients were male in 
IVM arm and 67% were male in 
SOC arm. 
Primary Outcomes: 
• By Day 5, a similar magnitude 
of VL reduction was seen in 
both arms. 
Other Outcomes: 
• Patients with higher IVM 
concentrations had greater 
reductions in VL (r 0.44; P < 
0.04). 
• Treated patients were divided 
into 2 groups based on IVM 
Cmax: IVM >160 ng/mL (median 
of 202 ng/mL) and <160 ng/ml 
(median of 109 ng/ml). 
o Median percentage of VL 
reduction by Cmax 
concentration vs. control {P = 
0.0096) was 72% (!QR 59% 
to 77%) in >160 ng/mL group 
(n = 9), 40% (!QR 21% to 
46%) in <160 ng/mL group (n 
= 11), and 42% (IQR 31% to 
73%) in SOC arm. 
o Median viral decay rate (P = 
0.04} was 0.64 day·1 in >160 
ng/mL group, 0.14 day·1 in 
<160 ng/mL group, and 0.13 
day·1 in SOC arm. 
• Percentages of AEs were 
similar between the arms (43% 
in IVM arm, 33% in SOC arm), 
and AEs were mostly mild. 
limitations and Interpretation 
daily), with minimal associated 
toxicities. 
• The study results showed large 
interpatient variation of IVM Cmax• 
Larger sample sizes a re needed to 
further assess the safety and 
efficacy of using higher doses of IVM 
to treat COVID-19. 
Effect of Early Treatment With lvermectin Versus Placebo on Viral load, Symptoms, and Humoral Response in Patients With Mild 
COVID-1925 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 71 of 141

Study Design 
A single-center, 
randomized, double-
blind, placebo-
controlled pilot trial 
in Spain (n = 24) 
Methods 
Key inclusion Criteria: 
• Laboratory-confirmed SARS-
CoV-2 infection 
• S72 hours of symptoms 
• No risk factors for severe 
disease or COVID-19 
pneumonia 
Interventions: 
• Single dose of IVM 400 µg/kg 
• Nonmatching placebo tablet 
administered by a nurse who 
did not participate in the 
patient's care 
Primary Endpoint: 
• Positive SARS-CoV-2 PCR 
result from an NP swab at 
Day 7 post-treatment 
Results 
Number of Participants: 
• IVM (n = 12) and placebo (n = 12) 
Participant Characteristics: 
• Mean age was 26 years (range 
18-54 years). 
• 50% of patients were male. 
• All patients had symptoms at 
baseline; 70% had headache, 
66% had fever, 58% had 
malaise, and 25% had cough. 
• Median onset of symptoms was 
24 hours in IVM arm and 48 
hours in placebo arm. 
Outcomes: 
• At Day 7, 12 patients (100%) in 
both groups had a positive PCR 
(for gene N), and 11 of 12 who 
received IVM (92%) and 12 of 12 
who received placebo (100%) 
had a positive PCR (for gene E); 
P" 1.0 for both comparisons. 
• In a post hoc analysis, the 
authors reported fewer patient-
days of cough and anosmia in 
the IVM-treated patients, but no 
differences in the patient-days 
for fever, general malaise, 
headache, and nasal 
congestion. 
limitations and Interpretation 
Key !..imitations: 
• Small sample size 
• PCR is not a validated surrogate 
marker for clinical efficacy. 
• PCR cycle threshold values were 
higher for patients who received IVM 
than those who received placebo at 
some time points, but these 
comparisons are not statistically 
significant. 
• Symptom results were not a 
prespecified outcome and are of 
unclear statistical and clinical 
significance. 
Interpretation: 
• Patients who received IVM showed 
no difference in viral clearance 
compared to those who received 
placebo. 
• The small sample size and large 
number of comparisons make it 
difficult to assess the clinical 
efficacy of IVM in this population. 
lvermectin Plus Doxycycline Plus Standard Therapy Versus Standard Therapy Alone in Patients With Mild to Moderate COVID-1926 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 72 of 141

Study Design 
Randomized, 
unblinded, single-
center study of 
patients with 
laboratory-
confirmed SARS-
CoV-2 infection in 
Baghdad, Iraq (n = 
140) 
This is a preliminary 
report that has not 
yet been peer 
reviewed. 
Methods 
Key Inclusion Criteria: 
• Diagnosis by clinical, 
radiological, and PCR testing 
• Outpatients had mild or 
moderate COVID-19, while 
inpatients had severe and 
critical COVID-19. 
Interventions: 
• IVM 200 µg/kg PO daily for 2 
days. Jf patient required more 
time to recover, a third dose 
was given 7 days after the 
first dose, plus DOX 100 mg 
twice daily for 5-10 days plus 
standard therapy {based on 
clinical condition). 
• Standard therapy was based 
on clinical condition and 
included AZM, 
acetaminophen, vitamin C, 
zinc, vitamin 03, 
dexamethasone 6 mg daily or 
methylprednisolone 40 mg 
twice daily if needed, and 
oxygen or mechanical 
ventilation if needed. 
• All critically ill patients were 
assigned to receive IVM plus 
DOX. 
lvermectin in Patients With Mild to Moderate COVID-1927 
Double-blind RCT in 
patients with mild to 
moderate COVID-19 
in India (n = 157) 
Key Inclusion Criteria: 
• Aged ~18 years 
• Positive SARS-CoV-2 RT-PCR 
or antigen test 
• Nonsevere COVID-19 (defined 
as Sp02 >90% on RA and no 
hypotension or need for 
mechanical ventilation) 
Key Exclusion Criteria: 
Results 
Number of Participants: 
• IVM plus DOX plus standard 
therapy (n = 70} and standard 
therapy alone (n = 70) 
Participant Characteristics: 
• Median age was 50 years in IVM 
arm and 47 years in standard 
therapy arm. 
• 50% of patients were male in 
IVM arm and 53% were male in 
standard therapy arm. 
• In IVM arm, 48 patients had 
mild or moderate COVID-19, 11 
had severe COVID-19, and 11 
had critical COV!D-19. 
• In standard therapy arm, 48 
patients had mild or moderate 
COVID-19, 22 had severe 
COVID-19, and no patients had 
critical COVID-19. 
Outcomes: 
• Mean recovery time in IVM arm 
was 10.1 days (SD 5.3 days) vs. 
17.9 days (SD 6.8 days) for 
standard therapy arm (P < 
0.0001). This result was only 
significant for those with mild 
to moderate disease. 
• Disease progression occurred in 
3 of 70 patients (4.3%) in IVM 
arm and 7 of 70 (10.0%) in 
standard therapy arm {P = 0.19) 
• 2 of 70 patients (2.85%) in JVM 
arm and 6 of 70 (8.57%) in 
standard therapy arm died (P = 
0.14) 
Number of Participants: 
• ITT analysis (safety): IVM 24 mg 
{n = 51), IVM 12 mg (n = 49), and 
placebo {n "' 52) 
• mlTT analysis (included only 
those with positive NP/OP RT• 
PCR result): IVM 24 mg (n = 40), 
lVM 12 mg (n = 40), and placebo 
(n=45) 
Limitations and Interpretation 
Key limitations: 
• Notblinded 
• Patient deaths prevent an accurate 
comparison of mean recovery time 
between arms in this study, and the 
authors did not account for 
competing mortality risks. 
• Relies heavily on post hoc subgroup 
comparisons. 
• Substantial imbalance in disease 
severity at baseline 
• Authors noted that critical patients 
were not assigned to standard 
therapy arm; thus, the arms were not 
truly randomized. 
• Unclear how many patients required 
corticosteroids. 
Interpretation: 
• IVM may shorten the time to recovery 
for patients with mild or moderate 
disease, but the lack of control for 
competing mortality causes in the 
study limits the ability to interpret 
the results. 
Key limitations: 
• Small sample size 
Interpretation: 
• Though the rate of negative RT-PCR 
results was numerically higher in the 
!VM arms than in the placebo arm on 
Day 5, the result was not statistically 
significant. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 73 of 141

Study Design 
• CrCl <3°t&YJB!fs 
• Transaminases >5 times ULN 
• Ml or heart failure in previous 
90 days 
• QTc interval >450 ms 
• Severe comorbidity 
Interventions 
• Single dose of IVM 24 mg in 
alcohol-based elixir prepared 
by pharmacy 
• Single dose of same elixir 
with IVM 12 mg 
• Single dose of same elixir 
without lVM (placebo) 
Primary Endpoint: 
• Reduction of SARS-CoV-2 VL 
as measured by NP and OP 
swab at Day5 
• Conversion to negative RT-
PCR at Day5 
Key Secondary Endpoints; 
• Qualitative and quantitative 
RT-PCR on Days 3 and 7 
• Time to cUnical resolution 
• Frequency of clinical 
worsening 
• Clinical status at Day 14 
• Number of hospital-free days 
at Day 28 
Results 
• 64% of patients had mild 
disease (including 
asymptomatic disease) and 
36% had moderate disease 
Participant Characteristics: 
• Mean age was 35.5 years (SD 
10.4 years). 
• 88.8% of patients were male. 
• Mean BMI was 25. 
• Median duration of symptoms 
was similar between the arms 
(5 days; IQR 3-7 days). 
• 10% of patients received 
concurrent antivirals (RDV. 
favipiravir, or HCQ). No 
difference in use of antivi rats 
between arms. 
Primary Outcomes: 
• Proportion of patients with 
negative RT-PCR result on Day 
5: 47.5% in IVM 24 mg arm, 
35.0% in IVM 12 mg arm, and 
31.1% in placebo arm (P = 0.30) 
• VL at enrollment did not impact 
conversion to negative RT-PCR 
on Day 5. 
• No significant difference in VL 
decline by Day 5 between the 
arms 
• No difference in VL decline in 
the mild or moderate disease 
strata at Day 5 
Secondary Outcomes: 
• No difference between arms in 
mean time to symptom 
resolution or number of 
hospital-free days at Day 28 
• Proportions of patients with 
clinical worsening were similar 
across the arms: 7.5% in IVM 24 
mg arm, 5.0% in IVM 12 mg arm, 
and 11.1% in placebo arm (P = 
0.65) 
• No difference between arms in 
frequency of A Es or SAEs 
Efficacy and Safety of lvermectin and Hydroxych!oroquine in Patients With Severe COVI0-1928 
Limitations and Interpretation 
• No difference in clinical outcomes or 
frequency of AEs. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 74 of 141

Study Design 
Randomized, 
double-blind trial of 
hospitalized adults 
with COVID-19 
pneumonia in 
Mexico (n = 106) 
This is a preliminary 
report that has not 
yet been peer 
reviewed. 
Methods 
Key Inclusion Criteria: 
• laboratory-confirmed SARS-
CoV-2 infection 
• Pneumonia, diagnosed by 
CXR or high-resolution chest 
CT scan 
• Recently established 
hypoxemic respiratory failure 
or deterioration of pre-
existing lung or heart disease 
Key Exclusion Criteria: 
• Receipt of HFNC oxygen or 
invasive mechanical 
ventilation 
• Patients with QT intervals 
~soo ms were not eligible tor 
HCQ but were eligible for 
IVM. 
Interventions: 
• HCQ 400 mg twice daily on 
Day 1, then HCQ 200 mg/kg 
twice dally for 4 days 
• Single dose of IVM 12 mg (in 
patients weighing ,s80 kg) or 
18 mg (in those weighing >80 
kg) plus calcium citrate for 
subsequent doses 
• Calcium citrate placebo 
Primary Endpoint: 
• Time to discharge due to 
recovery 
Results 
Number of Participants: 
• HCQ (n = 33), IVM {n = 36), and 
placebo (n = 37) 
Participant Characteristics: 
• Mean age was 53 years {SD 16.9 
years). 
• 62% of patients were male. 
• 34% of patients had diabetes, 
32% had hypertension, and 
72% had any comorbidity. 
• Mean BMI was 29.6 (SD 6.6). 
Outcomes: 
• Median time to discharge due 
to recovery was 7 days (IQR 3-9 
days) in HCQ arm, 6 days {IQR 
4-11 days) in IVM arm, and 5 
days {!QR 4-7 days) in placebo 
arm. The differences between 
arms were not statistically 
significant. 
• Proportion of patients 
discharged alive: 79% in HCQ 
arm, 75% in IVM arm, and 73% 
in placebo arm 
• Mortality: 6% of patients in 
HCQ arm, 14% in IVM arm, and 
16% in placebo arm 
lvermectin as Adjunctive Therapy to Hospitalized Patients With COVID-1929 
limitations and Interpretation 
Key Limitations: 
• Smallstudy 
• length of follow-up period is unclear. 
• The study was stopped prior to 
achieving its target sample size. 
Interpretation: 
• In hospitalized patients with COVID-
19 pneumonia who were not critically 
ill, neither IVM nor HCQ decreased 
the number of in-hospital days, rate 
of respiratory deterioration, or 
mortality. 
• The small sample size and large 
number of comparisons make it 
difficult to assess the clinical 
efficacy of IVM in this population. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 75 of 141

Study Design 
Randomized, 
double-blind, 
placebo-controlled, 
multicenter, Phase 2 
clinical trial of 
hospitalized adults 
with mild to severe 
SARS-CoV-2 
infection in 5 
facilities in Iran (n = 
180) 
This is a preliminary 
report that has not 
yet been peer 
reviewed. 
Methods 
Key Inclusion Criteria: 
• Symptoms suggestive of 
COVID-19 pneumonia, with 
chest CT compatible with 
mild to severe COVID-19 or 
positive RT-PCR result for 
SARS-CoV-2 
Key Exclusion Criteria: 
• Severe immunosuppression, 
malignancy, or chronic kidney 
disease 
• Pregnancy 
Interventions: 
• HCQ 200 mg/kg twice daily 
alone as SOC (standard arm} 
• SOC plus 1 of the following: 
o Placebo 
o Single dose of IVM 200 
µg/kg 
o IVM 200 µg/kg on Days 1, 
3,and 5 
o Single dose of IVM 400 
µg/kg 
o IVM 400 µg/kg on Day 1, 
then IVM 200 µg/kg on 
Days 3and 5 
Primary Endpoint: 
• Clinical recovery within 45 
days of enrollment (defined 
as normal temperature, 
respiratory rate, and Sp02 
>94% for 24 hours) 
Results 
Number of Participants: 
• All 6 arms (n = 30 in each arm) 
Participant Characteristics: 
• Average age was 56 years 
{range 45-67 years). 
• 50% of patients were mate. 
• Disease stratification (based on 
CT findings): negative (1%), mild 
{14%), moderate (73%), and 
severe (12%) 
• Mean SpOg at baseline was 
89%. 
Primary Outcomes: 
• Durations of hypoxemia and 
hospitalization were shorter in 
IVM arms than placebo arm (P = 
0.025 and P = 0.006, 
respectively), and mortality was 
tower in the IVM arms {P= 
0.001). 
• There was no difference in 
number of days of tachypnea {P 
= 0.584) or return to normal 
temperature (P = 0.102). 
• Significant differences in 
change from baseline to Day 5 
in absolute lymphocyte count, 
platelet count, erythrocyte 
sedimentation rate, and CRP. 
• Higher mortality was reported 
in standard and placebo arms 
than IVM arms. 
Retrospective Analysis of lvermectin in Hospitalized Patients With COVID-1930 
Limitations and Interpretation 
Key Limitations: 
• Small study 
• Power estimation is confusing. 
• Mortality was not listed as the 
primary or secondary outcome. 
• It is unclear whether IVM patients 
also received HCQ. 
• It is unclear whether the between-
group comparisons are between 
combined IVM groups and placebo 
plus SOC. 
• Patients were stratified by disease 
severity based on CT findings. These 
categorizations are unclear and were 
not taken into account in outcome 
comparisons. 
• The post hoc grouping of randomized 
arms raises risk of false positive 
findings. 
Interpretation: 
• IVM appeared to improve laboratory 
outcomes and some clinical 
outcomes (shorter duration of 
hypoxemia and hospitalization) and 
lowered mortality. 
• The small size of the study, the 
unclear treatment arm assignments, 
and the lack of accounting for 
disease severity at baseline make it 
difficult to draw conclusions about 
the efficacy of using IVM to treat 
patients with mild COVID-19. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 76 of 141

Study Design 
Retrospective 
analysis of 
consecutive 
patients with 
laboratory-
confirmed SARS-
CoV-2 infection who 
were admitted to 4 
Florida hospitals (n 
=276) 
Methods 
Key Inclusion Criteria: 
• Positive NP swab with SARS-
CoV-2 RNA 
Interventions: 
• Single dose of IVM 200 
µg/kg, repeated on Day 7 at 
the doctors' discretion; 90% 
of patients also received 
HCQ. 
• Usual care: 97% of patients 
received HCQ and most also 
received AZM. 
Primary Endpoint: 
• All-cause, in-hospital 
mortality 
Results 
Number of Participants: 
• IVM (n = 173; 160 patients 
received a single dose, 13 
patients received a second 
dose) and usual care (n = 103) 
Participant Characteristics: 
• Mean age was 60.2 years in IVM 
arm and 58.6 years in usual 
care arm. 
• 51.4% of patients were mate in 
IVM arm and 58.8% were male 
in usual care arm. 
• 56.6% of patients were Black in 
lVM arm and 51.4% were Black 
in usual care arm. 
Outcomes: 
• All-cause mortality was lower in 
IVM arm than in usual care arm 
(OR 0.27; 95% Cl, 0.09-0.80; P 
= 0.03); the benefit appeared to 
be limited to the subgroup of 
patients with severe disease. 
• No difference in median length 
of hospital stay between arms 
{7 days for both) or proportion 
of mechanically ventilated 
patients who were successfully 
extubated (36% in IVM arm vs. 
15% in usual care arm: P = 0.07). 
Limitations and Interpretation 
Key Limitations: 
• Not randomized 
• Little to no information on Sp02 or 
radiographic findings 
• Timing of therapeutic interventions 
was not standardized. 
• Ventilation and hospitalization 
duration analyses do not appear to 
account for death as a competing 
risk. 
• No virologic assessments were 
performed. 
Interpretation: 
• IVM use was associated with lower 
mortality than usual care. However, 
the limitations of this retrospective 
analysis make it difficult to draw 
conclusions about the efficacy of 
using IVM to treat patients with 
COVID-19. 
Observational Study on the Effectiveness of Hydroxychloroquine, Azithromycln, and lvermectin Among Hospitalized Patients With 
COVID-1931 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 77 of 141

Study Design 
Retrospective 
cohort study of 
hospitalized adults 
with COVID-19 in 
Peru (n = 5,683) 
This is a preliminary 
report that has not 
yet been peer 
reviewed. 
Methods 
Key Inclusion Criteria: 
• Aged ~18 years 
• Symptomatic 
• Laboratory-confirmed SARS-
CoV-2 infection 
• No life-threatening illness at 
admission 
Key Exclusion Criteria: 
• Required oxygen at 
admission 
• Use of tocilizumab, LPV /RTV, 
orRDV 
Interventions: 
• One of the following 
interventions administered 
within 48 hours of admission: 
o HCQ or CQ alone 
o IVM alone 
o AZM alone 
o HCQ or CQ plus AZM 
o IVM plus AZM 
o SOC (e.g., supportive care, 
antipyretics, hydration) 
Primary Endpoint: 
• AU-cause mortality 
Secondary Endpoint: 
• All-cause mortality and/or 
transfer to ICU 
Results 
Number of Participants: 
• HCQ or CQ alone (n = 200), IVM 
alone (n = 203), AZM alone (n = 
1,600), HCQ or CQ plus AZM (n = 
692), IVM plus AZM (n = 358), 
and SOC (n = 2,630) 
Participant Characteristics: 
• 63% of patients were male. 
• Mean age was 59.4 years 
(range 18-104 years). 
• All patients had mild or 
moderate disease. 
Outcomes: 
• Median follow-up time was 7 
days. Mortality rate was 18.9% 
at the end of follow-up. 
• IVM alone was associated with 
increased risk of death and/or 
ICU transfer compared to SOC 
(wHR 1.58; 95% Cl, 1.11-2.25). 
• IVM plus AZM did not have an 
effect on deaths or any 
secondary outcomes (all-cause 
death and/or ICU transfer, all• 
cause death and/or oxygen 
prescription) compared to SOC. 
• HCQ or CQ plus AZM was 
associated with a higher risk of 
death (wHR 1.84; 95% Cl, 1.12-
3.02), death and/or ICU transfer 
(wHR 1.49; 95% Cl, 1.01-2.19), 
and death and/or oxygen 
prescription (wHR 1.70; 95% Cl, 
1.07-2.69) compared to SOC. 
Retrospective Study of lvermectin Versus Standard of Care in Patients With COVI0-1932 
limitations and Interpretation 
Key I.imitations: 
• Not randomized 
• Unclear whether all patients received 
IVM or other medications according 
to Peruvian guidelines referred to in 
the manuscript. 
• Dosing and timing of administration 
are unclear. 
Interpretation: 
• Compared to SOC, IVM alone was 
associated with increased risk of 
death and/or ICU admission. Using 
IVM in combination with AZM was 
not associated with effects on 
mortality, ICU transfer, or oxygen 
prescription compared to SOC. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 78 of 141

Study Design 
Retrospective study 
of consecutive adult 
patients 
hospitalized in 
Bangladesh with 
laboratory-
confirmed SARS· 
CoV-2 infection (n = 
248) 
This is a preliminary 
report that has not 
yet been peer• 
reviewed. 
Methods 
Key Inclusion Criteria: 
• Aged ~18 years 
• Positive NP swab with SARS· 
CoV-2 RNA 
• "Free from any other serious 
pathological conditions" 
Interventions: 
• Single dose of IVM 12 mg 
within 24 hours of hospital 
admission 
• soc 
Primary Endpoint: 
• Not specified 
Results 
Number of Participants: 
• NM {n = 115) and SOC (n = 133) 
Participant Characteristics: 
• Median age in IVM arm was 34 
years; 70% of patients were 
male. 
• Median age in SOC arm was 35 
years; 52% of patients were 
male. 
• All patients had mild or 
moderate disease . 
• 12% of patients had 
hypertension in both arms. 
• 17% of patients in IVM arm and 
12% in SOC arm had DM. 
Outcomes: 
• Fewer patients in IVM arm had 
evidence of disease progression 
compared to SOC arm (P < 
0.001): moderate respiratory 
distress (2.6% vs. 15.8%), 
pneumonia (0% vs. 9.8%), 
ischemic stroke (0% vs. 1.5%). 
• Fewer patients in IVM arm 
required intensive care 
management compared to SOC 
arm (0.9% vs. 8.8%; P < 0.001). 
• Fewer patients in IVM arm 
required antibiotic therapy 
(15.7% vs. 60.2%; P < 0.001) or 
supplemental oxygen (9.6% vs. 
45.9%; P < 0.001) compared to 
SOC arm. 
• Shorter median duration of viral 
clearance in IVM arm compared 
to SOC arm (4 vs. 15 days; P < 
0.001). 
• Shorter median duration of 
hospital stay in IVM arm 
compared to SOC arm (9 vs. 15 
days; P < 0.001) 
• Lower mortality in IVM arm 
compared to SOC arm (0.9% vs. 
6.8%; P < 0.05) 
limitations and Interpretation 
Key limitations: 
• Not randomized 
• Disease severity at admission was 
reported as mild or moderate, but 
12% of patients in lVM arm and 9% in 
SOC arm had Sp02 <94% 
• Even though only 10% of patients 
developed pneumonia, 60% received 
antibiotics. 
• Possibility of harm from concomitant 
medications 
Interpretation: 
• Compared to SOC, IVM use was 
associated with faster rates of viral 
clearance and better clinical 
outcomes, including shorter hospital 
stay and lower mortality. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 79 of 141

Study Design 
Methods 
Results 
limitations and Interpretation 
Key: AE = adverse event; AZM = azithromycin; BM!= body mass index; CAD= coronary artery disease; Cmax = maximum concentration; CQ 
= chloroquine; CrCI = creatinine clearance; CRP = C-reactive protein; CT= computed tomography; CXR = chest X-ray; CYP = cytochrome 
P450; DM = diabetes mellitus; DOX = doxycycline; HCQ"' hydroxychloroquine; HFNG = high-flow nasal cannula; HTN = hypertension; ICU 
= intensive care unit; lg= immunoglobulin; ITT= intention-to-treat; !VM = ivermectin; LDH = lactose dehydrogenase; LPV/RTV = 
lopinavir/ritonavir; MDR1 = multidrug resistance mutation 1; Ml= myocardial infarction; mlTT = modified intention-to-treat; NP= 
nasopharyngeal; OP= oropharyngeal; the Panel= the COVID-19 Treatment Guidelines Panel; Pa02/Fi02 = ratio of arterial partial pressure 
of oxygen to fraction of inspired oxygen; PCR = polymerase chain reaction; PK = pharmacokinetic; PO= orally; r"" correlation coefficient; 
RA= room air; RCT = randomized controlled trial; RDV = remdesivir; RT-PCR = reverse transcriptase polymerase chain reaction; SAE= 
severe adverse event; SNP = single-nucleotide polymorphism; SOC= standard of care; SOFA - sequential organ failure assessment; Sp02 
= oxygen saturation; ULN = upper limit of normal; VL = viral load 
www.covid19trnatmentguide1ines.nih.gov 
An official website of the N<!tigm1l ln§titutes gf Heeltb 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 80 of 141

Q)Cochrane 
Trusted evidence. 
informed decisions. 
Better health. 
lvermectin for preventing and treating COVID-19 
0:00 J 4:39 
Is ivermectin effective for COVH>-191 
Key messages 
We found no evidence to support the use of ivermectin for treating or preventing COVID-19 infection, but the 
evidence base is limited. 
Evaluation of ivermectin is continuing in 31 ongoing studies, and we will update this review with their results 
when they become available. 
What is ivermectin? 
lvermectin is a medicine used to treat parasites such as intestinal parasites in animals and scabies in humans. It is 
cheap and is widely used in regions of the world where parasitic infestations are common. It has few unwanted 
effects. 
Tests in the laboratory show ivermectin can slow the reproduction of the COVID-19 {SARS-CoV-2) virus but such 
effects would need major doses in humans. Medical regulators have not approved ivermectin for COVID-19. It 
should only be used as part of well-designed studies (called randomized controlled trials) evaluating potential 
effects. 
What did we want to find out? 
We wanted to know if ivermectin reduces death, illness, and length of infection in people with COVID-19, or is 
useful in prevention of the disease. We included studies comparing the medicine to placebo (dummy treatment), 
no treatment, usual care, or treatments for COVID-19 that are known to work to some extent, such as remdesivir 
EXHIBITK 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 81 of 141

or dexamethasone. We excluded studies that compared ivermectin to other drugs that do not work, such as 
hydroxychloroquine, or that are not known to be effective against COVID-19. 
We evaluated the effects of ivermectin in infected people on: 
- people dying; 
- whether people's COV!D-19 symptoms got better or worse; 
- unwanted effects; 
- hospital admission or time in hospital; 
- viral clearance. 
For prevention, we sought the effect on preventing COVID-19 and SARS-CoV-2 infection. 
What did we do? 
We searched for randomized controlled trials that investigated ivermectin to prevent or treat COVID-19 in 
humans. People being treated with ivermectin had to have laboratory-test confirmed COVID-19 and be receiving 
treatment in hospital or as outpatients. 
We compared and summarized the results of the studies and rated our confidence in the evidence, based on 
common criteria as to how reliable the evidence is. 
What did we find? 
We found 14 studies with 1678 participants that investigated ivermectin compared to no treatment, placebo, or 
usual care. 
For treatment, there were nine studies of people with moderate COVID-19 in hospital and four of outpatients with 
mild COVID-19. The studies used different doses of ivermectin and different durations of treatment. 
One study investigated ivermectin to prevent COVID-19. 
We also found 31 ongoing studies, and there are 18 studies still requiring clarification from the authors or not yet 
published. 
Main results 
Treating people in hospital with COVID-19 
We don't know whether ivermectin compared with placebo or usual care, 28 days after treatment: 
- leads to more or fewer deaths (2 studies, 185 people); 
- worsens or improves patients' condition assessed by need for ventilation (2 studies, 185 people) or oxygen (1 
study, 45 people); 
- increases or reduces unwanted events (1 study, 152 people). 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 82 of 141

Seven days after treatment, we don't know if ivermectin: 
- increases or reduces negative COV!D-19 tests (2 studies, 159 people). 
lvermectin compared to placebo or usual care may make little or no difference to improving patients' condition 
28 days after treatment (1 study, 73 people) or to length of hospital stay (1 study, 45 people). 
Treating outpatients with COVID-19 
We don't know whether ivermectin compared with placebo or usual care: 
- leads to more or fewer deaths 28 days after treatment (2 studies, 422 people); 
- worsens or improves patients' condition 14 days after treatment assessed by need for ventilation (1 study, 398 
people); 
- increases or reduces negative COVID-19 tests seven days after treatment (1 study, 24 people}. 
lvermectin compared to placebo or usual care may make little or no difference to improving outpatients' 
condition 14 days after treatment (1 study, 398 people) or to the number of unwanted events 28 days after 
treatment (2 studies, 422 people). 
No studies looked at hospital admissions in outpatients. 
Preventing COVll)-19 
We don't know whether ivermectin leads to more or fewer deaths compared with no drug (1 study, 304 people); 
no participant died 28 days after the drug. This study reported results for development of COVID-19 symptoms 
(but not confirmed SARS-CoV-2 infection) and unwanted events, but in a way that we could not include in our 
analyses. This study did not look at hospital admissions. 
What are the limitations of the evidence? 
Our confidence in the evidence is very low because we could only include 14 studies with few participants and 
few events, such as deaths or need for ventilation. The methods differed between studies, and they did not report 
everything we were interested in, such as quality of life. 
How up to date is this evidence? 
The evidence is up to date to 26 May 2021. 
Authors' conclusions: 
Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of 
ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 83 of 141

quality. Several studies are underway that may produce dearer answers in review updates. Overall, the 
reliable evidence available does not support the use of ivermectin for treatment or prevention of COVID-19 
outside of well-designed randomized trials. 
Background: 
lvermectin, an anti parasitic agent used to treat parasitic infestations, inhibits the replication of viruses in 
vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on 
severe acute respiratory syndrome coronavirus 2 {SARS-CoV-2) replication in the early stages of 
infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection 
and COVID-19 treatment is conflicting. 
Objectives: 
To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any 
other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for 
prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). 
Search strategy: 
We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science 
Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without 
language restrictions to 26 May 2021. 
Selection criteria: 
We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, 
placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, 
irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 
infection. 
Co-interventions had to be the same in both study arms. 
We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 84 of 141

Data coHection and analysis: 
We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with 
high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes l. to treat 
inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse 
events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild 
COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of 
life, and viral clearance; {3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 
symptoms, adverse events, mortality, admission to hospital, and quality of life. 
Main results: 
We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or 
standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine 
studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 
cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight 
studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results 
contributed by included studies, about one third were at overall high risk of bias. 
lvermectin doses and treatment duration varied among included studies. 
We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of 
inconsistencies. 
lvermectin compared to placebo or standard of care for inpatient COVID-19 treatment 
We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases 
mortality (risk ratio (RR) 0.60, 95% confidence interval (Cl) 0.14 to 2.51; 2 studies, 185 participants; very low-
certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation 
(IMV) (RR 0.55, 95% Cl 0.11 to 2.59; 2 studies, 185 participants; very tow-certainty evidence) or need for 
supplemental oxygen (O participants required supplemental oxygen; 1 study, 45 participants; very low-
certainty evidence), adverse events within 28 days {RR 1.21, 95% Cl 0.50 to 2.97; 1 study, 152 participants; 
very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% Cl 0.51 to 6.48; 2 studies, 159 
participants; very low-certainty evidence). lvermectin may have little or no effect compared to placebo or 
standard of care on clinical improvement up to 28 days (RR 1.03, 95% Cl 0.78 to 1.35; 1 study; 73 participants; 
low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% Cl -2.43 to 
2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. 
lvermectin compared to placebo or standard of care for outpatient covm~19 treatment 
We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases 
mortality up to 28 days (RR 0.33, 95% Cl 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 85 of 141

and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% Cl 0.12 to 72.47; 1 study, 398 
participants; very low-certainty evidence) or non-lMV or high flow oxygen requirement (0 participants 
required non-lMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain 
whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% C! 
0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). lvermectin may have little or no effect 
compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 
days (RR 1.04, 95% Cl 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events 
within 28 days (RR 0.95, 95% Cl 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the 
studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital 
admission or quality of life up to 14 days. 
ivermedin compared to no treatment for prevention of SARS-CoV~l infection 
We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are 
uncertain whether ivermectin reduces or increases mortality compared to no treatment (O participants died; 
l study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-
19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of 
bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. 
Share 
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J=HTTPS%3A%2F%2FWWW .. COCHRANE.ORG%2FCDOJ50.17%2FHAEMATOL_LVERMECTIN-
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30DY=HTTPS;3/g3A%~F%2FWWW.COJ;HRANE0 0RG¾._2FCD015017%2FHAEMATOL_LVERMECTIN-
PREVENTING-AND-TREATING-COVID-19) 
Published: 
28July2021 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 86 of 141

Authors: 
Popp M, Stegemann M, Metzendorf M-I, Gould S, Kranke P, Meybohm P, Skoetz N, Weibel S 
Primary Review Group: 
HaematoJQgyjjrquQ..(httR..s;//haematojogy»:ochrartE!&rg), tnfectiousDiseasesJ:)rouR (https:lLcidg.cochraJ)e.org) 
Popp M, Stegemann M, Metzendorf M-I, Gould S, Kranke P, Meybohm P, Skoetz N, Weibel S. lvermectin for preventing and treating 
COVID-19. Cochrane Database of Systematic Reviews 2021, Issue 7. Art. No.: CD015017. DOI: 10.1002/14651858.CD015017.pub2. 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 87 of 141

# 
Explore 
© Settings 
~ 
Tweet 
Our meta-analysis of survival for ivermectin had to be 
retracted after one of the main studies was suspected 
of medical fraud. With the revised version, there is no 
statistically significant survival benefit for ivermectin. 
So the original version should not be quoted 
318 
2,152 
EXHIBITL 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 88 of 141

Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection 
Andrew Hi111, Anna Garratt2, Jacob Levi3, Jonathan Falconer4, Leah Ellis5, Kaitlyn McCann5, 
Victoria Pilkington6, Ambar Qavi5, Junzheng Wang5, Hannah Wentzel5 
1. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, L 7 
3NY, UK 
2. Department of Infectious Diseases, University Hospital of Wales, Cardiff and Vale 
University Health Board, UK 
3. Department of Intensive Care, University College London Hospital, ULCH NHS Trust, 
London, UK 
4. Department of Infectious Diseases, Chelsea and Westminster Hospital, Imperial NHS 
Trust, London, UK 
5. Faculty of Medicine, Imperial College London, UK 
6. Oxford University Clinical Academic Graduate School, University of Oxford, UK 
Corresponding author: 
Dr Andrew Hill PhD 
Department of Pharmacology and Therapeutics 
University of Liverpool, 
70 Pembroke Place 
Liverpool L69 3GF, UK 
Email: microhaart@aol.com 
© The Author(s) 2021. Published by Oxford University Press on behalf ofinfectious 
Diseases Society of America. 
This is an Open Access article distributed under the terms of the Creative Commons 
Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-
nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any 
medium, provided the original work is not altered or transformed in any way, and that the 
work is properly cited. For commercial re-use, please contact joumals.permissions@oup.com 
EXHIBITM 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 89 of 141

Abstract 
lvermectin is an antiparasitic drug being investigated for repurposing against SARS-CoV-2. 
lvermectin showed in-vitro activity against SARS-COV-2 at high concentrations. This meta-
analysis investigated ivermectin in 24 randomized clinical trials (3328 patients) identified 
through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. lvermectin 
was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) 
and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-
dependent In 11 randomized trials of moderate/severe infection, there was a 56% reduction 
in mortality (Relative Risk 0.44 [95%C! 0.25-0.77); p=0.004; 35/1064 (3%) deaths on 
ivermectin; 93/1063 (9%) deaths in controls) with favorable clinical recovery and reduced 
hospitalization. Many studies included were not peer reviewed and a wide range of doses 
were evaluated. Currently, WHO recommends the use of ivermectin only inside clinical trials. 
A network of large clinical trials is in progress to validate the results seen to date. 
Keywords: SARS-CoV2, COVID-19, lvermectin, Repurposed 
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Introduction 
The SARS-CoV-2 pandemic continues to grow, with over 350,000 new infections and over 
7,000 deaths recorded worldwide daily in May 2021 [1]. Protective vaccines have been 
developed, but current supplies are too low to cover worldwide demand in the coming 
months [2]. Researchers worldwide are urgently looking for interventions to prevent new 
infections, or prevent disease progression, and lessen disease severity for those already 
infected. 
While research on new therapeutic agents for COVID-19 is key, there is also great interest in 
evaluating the potential of already existing medicines against COVID-19, and many clinical 
trials are in progress to 're-purpose' drugs normally indicated for other diseases. The known 
safety profiles, shortened development timelines, and well-established markets (with low 
price points and higher capacity to deliver at scale} for most of the already existing 
compounds proposed for COVID-19 are particularly advantageous compared to new drug 
discovery in a pandemic situation. Three re-purposed anti-inflammatory drugs have shown 
significant survival benefits to date: the corticqsteroid dexamethasone in the UK 
RECOVERY trial [3], and the lnterleukin-6 (fl-6) receptor antagonist drugs, tocilizumab and 
sarilumab, in the REMAP-CAP trial and RECOVERY trial [4,5]. Other re-purposed 
antimicrobials such as, hydroxychloroquine, lopinavir/ritonavir, rerndesivir and interferon-
beta, have shown no significantsurvival benefit in two large, randomized trials [3, 6] despite 
initial reports of efficacy, underscoring the need for caution when interpreting early clinical 
trial data. 
Dexamethasone is recommended for use by the WHO and has proven survival benefits for 
oxygen-dependent patients with COVID-19, while tocilizumab and sarilumab improve 
survival for patients in intensive care [3, 4]. Preliminary data suggest that nitazoxanide and 
budesonide may have a role in mild infection {7,8]. However, there are no approved 
treatments for patients with mild SARS-CoV-2 infection, either to prevent disease 
progression or reduce viral transmission. Treatments increasing viral clearance rate may 
reduce the risk of onward transmission but this requires empirical demonstration. 
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lvermectin is a well-established anti-parasitic drug used worldwide for a broad number of 
parasites and also for topical use against rosacea. Antiviral activity of ivermectin has been 
demonstrated recently for SARS-CoV-2 in Vero/hSLAM cells [9J. However, concentrations 
required to inhibit viral replication in-vitro (EC50=2.2 - 2.8µM; EC90=4.4µM) are not achieved 
systemically after oral administration of the drug to humans [9, 10]. 
The drug is estimated to accumulate in lung tissues (2.67 times that of plasma} [11J, but this 
is also unlikely to be sufficient to maintain target concentrations for pulmonary antiviral 
activity [10, 12]. Notwithstanding, ivermectin is usually present as a mixture of two agents 
and although mainly excreted unchanged in humans, has two major metabotites{13]. 
Current data are insufficient to determine whether the minor form or a circutating metabolite 
has higher direct potency against SARS-CoV-2, but it seems likely that it would need to be 
profoundly more potent than the reported values. 
lvermectin has also demonstrated immunomodulatory and anti-inflammatory mechanisms of 
action in preclinical models of several other indications. In-vitro studies have demonstrated 
that ivermectin suppresses production ofthe inflammatory mediators nitric oxide and 
prostaglandin E2 [14]. Furthermore, avermectin (from which ivermectin is derived) 
significantly impairs pro-inflammatory cytokine secretion (IL-1(3 and TNF-a) and increases 
secretion of the immunoreguiatory cytokine IL-10 [15]. lvermectln also reduced TNF-a, IL-1, 
and IL-6, and improved sutvivalin mice given a lethal dose of lipopolysaccharide [16]. 
Preclinical evidence to support these immunomodulatory and anti-inflammatory mechanisms 
of action have also been generated in murine models [17, 18]. Finally, in Syrian golden 
hamsters infected with SARS-CoV-2, subcutaneous ivermectin demonstrated a reduction in 
the IL-6/IL~10 ratio in lung tissues. In this study, ivermectin also prevented pathological 
deterioration [19]. Ultimately, various potential mechanisms of action for ivermectin against 
COV!D19 exist and are undergoing further investigation, as recently summarised in a review 
article {20]. 
At standard doses, of 0.2-0.4mg/kg for 1-2 days, ivermectin has a good safety profile and 
has been distributed to billions of patients worldwide in mass drug administration programs. 
A recent meta-analysis found no significant difference in adverse events in those given 
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higher doses of ivermectin, of up to 2mg/kg, and those receiving longer courses, of up to 4 
days, compared to those receiving standard doses (21]. lvermectin is not licensed for 
pregnant or breast-feeding women, or children <15kg. The WHO Guidelines Group found 
that in 16 RCTs with 2407 participants ivermectin improved mortality outcomes compared 
with control but rated the quality of available evidence as low or very low [22]. Currently, the 
WHO does not recommend the use of ivermectin outside clinical trials. 
The objective of this systematic review and meta-analysis was to combine available results 
from new published or unpublished randomized trials of ivermectin in SARS-CoV-2. infection 
to inform current guidelines. 
Methods 
The systematic review and meta-analysis was conducted according to PRISMA guidelines. 
A systematic search of PUBMED and EMBASE was conducted to identify randomized 
control trials (RCTs) evaluating treatment with ivermectin for SARS-CoV-2 infected 
patients. Clinical trials with no control arm, or those evaluating prevention of infection were 
excluded alongside non-randomized trials and case-control studies. Key data extracted 
included baseline characteristics (age, sex, weight, oxygen saturation, stage of infection), 
changes in inflammatory markers, viral suppression after treatment, clinical recovery, 
hospitalization and survival. Data were extracted and cross-checked by two independent 
reviewers (HW and LE). 
Search strategy and selection criteria 
RCTs were eligible for inclusion if they compared an ivermectln-based regimen with a 
comparator or standard of care (SOC) for the treatment of SARS-CoV-2 infection. PRISMA 
checklist, PRISMA flow diagram, the search terms, and inclusion/exclusion criteria used are 
detailed in Supplementary Figure 1, Supplementary Tables 1, 2 and 3. 
Registry databases were searched up until the 12th of May 2021. Clinicaltrials.gov [23] was 
searched using key words COVID, SARS-CoV-2 and ivermectin to identify studies. The 
WHO International Clinical Trials Registry Platform (ICTRP) was accessed via the COVID-
NMA Initiative's mapping tool (24] and Stanford University's Coronavirus Antiviral Research 
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Database (CoV-RDB) [25} to identify additional trials listed on other national, and 
international registries. literature searches via PubMed, Embase, and the preprint servers 
MedRxiv and Researchsquare were conducted to identity published studies. Duplicate 
registrations, non-randomised studies and prevention studies were excluded following 
discussion between the authors. 
Additionally, the research teams conducting unpublished clinical trials were contacted and 
requested to join regular international team meetings from December 2020 to May 2021. All 
results available from eligible unpublished studies were also included in this systematic 
review. 
All of the clinical trials included in this meta-analysis were approved by local ethics 
committees and all patients gave Informed consent. 
The primary outcome was all-cause mortality from randomization to the end of follow-up. 
Secondary outcomes included time to viral clearance, PCR negativity at day 7, clinical 
recovery, time to clinical recovery, mechanical ventilation, duration of hospitalization and 
number of hospitalizations. Changes in inflammatory markers, viral suppression, clinical 
recovery and hospitalization were also summarized tor individual trials where endpoints 
could not be combined. 
Data analysis 
Statistical analyses for all-cause mortality, time to viral clearance and clinical recovery were 
conducted using published data summaries. For the mortality outcome, clinical trials with at 
least one death reported were included in this analysis. Furthermore, any hospitalization 
within 12 hours of randomization was excluded. Treatment effects were expressed as risk 
ratios (RR) for binary outcomes and mean difference (MD) for continuous outcomes. For 
each outcome, we pooled the Individual trial statistics using the random•effects inverse-
variance model; a continuity correction of 0.5 was applied to treatment arms with no deaths. 
Heterogeneity was evaluated by /2. The significance threshold was set at 5% (two-sided) and 
all analyses were conducted using Revman 5.3. A funnel plot for the mortality outcome was 
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created to assess publication bias and small study effects; the p-value was estimated from 
the regression-based Harbord test for small study effects. 
All studies included in this analysis were assessed for risk of bias using the Cochrane 
Collaboration risk of bias standardized assessment tool [26]. The outcome of this 
assessment is given in Supplementary Table 3. Each study was assessed for risk of bias for 
the primary endpoint, viral load, and survival outcomes. The primary endpoint in the trials 
tended to be clinical recovery which is more subjective and likely to be influenced by 
knowledge of treatment arms. An assessment was also carried out on more objective 
endpoints including survival and viral load which are less likely to be influenced by this bias. 
Where information was not available in published papers, clinical trial investigators were 
proactively contacted to inform the risk bias analysis. 
Results 
24 RCTs involving a total of 3328 participants were included in this meta-analysis. The 
sample sizes of each trial ranged from 24 to 400participants. Of the 24 included studies, 
eight were published papers, nine were available as pre-prints, six were unpublished results 
shared for this analysis, and one reported results via a trial registry website. 
Overall, nine trials investigate<i ivermectin as a single dose (Table 1A) [27-35], 15 trials 
investigated multi-day dosing up to seven days (Table 1 B) [36-50] , of which four trials were 
dose-ranging [28,39, 46, 48j. In the included trials, ivermectin was largely investigated in 
mild/moderate participants (15 trials). Overall, i8 trials were either single or double-blinded 
and six were open~label. 
Evaluation of Studies. 
An evaluation of the quality of the studies included in this meta-analysis was conducted 
according to the Cochrane Collaboration tool to assess the risk of bias across the following 
outcomes: primary endpoints, viral load, and survival. For the primary outcome assessment, 
6/24 (25%) studies were assessed as high risk of bias [Supplementary table 3A]. However, 
in assessments of more objective outcomes, including viral load and mortality, the number of 
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high risk studies was lower. In the PCR assessment, 3/15 (20%) of the studies were 
assessed as high risk (Supplementary Table 3BJ. In the survival assessment, 1/11 (9%) of 
the studies were assessed as high risk of. [Supplementary Table 3CJ. 
Effects on Inflammatory Markers 
Five trials provided results of the effect of ivermectin on inflammatory markers including C-
reactive protein (CRP), ferritin and d-dimer (Table 2). Four of these trials demonstrated 
significant reductions in CRP compared to control. Furthermore, in the Elgazzar trial {36J, 
ivermectin significantly reduced ferritin levels compared to control in the severe patient 
population while no significant difference was demonstrated in the mild/moderate population. 
The Okumus trial [4 7} showed significantly greater reductions in ferritin on day 1 0 of follow-
up for ivermectin versus control. The Chaccour [35] and Ahmed{46} trfafs showed no 
significant difference in ferrltin count between ivermectin and contra¼. Elgazzar [36} showed 
significant differences in d-dimer between ivermectin and control in both the mild/moderate 
and severe populations. Okumus [47] showed significant differences ind-dimer on day 5 
whilst Chaccour [35J found no significant differences in ct-dimer between ivermectin and 
control, but with a smaller sample size. 
Effects on Viral Clearance 
Three different endpoints were used to analyze viral clearance: the percentage of patients 
undetectable on a set day (Table 3A), the number of days from randomization to negativity 
(Table 38), and other measures such as cycle time (Ct) values and dose-response 
correlations (Table 30). The Kirti {431 and Okumus [47] trials included viral load analysis only 
in a subset of patients. The effects of ivermectin on viral clearance were generally smaller 
when dosed on onfy one day. Several studies showed no statistically significant effect of 
ivermectin on viral clearance [28, 29, 34]. 
The three studies randomizing patients to different doses or durations of ivermectin showed 
apparent dose-dependent effects on viral clearance. First, in the Babalola trial (n=60) [48}, 
the 0Amg/kg dose showed trends for faster viral clearance than the 0.2mg/kg dose. Second, 
in the Mohan trial (n=125) [28J, the 0.4 mg/kg dose of ivermectln led to a numerically higher 
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percentage of patients with viral clearance by day five than the 0.2mg/kg dose. Third, in the 
Ahmed trial (n=72) [46], ivermectin treatment for five days led to a higher percentage of 
patients with viral clearance at day 13 compared with one day of treatment. Finally, in 
Krolewiecki (n=45) [50], PK/PD correlations showed significantly faster viral clearance for 
patients with PK exposures above 160ng/mL. 
The effect of ivermectin on viral clearance was most pronounced in the randomized trials 
evaluating doses of up to five days of ivermectin using doses of 0.4mg/kg. At these doses, 
there were statistically significant effects on viral clearance in all four randomized trials. In a 
meta-analysis of viral clearance with subgroups of dose duration, there were significant 
differences in time to viral clearance in favour of ivermectin (Mean Difference -3.00 days 
[95%CI -4.96, -1.03}; p=0.003, Figure 1A]. In a sensitivity analysis excluding high risk of bias 
studies, similar effects of ivermectin on time to viral clearance were seen [Supplementary 
Figure 2). Furthermore, in another analysis, ivermectin showed improved viral clearance at 
day 7 (Relative Risk 1.35 [95%CI 1.05-1. 75]; p=0.02, Figure 1B]. 
Effects on Clinical Recovery and Duratfon.ofHospitalizatlon 
Definitions of clinical recovery varied across trials, as shown in Table 4. In Table 4A, three of 
the six trials showed significanUy faster time to clinical recovery on ivermectin compared to 
control. In four trials, ivermectin showed significantly shorter duration of hospitalization 
compared to control (Table. 48). 
In a meta-analysis of plin~I recovery with subgroups of dose duration, there were 
significant differences m time to clinical recovery in favour of ivermectin (Mean Difference -
1.58 days f95%CJ .. 2.80, -0.35); p=0.01, Figure 1 CJ. Additionally, ivermectin showed a 29% 
improvement in clinical recovery in an analysis with subgroups of dose duration (RR 1.29 
[95%CI 'L12-1.47]; p=0.0003, Figure 1D]. 
lvermectin demonstrated a shorter duration of hospitalization compared to control (Mean 
Difference -4.27 days [95%CI -8.60-0.06]; p=0.05, Figure 1E). lvermectin was not associated 
with a lower risk of hospitalization compared to control (RR 0.40 [95%CI 0.14-1.08]; p=0.07, 
Figure 1 F). However, this analysis involved only four trials in 704 participants. In a sensitivity 
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analysis including any hospitalization within 12 hours of randomization, there were 
significantly fewer hospitalisations compared to control (RR 0 .32 [95%CI 0.13-0.80]; p=0.0 1, 
Supplementary Figure 3). 
Effects on Survival 
11 randomized trials reported that at least one person had died post-randomization and 
were included in the analysis (Table 5). Across these 11 trials in 2127 patients, there were 
35/1064 {3%) deaths in the ivermectin arms, versus 93/1063 (9%) deaths in the control 
arms. In a combined analysis using inverse variance weighting, ivermectin showed a 56% 
reduction in mortality (RR 0.44 [95%CI 0.25-0.77]; p=0.004, Figure 1G). Heterogeneity was 
moderate, 12 = 43%. There was a 70% improvement in survival in the subgroup of 
mild/moderate participants (RR 0.30 [95%CI 0.15-0.58]; p=0.0004). The total number of 
deaths was small, the analysis was based on 128 deaths and there was no significant 
difference between ivermectin and control in the severe subgroup (0.58 [95%CI 0.25-1.32}; 
p=0.19). 
Consistent results were observed in an analysis excluding high risk of bias studies (RR 0.45 
(95%CI 0.24-0.82); p=0.01, Supplementary Figure 4). When only low risk of bias studies 
were included this result was also maintained (RR 0.31 [95%CI 0.10-0.90]; p=0.03, 
Supplementary Figure 5). 
Additional subgroup analysis of the mortality outcome with trials separated by dose-duration, 
blinding and control group showed consistent survival benefit and no significant subgroup 
differences were found (Supplementary Figures 6, 7 and 8). 
A leave-one-out sensitivity analysis was performed and no single study had a substantial 
effect on the overall effect size (Supplementary Table 4). 
A funnel plot for the mortality outcome showed no significant effects of publication bias: the 
treatment effects were similar in studies of different sizes, p== 0.618 (Supplementary Figure 
9). 
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lvermectin was not associated with lower risk of mechanical ventilation (RR 0.97 [95%CI 
0.57-1.67]; p=0.92, Figure 1H]. However, this estimate was based on five studies in 641 
participants including only 49 events. 
Discussion 
This systematic review and meta-analysis of 24 RCTs (n = 3328) showed ivermectln 
treatment reduces inflammatory markers, achieves viral clearance more quickly and 
improves survival compared with SOC. The effects of ivermectin on viral clearance were 
stronger for higher doses and longer durations of treatment. These effects were seen 
across a wide range of RCTs conducted in several different countries. 
The results from this analysis have emerged from the International lvermectin Project Team 
.. 
. 
meetings between December 2020 and May 2021. Independent research teams were 
conducting the trials across 16 countries and agreed to share their data, which was often 
unpublished, to accelerate the speed of reporting and to ensure their fragmented research, 
widespread across the world, could contribute to global learning. Viral clearance was 
evaluated by Polymerase Chain Reaction (PCR) assays in all the studies. We have only 
included randomized clinicaltriats in this meta-analysis. The 24 RCTs included were 
designed and conducted independently, with results combined in May 2021. However each 
individual trial was small and a wide range of population types included. Clinical recovery 
definitions differed between trials and there were no significant differences on survival in 
severe participants. 
Secondary Endpoints 
Secondary endpoints for some RCTs included biomarkers of disease severity. Some of 
these provide evidence for an anti-inflammatory mechanism of action of ivermectin in SARS-
CoV-2 infected patients. Previous meta-analyses have demonstrated that high levels of 
CRP, ferritin, d-dimer and lymphocytopenia are related to COVID-19 severity and hyper-
inflammation {51, 52]. Studies of ll-6 receptor antagonists have been shown to reduce CRP 
and d-dimer levels in patients with COVID-19 [5}. 
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lvermectin may also have a role in short-term prevention of SARS-CoV-2 infection, 
suggested by pilot studies [53, 54]. This potential benefit also needs to be validated in larger 
randomized trials. 
Mechanism of action 
At the time of writing, knowledge gaps prevent a robust conclusion about the mechanism of 
action of ivermectin. lvermectin's broad-spectrum anti-viral effects have been proposed to be 
related to its impact on the NF-KB pathway and via binding to the host cell importin a/~ 1 
heterodimer, nuclear transport proteins responsible for nuclear entry of cargoes, and these 
effects in turn also prevent viral replication. 
As discussed in the introduction, the current in-vitro EC50 estimates (2.2µ, 2.4µM and 2.8µM 
depending on gene assay analyzed by RT-qPCR) are still 35 times higher than plasma 
concentrations following normal oral dosing. Even doses 8.5x fold the FDA recommended 
200µg/kg of 1.7mg/kg only reach plasma concentrations of 0.28µM [55}. The increased 
bioavailability in the fed state and higher concentrations seen in lung tissue compared to 
plasma is still below the current published EC50 results. 
However, EC5o results can vary greatly depending on lab methodology; eel! lineage, viral 
quantification methods, the strain of the virus cultured and the Multiplicity of infection used. 
This is an established phenomenon: viral polymorphisms of influenza demonstrated a 5-fold 
variation in EC50 of different neuraminidase assays that looked at the susceptibility of field 
isolates of influenza virus against oseltamivir [56]. Specifically in SARS-CoV-2, ECs0s for 
previously repurposed drugs have varied significantly. Remdesivir, now licensed for SARS-
CoV-2, performed > 10 fold better in hACE2 augmented A549 cells (0.115 µM) than Vero E6 
(1.2BµM) [57]. whereas other examples of repurposed drugs like sofosbuvir demonstrated 
over 10-fo!d variation in EC50 when used in Vero E6 cells versus HUH7 [58]. Consequently, 
the EC50 so far demonstrated for ivermectin against SARS-CoV-2 should be interpreted with 
caution as it is unlikely to be one set value and liable to change depending on the lab 
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methodology used. In vitro assays for ivermectin should be repeated for different cell types 
using different measures of activity. 
limitations 
A key limitation to this meta-analysis is the comparability of the data, with studies differing in 
dosage, treatment duration, and inclusion criteria. Furthermore, the standard of care used in 
the control arm differed between trials. In this meta-analysis, trials that used active controls 
such as hydroxychloroquine or lopinavir/ritonavir were combined together with those that 
used placebo or standard care. However, lopinavir/ritonavir and hydroxychloroquine have 
shown no overall benefit or harm in large randomized trials and meta-analyses. [7, 59-61) 
Furthermore, additional analyses in this paper separating trials by subgroups of standard 
care/ placebo and active control showed no significant difference between groups. 
Another limitation is that ivermectin was given in combination with doxycycline in three trials. 
Individual trials may not have power to detect treatment effects on rare endpoints such as 
survival. Outcome measures were not standardized; viral clearance was measured in most 
trials, but at different time points and with different PCR cycle thresholds. The reliability of 
PCR tests for quantification purposes has been the subject of substantive debate. Most 
studies were conducted in populations with only mild/moderate infection and some trials 
excluded patients with multiple comorbidities. 
For open label studies, there is a risk of bias in the evaluation of subjective endpoints such 
as clinical recovery and hospital discharge. However, the risk is lower for objective endpoints 
such as viral clearance and survival. We have attempted to control for publication bias by 
contacting each research team conducting the trials directly. This has generated more 
results than would be apparent from a survey of published clinical trials only but means that 
many of the included trials have not been peeMeviewed. Review and publication of RCTs 
generally takes three to six months. It has become common practice for clinical trials of key 
COVID-19 treatments to be evaluated from pre-prints, such as for the WHO SOLIDARITY, 
RECOVERY and REMAP-CAP trials [4,5, 7J. 
12 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 101 of 141

These RCTs have been conducted in a wide range of countries, often in low-resource 
conditions and overburdened healthcare systems. larger RCTs are currently underway in 
Spain, South America, Africa and North America, with results from an additional 5000 
participants expected in Summer 2021 (Supplementary Table 5). 
Despite limitations, this analysis suggests a dose and duration-dependent impact of 
ivermectin on rate of viral clearance. These trials evaluated a wide range of ivermectin 
dosing, from 0.2mg/kg for 1 day to 0.6mg/kg for 5 days. This wide range of doses allowed an 
estimation of dose•dependency on viral clearance but reduces the number of patients 
included that were consistently administered the same dose for the same duration. The 
maximum effective dose of ivermectin is not yet clear and new clinical trials are evaluating 
higher doses, up to 1.2mg/kg for 5 days. 
The 56% survival benefit seen in this meta-analysis is based on 128 deaths, in 11 different 
clinical trials. This is a smaller total number of deaths than the RECOVERY trial, which led to 
the approval of dexamethasone and is based on 1592 deaths. However, the observed 
survival benefit of 56% in ivermectin is stronger than for other repurposed drugs, requiring a 
smaller sample size to be demonstrated. Emerging mortality results from larger studies of 
ivermectin will require careful evaluation and may change the conclusions from the current 
analysis. 
Several other repurposed medications have shown promise in early smaller trials for 
example sofosbuvir/daclatasvir, colchicine and remdesivir but the benefit was not seen later 
in larger trials. This meta-analysis of 24 RCTs in 3328 patients showed a 56% improvement 
in survival, faster time to clinical recovery and signs of a dose-dependent effect of viral 
clearance for patients given ivermectin versus control treatment. This benefit needs to be 
validated in larger confirmatory trials. 
13 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 102 of 141

Acknowledgements 
We would like to thank all the clinical staff, the research teams and the patients who 
participated in these studies. 
Funding: Rainwater foundation 
Potential Conflicts of Interest: None of the authors has declared a conflict of interest 
Patient Consent Statement: All of the clinical trials included in this meta~analysis were 
approved by local ethics committees and all patients signed informed consent. 
14 
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References 
1. 
WHO. WHO Coronavirus Disease (COVID-19) Dashboard [Internet]. 2020 [cited 2021 March 
9]. Available from: https://covid19.who.inU 
2. 
Stolberg SG, LaFraniere S. Warning of Shortages, Researchers look to Stretch Vaccine 
Supply. New York Times [Internet). 2020; Available from: 
https:/lwww.nytimes.com/2021/01/05/us/politics/coronavirus-vaccine-sum~ly.html 
3. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19-
preliminary report. New England Journal of Medicine. 2020. DOI: 10.1056/NEJMoa:2021436 
4. 
The REMAP-CAP Investigators. lnterleukin-6 Receptor Antagonists in Critically IU Patients 
with Covid-19 - Preliminary report. medrXiv [preprint] 2020; Available at; 
https://doi.org/10.1101/2021.01 .07.21249390 
5. 
RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 
(RECOVERY): a randomised, controlled, open-label, platform trial. lancet (London, England). 
2021 May 1 ;397(10285):1637-45. 
6. 
WHO Solidarity Trial Consortium. 2021. "Repurposed Antiviral Drugs for Covid-19 - Interim 
WHO Solidarity Trial Results." The New f::ngland Journal of Medicine 384 (6): 497-511. 
https:f/doi.org/10.1056/NEJMoa2023184. 
7. 
Mahase E. Covid-19: Budesonide shortens recovery time in patients not admitted to hospital, 
study finds BMJ 2021; 373:n957 doi:10.1136/bmj.n957 
8. 
Romark. ROMARK ANNOUNCES INITIAL RESULTS OF PHASE 3 CLINICAL TRIAL OF NT-
300 TABLETS FOR THE TREATMENT OF COVID-19 [Internet]. 2020 [cited 2021 Apr 22]. 
Available from: https;//www.romark.com/romark-announces-initial-results-of-phase-3-clinical-
trial-of-nt-300-tablets-for-the-treatment-of -covid-19/ 
9. 
Caly L, Oruce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin 
inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 
10.1016/j.antiviral.2020.104787. 
10. Arshad U, Pertinez H, Box H, et al. Prioritization of Anti-SARS-Cov-2 Drug Repurposing 
Opportunities Based on Plasma and Target Site Concentrations Derived from their 
Established Human Pharmacokinetics. Ciin Pharmacol Ther. 2020 Oct;108(4):775-790. doi: 
10 .1002/cpt.1909. 
11. Schmith, V., Zhou, J. lohmer, 2020. The Approved Dose of lvermectin Alone is not the Ideal 
Dose for the Treatment of COVID-19. Clinical Pharmacology & Therapeutics, 108(4), pp.762-
765. 
15 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 104 of 141

12. Jermain B, Hanafin PO, Cao Y, Lifschitz A, Lanusse C, Rao GG. Development of a Minimal 
Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans 
Following Oral Administration of lvermectin for COVID-19 Drug Repurposing. J Pharm Sci. 
2020;109(12):3574-3578. doi:10.1016/j.xphs.2020.08.024 
13. Gonzalez Canga A, Sahagun Prieto AM, Diez Liebana MJ, et al. The pharmacokinetics and 
interactions of ivermectin in humans--a mini-review. MPS J. 2008;10(1):42-46. 
doi:10.1208/s12248-007-9000-9 
14. Zhang X, Song Y, Xiong H, et al. Inhibitory effects of ivermectin on nitric oxide and 
prostaglandin E2 production in LPS-stimulated RAW 264. 7 macrophages. Int 
lmmunopharrnacol. 2009 Mar;9(3):354-9. doi: 10.1016/j.intimp.2008.12.016. 
15. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downrj:lgUl;ating the 
nuclear transcription factor kappa-B and mitogen-activated protein kinase actjvatlon pathway. 
Fundam Clin Pharmacol. 2009 Aug;23(4):449-55. doi: 10.1111/j.1472,"'8206.2009.00684.x. 
16. Zhang X, Song Y, Ci X, et al. lvermectin inhibits LPS-induced production of inflammatory 
cytokines and improves LPS-induced survival in mice. lnflamm Res. 2008 Nov;57(11 ):524-9. 
doi: 10.1007/s00011-008-8007-8 
17. Ventre E, Rozieres A, Lenief V, et al. Topical iven:riectin improves allergic skin inflammation. 
Allergy. 2017 Aug;72(8):1212-1221. doi: 10.1111/alt,13118. 
18. Yan S, Ci X, Chen N, Chen C, et al. Anti--inflammatory effects of ivermectin in mouse model of 
allergic asthma. lnflamm Res. 2,011 Jun;60(6):589-96. doi: 10.1007/s00011-011-0307-8. 
19. de Melo GD, Lazarini F, Larrous F, et al. Anti-COVID-19 efficacy of ivermectin in the golden 
hamster. bioRxiv 2020.11.21.392639; doi: https://doi.org/10.1101 /2020.11.21.392639 
20. Navarro, M., Camprubi, D., Requena-Mendez, A., et al. 2020. Safety of high-dose ivermectin: 
a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy, 75(4), 
pp.827-834. 
. 
21. Zaidi AK1 Dehgani-Mobaraki P. The mechanisms of action of lvermectin against SARS-CoV-
2: An evidence-based clinical review article. The Journal of Antibiotics. 2021 Jun 15:1-3. 
22. WHO. Therapeutics and COV!D-19: living guideline [Internet]. 2020. (cited 2021 Apr 22]. 
Available from: https://www .who.int/publications/i/item/W HO-2019-nCo V-therapeutics-2021.1 
23. NIH Clinica!Trials.gov. [Accessed 14th December] 
24. Thu Van Nguyen, Gabriel Ferrand, Sarah Cohen-Boulakia, Ruben Martinez, Philipp Kapp, 
Emmanuel Coquery, for the COVID-NMA consortium. (2020). RCT studies on preventive 
measures and treatments for COVID-19 [Data set]. Zenodo. 
http://doi.org/10.5281 /zenodo .4266528 
16 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 105 of 141

25. Tzou PL, Tao K, Nouhin J, et al. Coronavirus Antiviral Research Database (CoV-RDB): An 
Online Database Designed to Facilitate Comparisons between Candidate Anti-Coronavirus 
Compounds. Viruses. 2020;12(9):1006. Published 2020 Sep 9. doi:10.3390/v12091006 
26. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of 
Interventions version 6.1 (updated September 2020). Cochrane, 2020. Available from 
www .training.cochrane.org/handbook. 
27. Mahmud et al. ClinicalTriafs.gov. National Library of Medicine. NCT04523831. Clinical trial of 
ivermectin plus doxycycline for the treatment of confirmed COVID-19 infection. Available at 
https://cllnicaltrials.gov/ct2/show/study/NCT04523831 [Accessed 15/12/2020] 
28. Mohan A, Tiwari P, Suri T et al. lvermectin in mild and moderate COVID-19 (RIVET-
COV): a randomized, placebo-controlled trial. Research Square. 2021. 
https://doi.org/10.21203/rs.3.rs-191648/v1 [preprint] 
29. Chowdhury et al. A randomised trial of lvermectin-Doxycycline .and Hydroxychloroquine-
Azithromycin therapy on COV!D19 patients. 2020 [Internet} Available at 
https://doi.org/10.21203/rs.3.rs-38896/v1 
30. Gonzalez et al. Efficacy and safety of lvermectin and Hydroxychloroquine in patients with severe 
COVID-19. A randomized controlled trial. medRxiv. Available at: 
ht;tps://www.medrxiv.org/content/10.1101/2021.02.18.21252037v1. [preprint] 
31. Raad et al. 2020. In vivo use of iverrnectin (IVR} for treatment for corona virus infected 
patients (COVID-19): a randomized controlled trial. 2020 
Avaiable at: httg://www.chictr.or£j.cn/show12roj.aspx?groj=54707 [unpublished] 
32. Bukhari, Asghar, Perveen et al, Efficacy of lverrnectin in COVID-19 Patients with Mild to 
Moderate Disease. medRXiv. 2020. https:l/doi.org/10.1101 /2021.02.02.21250840 [preprint] 
33. Rezai et al. Effect of lvermectin on COVID-19: A multicenter double-blind randomized clinical 
trial. 2020. Avaifable at httgs:/len.irct.ir/trial/49174 [unpublished) 
34. Podder S, Chowdhury N, Sina M, UI Haque W, Outcome of ivermectin treated mild to 
moderate COVID-19 cases: a single-centre, open-label, randomized controlled study. IMC J 
Med Sci 2020; 14 (2): 002 
35. Chaccour C, Casellas A, Blanco-Di Matteo A, Pineda I, Fernandez-Montero A, Ruiz-Castillo 
P, Richardson MA, Rodriguez-Mateos M, Jordan-Iborra C, Brew J, Carmona-Torre F. The 
effect of early treatment with ivermectin on viral load, symptoms and humoral response in 
patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized 
clinical trial. EClinicalMedicine. 2021 Jan 19:100720. 
36. Elgazzar A, Hany B, Youssef S, Hafez M, Moussa H, Eltawee! A. Efficacy and safety of 
ivermectin for treatment and prophylaxis of COVID-19 pandemic. [Pre-print]. 28th December 
2020. Research Square. https://www.researchsquare.com/article/rs-100956/v3 
17 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 106 of 141

37. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of lvermectin on Time to Resolution of 
Symptoms Among Adults With Mild COVID-19: A Randomized Clinical 
Trial. JAMA. Published online March 04, 2021. doi:10.1001(jama.2021.3071 
38. Chahla R, Ruiz L, Mena T et al. Cluster Randomised Trials - lvermectin Repurposing For 
COVID-19 Treatment Of Outpatients With Mild Disease In Primary Health Care Centers. 
Researchsquare. 2021. Available at: https://doi.org/10.21203/rs.3.rs-495945/v1 [preprint] 
39. Niaee M, Gheibi N, Namdar P, et al. lnvermectin as an adjunct treatment for hospitalized 
adult COVID-19 patients: a randomized, multi-center clinical trial. [Preprint}. 24th November 
2020. Research Square. Available at httQs://doi.org/10.212Q3/rs.3.rs-109670/v1 
40. Galan et al (2021) Phase 2 randomized study on chloroquine, hydroxychloroquine or 
ivermectin in hospitalized patients with severe manifestations of SARS-CoV-2 
infection, Pathogens and Global Health, DOI: 10.1080/20477724.2021.1890887 
41. Abd-Elsalam et al. lvermectin as a Novel Therapy for COVID-19 Treatemerits. Available at: 
httQs://clinicaltrials.gov/ct2/show/NCT04403555 [unpublished] 
42. Hashim H, Maulood M, Rasheed A, Fatak D, Kabah K, Abdulamir A. Controlled randomized 
clinical trial on using lvermectin with doxycycline for treating GOVID-19 patients in Baghdad, 
Iraq. [Preprint]. 27th October 2020. medRxiv. Available at: 
httgs://doi.org/10, 1101/2020.10.26.20219345 
43. Kirti R, Roy R, Pattadar C, et at. lvermectin as a potential treatment for mild to moderate 
COVID-19: A double blind randomized placebo-controlled trial. [Preprint). 9
th January 2021. 
Medrxiv. doi: https://doi.org/10:1101/2021.01 .05.21249310 
44. Petkov S. Multicenter, randomized, double-blind, placebo-controlled study investigating 
efficacy, safety and tolerability of ivermectin HUVE-19 in patients with proven SARS-CoV-2 
infection (covid-19) and manifested clinical symptoms. 2021. 
https://www.clinicaltriatsregister.eu/ctr-search/trial/2020-002091-12/BG (accessed January 
2021) [unpubltshed} 
45. Schwartz E. lvermectin vs. Placebo for the Treatment of Patients With Mild to Moderate 
covid-19. 2020. Available at https:l/clinicaltrials.gov/ct2/show/NCT04429711 [unpublished) 
46. Ahmed S, Karim M, Ross A, et al. A five day course of ivermectin for the treatment of COVID-
19 may reduce the duration of illness. Int J Infect Dis. 2020 Dec 2:81201-9712(20)32506-6. 
doi: 10.1016/j.ijid.2020.11.191. 
47. Okumw:?, N., Demirturk, N., Cetinkaya, R.A. et al. Evaluation of the effectiveness and safety 
of adding ivermectin to treatment in severe COVID-19 patients. BMC Infect Dis 21, 411 
(2021 ). https://doi.org/10.1186/si2879-021-06104-9 
48. 0 E Babalola, C O Bode, A A Ajayi, et al. lvermectin shows clinical benefits in mild to 
moderate COV!D19: A randomised controlled double-blind, dose-response study in 
18 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 107 of 141

Lagos, QJM: An International Journal of Medicine, 
2021; https://doi.org/10.1093/gjmed/hcab035 
49. Chachar A, Khan K, Asif M, Khaqan A, Basri R. Effectiveness of ivermectin in SARS-CoV-2 I 
COVID-19 patients. International Journal of Sciences 09(2020):31-35 DOI: 
10.18483/ijSci.2378 
50. Krolewiecki A, Lifschitz A, Moragas M, et al. Antiviral Effect of High-Dose lvermectin in Adults 
with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial. [Preprint]. 
11th November 2020. SSRN. Available at http://dx.doi.org/10.2139/ssrn.3714649 
51. Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemica!and 
immune biomarker abnormalities associated with severe illness and mortality in coronavirus 
disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020;58(7}:1021, 
1028. https://doi.org/10.1515/cclm-2020-0369 
52. Singh K, Mittal S, Gollapudi S, Butzmann A, Kumar J, Ohgami RS. A meta-analysis of SARS-
CoV-2 patients identifies the combinatorial significance of O-dimer, C-reactive protein, 
lymphocyte, and neutrophil values as a predictor of disease severity. International journal of 
laboratory hematology. 2020 Oct 3. 
53. Clinicaltrials.gov. NCT04 701710. Prophylaxis Covid-19 In Healthcare Agents By Intensive 
Treatment With lvermectin And lota-Carrageenan. Available at: 
https://clinicaltrials.gov/ct2/show/NCT0470171019 [Accessed 12/01/2021]. 
54. Clinicaltrials.gov. NCT04422561. Prophylactic lvermectin In COVID-19 Contacts - Study 
Results. Available at https://clinicaltrials.gov/ct2/show/results/NCT04422561. [Accessed 
12/01/2021]. 
55. Wang K, Gao W, DouQ, et al. tvermectin induces PAK1-mediated cytostatic autophagy in 
breast cancer. Autophagy. 2016 Dec;12(12):2498-2499. doi: 
10.1080/15548627.2016.1231494. 
56. Abed Y, Saz M, Boivin G. et al. Impact of neuraminidase mutations conferring influenza 
resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds. Antiviral 
therapy. 2006 Jan 1 ;11 (8):971. 
57. Shi PY, Xie X, Muruato et al. nanoluciferase SARS-CoV-2 for rapid neutralization testing and 
screening of anti-infective drugs for COVID-19. bioRxiv. 2020 Jan 
1. https:/!www.biorxiv.org/contenUbiorxiv/early/2020/06/23/2020.06.22.165712.fu!l.pdf 
58. 54.Levi et al Interpreting in-vitro data for sofosbuvir against SARS-CoV-2: cell lineage is key. 
Oral abstract. ISIRV conference. 6-8 October 2020. 
59. Ghazy R, Almaghraby A, Shaaban R, Kamal A, Beshir H, Moursi A et al. A systematic review 
and meta-analysis on chloroquine and hydroxychloroquine as monotherapy or combined with 
19 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 108 of 141

azithromycin in COVID-19 treatment. Scientific Reports [Internet]. 2020;10(1). Available from: 
https://www.nature.com/artic1es/s41598-020-777 48-x 
60. Alhumaid, Saad, Abbas Al Mutair, Zainab Al Alawi, Naif Alhmeed, Abdul Rehman Zia Zaidi, 
and Mansour Tobaiqy. 2020. "Efficacy and Safety of Lopinavir/Ritonavir for Treatment of 
COVID-19: A Systematic Review and Meta-Analysis." Tropical Medicine and Infectious 
Disease 5 (4). http§://doi.org/1Q,3390/tropicalmed5040180. 
61. RECOVERY Collaborative Group. 2020. "lopinavir-Ritonavir in Patients Admitted to Hospital 
with COVID-19 (RECOVERY): A Randomised, Controlled, Open-Label, Platform Trial." 
Lancet {London, England) 396 (10259): 1345-52. bttes://doi.org/10.1016/S0140-
6736(20)32013-4. 
62. Mills et al. Hydroxychloroquine and lopinavir/ Ritonavir to Improve the Health of People With 
COVID-19: "The Hope Coalition -1". ClinicalTrials.gov [Internet]. 2020. 
https://www.clinicaltrials.gov/ct2/show/NCT04403100?term=NCT04403100&draw;:2&rank=1 
63. DNDi. ANTICOV Clinical Trial. 2020 [Internet] Available at: https://dndi.org/research-
development/portfolio/anticov/ 
64. Rezai et al. Double-blind placebo-controlled clinical trial of evaluating the effectiveness of 
lvermectin in treatment of outpatients with COVID-19 in 2021. IRCT [Internet]. 2020. 
https://www.irct.ir/trial/53949 
65. Rezai et al. Double-blind placebo-controlled clinical trial of evaluating the effectiveness of 
lvermectin in treatment of admitted with COVID-19 in 2021. !RCT [Internet]. 2020. Available 
at: httes://www.irct.ir/trial/54404 
66. Munoz et al. Multicenter, phase 111, double-blind, randomized, parallel, placebo-controlled trial 
to evaluate the efficacy and safety of an early administration of lvermectin for three 
consecutive days to prevent hospitalization related to SARS-Cov-2 (COVID-19) in adults over 
50 years old with less. than 5 days of symptoms. Exe/tis fpersonal communication] 
67. Mukonzo et at Safety and Efficacy of low dose aspirin/ ivermectin combination therapy for 
treatmentofcovid-19 patients (IVCOM). Clinicaltrials.gov [Internet]. Available at: 
https:l!clinicaltrials.gov/ct2/show/NCT04 768179?cond=COVID-
19&1ntr=tverrnectin&sfpd s=01 %2F02%2F2021 &sfpd e=12%2F03%2F2021 &draw=2 
68. Avila et at Efficacy of ivermectin in outpatients with non-severe Covid-19. Clinicaltrials.gov 
[Internet]. Available at: 
https://clinicaltrials.gov/ct2/show/NCT04834115?term=ivermectin&draw=2 
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List of Tables and figures 
Table 1: Trial Summaries 
A: lvermectin trials with Dosing on day 1 only 
B: lvermectin trials with multi-day dosing 
Table 2: Changes in Inflammatory Markers 
Table 3: Effects of ivermectin on viral clearance 
A: Effects of ivermectin on viral clearance (binary) 
B: Effects of ivermectin on time to viral clearance 
C: Effects of ivermectin on other measures of viral clearance 
Table 4: Effects on of ivermectin on clinical recovery and hospitalization 
A: Time to clinical recovery 
B: Effects of ivermectin on duration of hospitalization 
C: Number of Participants with clinical recovery by Day 7 to 10 post-randomization 
Table 5: Effects of ivermectin on survival 
21 
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Figure 1A: Forest plot of time to viral clearance by dose-duration. 
figure 1 B: Forest plot of PCR negativity at day 7 *Kirti et al and Schwartz et al measured at 
day6 
Figure 1C: Forest plot of time to clinical recovery by dose-duration. 
Figure 10: Forest plot of clinical recovery (binary) by dose duration 
Figure 1 E: Forest plot of duration of hospitalization by dose 
Figure 1F: Forest plot of new hospitalizations in trials on outpatients 
Figure 1G: Forest plot of survival by severity 
Figure 1H: Forest plot of mechanical ventilation 
22 
2 
3 
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Table 1: Trial Summaries 
Table 1A: lvermectin trials with Dosing on day 1 only 
Study 
Mahmud eta I 
[25! t 
Mohan et al 
[26] t 
Chowdhury 
[271 t 
Gonzalez [28] 
Raad et al 
[29] t 
Country 
Bangladesh 
India 
Bangladesh 
Mexico 
Lebanon 
Sample Size 
Daily dose 
Duration 
363 
12 mg 
1 day (DB) 
125 
0.2-0.4 mg/kg 
1 day (DB} 
(elixir) 
116 
0.2 mg/kg 
1 day (DB) 
106 
12mg 
1 day {DB) 
100 
0.2 mg/kg 
1 day {SB) 
Patients 
lvermectin Arm 
Comparator Arm 
Mild/ moderate 
!vermectin + 
soc 
Doxycycline + SOC 
Mild / moderate 
lvermectin + SOC 
Placebo + SOC 
0 
PCR positive 
lvermectin + 
HCQ + Azithromycin 
Doxycycline 
Severe 
lvermectin 
Placebo 
Mild 
lvermectin + SOC 
soc 
23 
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Asghar et al 
[32J t 
Rezai et al 
[31]" 
Podder et al 
[321 t 
SAINT 
[33) * 
Pakistan 
Iran 
Bangladesh 
Spain 
86 
0.2 mg/kg 
1 day(OL) 
69 
0.2 mg/kg 
1 day (DB) 
62 
0.2 mg/kg 
1 day (OL) 
24 
0.4 mg/kg 
1 day (DB) 
SOC:::: Standard of care; OL= open label; SB= single-blind; DB= double-blind 
Mild / moderate 
lvermectin + SOC 
soc 
Moderate I severe 
lvermectin + SOC 
soc 
Mild 
lvermectin + SOC 
soc 
Moderate 
!vermectin 
Placebo 
24 
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~] 
c, 
Table 1 B: lvermectin trials with multi-day dosing 
~ 
Ct 
<, 
Q_ 
Study 
Country 
Sample 
Daily dose 
Duration 
Patients 
lvermectin Arm 
Comparator Arm 
"' 
,:i. 
Size 
C 
3 
::, 
q; 
"'O 
~,: 
Elgazzar et al 
Egypt 
400 
0.4 mg/kg 
5 days (OB) 
Mild to severe 
lvermectin + SOC 
HCQ +SOC 
~;;;-g 
w 
Q. 
[36) t 
"' 
?, 
0 
(J 
C 
V 
Lopez-Medina et al 
Colombia 
398 
0.3 mg/kg 
5 days (DB) 
Mild 
!vermectin 
Placebo 
(") 
~ 
(37]* 
i5 li 
11.1 
0.. 
Chahla et al [38] • 
Argentina 
254 
24mg 
1 /week for 4 
Mild 
lvermectin + SOC 
soc 
< 
ru 
:::, 
weeks (OL) 
0 
ff 
!jj 
~. 
(S' 
in 
Niaee et al 
Iran 
180 
0.2 - 0.4 mg/kg 
1-3 days (DB) 
Mild / moderate 
lvermectin + SOC 
SOC + Placebo 
Ci 
Q 
·•" 
[39] * 
0 
(0 
w g 
Fonseca et al [40]* 
Brazil 
168 
14mg 
3 days (DB) 
Severe 
ivermectin 
Hydroxychloroquine 
Q_ 
~r 
or Chloroquine 
SJ v ,,, 
U\ 
s2 
Qi 
Abd-Elsalam et al 
Egypt 
164 
12mg 
3 days (OL) 
PCR Positive 
lvermectin +SOC 
soc 
~ 
CT) 
[41] t 
"' 
~ 
v 
'< 
w 
Hashim et al 
Iraq 
140 
0.2 mg/kg 
2-3 days (SB) 
Symptomatic 
lvermectin + 
soc 
g 
Yi 
Doxycycline + SOC 
0 
[42] t 
:3 
C) 
h) 
er:, 
(\; 
"S 
,j; 
::, 
IT 
25 
~ 
"" 
0 
l\,".t 
~ 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 114 of 141

0 
0 
Kirti et al [43] * 
India 
112 
12 mg 
2 days (DB) 
Mild I moderate 
lvermectin + SOC 
SOC + Placebo 
::;; 
:, g 
Q. 
a: 
Petkov et al [44] • 
0.4 mg/kg 
o. 
Bulgaria 
100 
3 days (DB) 
Mild/ moderate 
lvermectin 
Placebo 
-
0 
3 
:r 
Schwartz et al [45] t 
Israel 
94 
12-15mg 
3 days (DB) 
Mild/moderate 
lvermectin 
Placebo 
's 
5-': ;;;, 
fil n 
Ahmed et al 
Bangladesh 
12 
0.2 mg/kg 
5 days (DB) 
Mild 
lvermectin + SOC 
SOC + Placebo 
,,, 
3 ff 
0 
[46]" 
C 
tl 
('; 
C :, 
Okumus etal 
Turkey 
60 
0.2 mg/kg 
5 days (DB) 
Severe 
lverrnectin + SOC 
FAVI/HQ/AZI 
[ 
a 
(SOC) 
nr 
Q. 
[47] t 
< 
lll :, 
n z 
cl, 
Babalola et al 
Nigeria 
60 
0.1-0.2 mg/kg 
2 /week (DB) 
Mild 
lverrnectin + SOC 
Placebo + LPV/r 
u. 
"' 
(SOC) 
a: 
[48] * 
s 
:: 
0 
(D 
w 
Chachar et al 
Pakistan 
50 
0.2 mg/kg 
2 days (Ol) 
Mild 
lvermectin + SOC 
soc 
§: 
5.: 
o-
[49f 
iii' 
rr 
LV 
m 
a; 
Ji 
Krolewiecki et al 
Argentina 
45 
0.6 mg/kg 
5 days (Ol) 
Mild to 
!verrnectin + SOC 
soc 
<-: 
m 
moderate 
"' 
[50] t 
~ 
U' 
'< 
'° 
C 
ID 
• Denoted studies were evaluated as having fair or good overall quality of evidence using the Cochrane Risk of Bias Tool. See Supplementary Table 3 for further details. 
~-
0 :, 
t Denoted studies were evaluated as having limited overall quality of evidence using the Cochrane Risk of Bias Tool. See Supplementary Table 3 for further details. 
D 
M 
w 
re 
SOC = Standard of care 
"' 
ft 
3 
CT' 
26 
!!l 
N 
C) 
"' 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 115 of 141

Table 2: Changes in inflammatory Markers 
CRP {mg/L) 
Ferritin (µgit) 
D-dimer (mg/l) 
lvermectin 
Control 
p value 
lvermectin 
Control 
pvalue 
lvermectin 
Control 
p value 
Elgazzar, Egypt (n=200, mild/moderate COVll>-19) 
Baseline 
48.4 
50.6 
168 
172 
4.8 
5.4 
Day? 
4,8 
8.3 
p<0.001 
95 
98 
0.62 
0.5 
0.7 
p<0.001 
Elgazzar, Egypt (n•200, ievere COVll'.M9) 
Baseline· 
64.8 
68.2 
420 
334 
8.2 
8.6 
Day? 
28.6 
58.6 
p<0.001 
104 
294 
p<0.001 
0.7 
1.9 
p<0.001 
Okumus, Turkey (n=60) 
Baseline 
340.3 
215.0 
683 
747 
1.3 
1.3 
Day5 
51.8 
194.3 
p<0.01 
875 
1028 
0.12 
5.9 
3.6 
0.22 
Day 10 
36.1 
92.4 
p<0.05 
495 
1207 
p<0.01 
0.7 
1.5 
p<0.05 
Chaccour, Spain (n=24)* 
27 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 116 of 141

Baseline 
3.5 
3.0 
Day7 
1.0 
1.1 
Day 14 
0.8 
0.6 
Ahmed, Bangladesh (n=45, lvermectin 5 days) 
Baseline 
22.0 
29.0 
Day7 
3.0 
14.0 
Ahmed, Bangladesh (n= 46, lvermectin.1 day) 
Baseline 
26.0 
29.0 
Day7 
11.0 
14.0 
Iran Niaee (n=60, ivermectin- 0.2 mg)* 
Baseline 
200.0 
270.0 
Oay5 
85.0 
245.0 
Iran Niaee (n=60, fvermectin• 0.2, 0.2, 0.2 mg)* 
Baseline 
390.0 
270.0 
Days 
200.0 
245.0 
Iran Niaee {n=60, lvermectin• 0.4 mg)* 
Baseline 
250.0 
270.0 
165 
n.s•• 
125 
n.s .. 
152 
269 
p<0.05+ 
211 
259 
0.07+ 
213 
p<0.001++ 
p<0.001++ 
156 
199 
n.s** 
145 
n.s•• 
222 
218 
0.06+ 
222 
218 
0.17+ 
0.3 
0.3 
0.3 
0.3 
0.3 
0.3 
n.s•• 
28 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 117 of 141

Day5 
80.0 
245.0 
Iran Niaee (n=SO, lvermectin- 0.4, 0.2, 0.2 mg)* 
Baseline 
Day5 
340.0 
170.0 
*Median presented, all other data mean. 
270.0 
245.0 
p<0.001++ 
p<0.001++ 
•• 'n.s.' was used when no statistically significant difference was found, but the actual p-value was ot reported by the individual authors and could not be calculated by current authors 
+p value compares within group changes from baseline to end point of ivermectin group. ++p value shows significance of total changes from baseline. All other p values compare ivermectin vs. 
control 
Normal ranges: CRP(<10mg/L), Ferritin(H-3361,1gll} D-dimer(<0.5mg!L). 
29 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 118 of 141

0 
Q 
Table 3: Effects of ivermectin on viral clearance 
~ 
~ 
Table 3A: 
o. 
a, 
Ct 
··• 
0 
3 
Study 
Country (n) 
Daily dose 
Duration 
Viral load 
Result 
P value 
::r 
,:;; 
endpoint 
" 
!',f, 
:..:, 
IVM VS Control 
I\\' 
,., 
"' 
a. 
"' 
Number Detectable or Undetectable (%) 
g, 
0 
C u 
0 
Mahmud et al 
Bangladesh, 
12 mg 
1 day (DB) 
Undetectable 
92% vs 80% 
p < 0.001 
0 ! 
a: 
n=363 
Day 14 
?if 
n. 
< 
P} 
:::; 
" 
"' 
Asghar et al 
Pakistan, 
0.2 mg/kg 
1 day 
Undetectable 
90% vs 44% 
p < 0.001 
ii 
~ 
ft 
c. 
n=86 
Day? 
5 
p 
~ 
0 
Mohan eta! 
flldia, 
0.2mg/kg 
1 day 
Undetectable 
35% VS 31% 
p::: 0.3 
(D 
u a· 
"" 
n=125 
Elixir 
Day5 
~ 
'"' 
c-
(,.", 
en 
OJ 
Mohan et al 
India, 
0.4mg/kg 
1 day 
Undetectable 
48% vs 31% 
p =0.3 
<Yi 
':'.;: 
m 
N 
n=125 
Elixir 
Days 
~ 
0 
'< 
'@ 
"' 
Kirti et al 
India, 
12 mg 
2 days 
Undetectable 
24% VS. 32% 
p = 0.35 
¼. g 
0 
n=112 
Day6 
N 
(JJ 
'" j 
3 
l:Y 
30 
~ 
"' 
0 
!',) 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 119 of 141

Podder et al 
Okumus et al 
Bangladesh, 
n=62 
Turkey, 
n=60 
Schwartz et al 
Israel n=100 
0.2 mg/kg 
1 day (OL) 
0.2 mg/kg 
5 days (OB) 
12~15mg 
3 days (OB} 
Day 10 PCR neg 
Day 10 PCR 
Neg 
Day 10 PCR Neg 
Ct>30 
90% vs 95% 
88% vs 38% 
81% vs 60% 
p > 0.05 
p = 0.01 
p=0.02 
31 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 120 of 141

a 
Table 38: Effects of lvermectin cm Time to Viral Clearance 
Q 
Ce' 
::, 
0 ,, 
l1 
Ill 
Q. 
3' 
Study 
Country (n) 
Daily dose 
Duration 
J 
Viral load 
Result 
P value 
~ 
endpoint 
ti 
'" 
IVM VS Control 
~ 
£ 
Q. 
~ 
Time to Viral Clearance (Days) 
ff 
Q 
;::: 
ti g 
Chowdhury 
Bangladesh, 
0.2 mg/kg 
1 day (DB} 
Time to PCR neg 
9 vs 9.3 days 
p = 0.23 
3 g 
0, 
n=112 
'" 
0, 
< 
ID 
::, n 
Elgazzar et al 
Egypt, 
0.4 mg/kg 
5 days (OL) 
Days detectable 
5 vs 10 days 
p < 0.001 
X 
cl. 
Q. 
"' 
Mild/Moderate 
n=200 
0: g 
E: 
0 
Elgazzar et al 
Egypt, 
0.4 mg/kg 
5 days (OL) 
Days detectable 
6 vs 12 days 
p < 0.001 
m 
w 
0 
~ 
8: 
Severe 
n=200 
0 it 
v 
v) 
t.J'l 
a, 
Babaloa et al 
Nigeria, 
0.1 mg/kg 
2 / week (DB) 
Time to PCR neg 
6 vs 9 days 
p = 0.003 
a, 
::: 
* 
cr, 
1::: 
n=60 
-1' 
Ci 
'< 
"'1 
fiS 
Babaloa et al 
Nigeria, 
0.2 mg/kg 
2 /week (DB) 
Time to PCR neg 
4.7 VS 9 days 
p = 0.003 
n 
g 
* 
CJ 
n=60 
N 
(/) 
"' 
"{) 
fo~ 
3 v 
32 
;J; 
N 
C 
"'' 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 121 of 141

Ahmed et al* 
Bangladesh, n=72 
0.2 mg/kg 
5 days (OB) 
Time to PCR neg 
10 VS 13 days 
p = 0.02 
Ahmed et al* 
Bangladesh, n=72 
0.2 mg/kg 
1 days (DB) 
Time to PCR neg 
11.5 vs 13 days 
p = 0.27 
Petkov et al 
Bulgaria n=100 
0.4 mg/kg 
3 days {DB) 
Time to PCR neg 
4.52 VS 5.06 
p=0.341 
33 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 122 of 141

Table 3C: Effect of ivermectin on other measures of viral clearance. 
Study 
Country (n) 
Daily dose 
Duration 
Viral load 
Result 
P value 
endpoint 
IVM vs Control 
Other Measures of Viral clearance 
Raad et al 
Lebanon, 
0.2 mg/kg 
1 day 
Day3 
Ct values 
p = 0.01 
n=100 
30.1 ± 6.22 
vs. 18.96 ± 3.26 
Krolewiecki et 
Argentina, 
0.6 mg/kg 
5 days 
PK/PD 
Dose-related 
p = 0.02 
al* 
n=45 
*Dose-response effect seen 
34 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 123 of 141

Table 4: Effects on of ivermectin on clinical recovery and hospitalization 
Table 4A: Time to clinical recovery 
Study 
Country 
Daily dose 
Duration 
Endpoint 
Results 
P value 
IVM vs control 
Time to clinical recovery 
Mohan etal 
India 
0.2mg/kg 
1 day (SB) 
Time to clinical 
4.8 vs 4.6 days 
p = 0.77 
recovery 
n=125 
Elixir 
Mohan et at 
India 
0.4 mg/kg 
1 day (SB) 
Time to clinical 
4.3 vs 4.6 days 
p = 0.77 
recovery 
n=125 
Elixir 
Hashim eta! 
Iraq 
0.2 mg/kg 
2-3 days (SB) 
Time to clinical 
10.6 VS 17.9 days 
p < 0.001 
recovery 
n=140 
Chowdhury et al 
Bangladesh 
0.2 mg/kg 
1 day (DB) 
Time 1o clinical 
5.9 VS 6.9 days 
p = 0.071 
recovery 
n=116 
35 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 124 of 141

Podder et al 
Bangladesh 
0.2 mg/kg 
1 day(OL) 
Time to clinical 
5.3 vs 6.3 days 
p > 0.05 
recovery 
n=62 
Rezai et al 
Iran 
0.2 mg/kg 
1 days (OL) 
Time to clinical 
4.1 vs 5.2 days 
p = 0.018 
recovery 
n=69 
Lopez-Medina et al 
Colombia 
0.3 mg/kg 
5 days (DB) 
Time to clinical 
10 vs 12 days 
p=0.53 
recovery 
n=398 
36 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 125 of 141

Table 48: Effect of ivermectin on duration of hospitalization 
Study 
Country 
Daily dose 
Duration 
Endpoint 
Results 
P value 
IVM VS control 
Duration of hospitalization 
Rezai et al 
Iran 
0.2 mg/kg 
1 days (OL) 
Days in hospital 
6.9 VS 8.4 days 
p = 0.01 
n=69 
Raad et al 
Lebanon 
0.2 mg/kg 
1 day (Ol) 
Hospitalization 
0% vs6% 
p = 0.00 
n=i00 
Niaee et al 
Iran 
0.2 - 0.4 mg/kg 
1-3 days (DB) 
Days in hospital 
6.5 vs 7.5 days 
p = 0.006 
n=165 
Elgazzar et al 
Egypt 
0.4 mg/kg 
5 days (Ol) 
Days in hospital 
5 vs 15 days 
p < 0.001 
Mild/moderate 
n=200 
Elgazzar et al 
Egypt 
0.4 mg/kg 
5 days (Ol) 
Days in hospital 
6 vs 18 days 
p < 0.001 
37 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 126 of 141

Severe 
n=200 
Ahmed et al 
Bangladesh, 
0.2 mg/kg 
5 days (DB) 
Days in hospital 
9.6 VS 9.7 
p=0.93 
n=72 
Ahmed et al 
Bangladesh, 
0.2mg/kg 
1 days (DB) 
Days in hospital 
10.1 VS 9.7 
p=0.93 
n=72 
Abd El-Salam et al 
Egyptn=164 
12 mg 
3 days 
Days in hospital 
8.82 vs. 10.97 
p=0.09 
Gonzalez et al 
Mexico 
12mg 
1 day 
Days in hospital 
6 vs 5 
p=0.45 
n=106 
38 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 127 of 141

Table 4C: Number of Participants with clinical recovery by Day 7to 10 post"randomization 
Study 
Country 
Daily dose 
Duration 
Endpoint 
Results 
P value 
IVM vs control 
Number of Participants Recovered (%} 
Chachar et al 
Pakistan 
0.2 mg/kg 
2 days (Ol) 
Day 7 Clinical 
64%vs 60% 
p =0.5 
recovery 
n=50 
Okumus et al 
Turkey 
0.2 mg/kg 
5 days (DB) 
Day 10 Clinical 
73% vs 53% 
p = 0.10 
n=60 
improvement 
Mahmud etal 
Bangladesh 
12 mg 
1 day (DB) 
Day 7 Clinical 
61% VS 44% 
p <0.03 
recovery 
n=363 
Petkov et al 
Bulgaria 
0.4 mg/kg 
3 days (DB) 
Day 7 Clinical 
20% VS 14% 
n/a 
n=100 
recovery 
Elgazzar et al 
Egypt, 
0.4 mg/kg 
5 days (OL) 
Clinical 
99% VS 74% 
p<0.001 
improvement 
Mild/Moderate 
n=200 
39 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 128 of 141

Elgazzar et al 
Egypt, 
0.4 mg/kg 
5 days (Ol) 
Severe 
n=200 
Chah!a et al 
Argentina 
24mg 
1/ week for 4 
n=254 
weeks (Ol) 
Clinical 
94% VS 50% 
improvement 
Clinical 
98% vs 87% 
improvement 
p<0.001 
p=0.0007 
40 
cr 
'< 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 129 of 141

Table 5: Effects of ivermectin on survival 
Trial 
Country 
Mahmud eta! 
Bangladesh 
Niaee et al 
Iran 
Hashim et al 
Iraq 
E!gazzar et al 
Egypt 
Okumusetal 
Turkey 
Kirti et al 
India 
Rezai et al 
Iran 
Abd-E!salam 
Egypt 
Gonzalez 
Mexico 
Dosing 
0.2 mg/kg, 1 day 
0.2 mg/kg 1-3 days 
0.2-0.4 mg/kg 2-3 days 
0.4 mg/kg 5 days 
0.2 mg/kg, 5 days 
12 mg, 5 days 
0 .2 mg/kg, 1 day 
0.2 mg/kg, 3 days 
0 .2 mg/kg, 1 day 
lvermectin 
0/183 
4/120 
2/70 
2/200 
6/30 
0/55 
1/35 
3/82 
5/36 
Control 
3/180 
11/60 
6/70 
24/200 
9/30 
4/57 
0/34 
4/82 
6/37 
41 
0 ::, 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 130 of 141

Lopez-Medina 
Colombia 
0.3 mg/kg 5 days 
0/200 
1/198 
Fonseca 
Brazil 
14mg 3 days 
12/53 
25/115 
Total 
35/1064 (3%) 
93/1063 (8.7%} 
42 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 131 of 141

.FlgurelA 
1A) 
lvermectin 
Control 
Mean Difference 
Study or Subgroup 
Mean 
SD Total Mean SD Total Weight 
IV, Random, 95% CJ 
5.2.l Single-day dosing 
Ahmed et al IVM+Doxy 
Bangladesh Chowdhury et al 
Subtotal (95% Cl) 
11.5 4.2 
9 
l.S 
24 
12.7 3.6 
60 
9.7 2.2 
84 
24 
12.2% 
-1.20 [-3.41, 1.01] 
56 
14.2% -·0,70 [-1.39, ··0.0ll 
80 
26.4% -0.74 [-1.40, -0.09} 
Heterogeneity: Tau' "'0.00; Chi' "' 0.18, df = 1 (P = 0.67); !1 "' 0% 
Test for overall effect: Z "" 2.21 (P"' 0.03} 
5.2.2 Multi-day dosing 
Ahmed et al IVM Sdays 
9.7 
5 
24 
12.7 3.6 
24 
Babalola et al 12mg 
4.7 3.2 
20 
9.2 7.4 
20 
Babalola et al 6mg 
6 
3 
20 
9.2 7.4 
20 
Bulgaria Petkov et al 
4.5 
2.8 
50 
5.1 2.9 
so 
Egypt Elgazzar Moderate 
s 
1 
100 
10 
4 
100 
Egypt Etgazzar Severe 
6 
1 
100 
12 
4 
100 
Subtotal (95% Cl) 
314 
314 
11.8% 
9.8% 
9.9% 
13.8% 
14.1% 
14.1% 
73.6% 
Heterogeneity: Tau2 "" 5.22; Chf ·"' 63.30, df"" 5 (P < 0.00001): 12 "" 92% 
Test for overall effect: Z "' 3.62 (P "' 0.0003) 
-3.00 [-5.46, -0.54) 
-4.so Hl.03, -0.97! 
-3.20 H:..70, o.30J 
··0.60 { 1.72, 0.52J 
-5.00 [-5.81, -4.191 
-6.00 (-6.81, -5.19] 
-3.74 [-5.77, -1.721 
Total (95% Cl) 
398 
394 100.0% -3.00 [-4.96, -1.03} 
Heterogeneity: Tau' = 6.94; Chi' = 139.86, df"' 7 (P < 0.00001); 12 "' 95% 
Test for overall effect: Z = 2.99 (P = 0.003) 
Test for subqroup differences: Chi' = 7.61, df = l (P = 0.006), !2 = 86.9% 
Mean Difference 
IV, Random, 95% Cl 
• 
---.-.--
-----.-. --
~--,.,,."'$: -· 
--~-
~ • 
I■ 
0 
2 
4 
Favours lvermectm Favours Control 
0 
3 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 132 of 141

Figure lB 
18) 
lvermectin 
Control 
... ~~~.r or Subiroup 
Events Total Events Total Weight 
3.7.l Single-day dosing 
Ahmed et al IVM+Doxy 
7 
24 
3 
24 
3.7% 
India Mohan et al 0.2mg/kg 
13 
36 
16 
42 
11.1% 
India Mohan et al 0.4mg/kg 
16 
36 
16 
42 
12.3% 
Pakistan Asghar et al 
37 
41 
20 
45 
17.8% 
Subtotal (95% Cl) 
137 
153 
44.9% 
Total events 
73 
55 
Heterogeneity: Tau1 = 0.10; Chi2 "'6.67, df = 3 (? = 0.08); 12 = 55% 
Test for overall effect: Z == 1. 71 (P == 0.09) 
3.7.2 Multi-day dosing 
Ahmed et al IVM 5days 
11 
24 
3 
24 
4.2% 
Bulgaria Petkov et al 
40 
50 
37 
50 
22.1% 
India Kirti et al 
13 
32 
18 
44 
11.8% 
Israel Schwartz et al 
33 
49 
21 
45 
17.0% 
Subtotal (95% Cl) 
155 
163 
55.1% 
Tota! events 
97 
79 
Heterogeneity; Tau2 == 0.05; Chi' = 5.93, df"" 3 (P = 0.11); tl = 49% 
Test for overall effect: Z = 1.45 (P == 0.15) 
Total (95% Cl) 
292 
316 100.0% 
Total events 
170 
134 
Heterogeneity: Tau'= 0.06: Chi'"' 15.90, df = 7 (P"" 0.03); 12 "" 56% 
Test for overall effect: Z = 2.33 (P"" 0.02) 
Test for subgroup differences: Chi" = 0.29, df"" l (P"' 0.59), I' = 0% 
Risk Ratio 
IV, Random, 95% Cl 
2.33 {0.68, 7.97) 
0.95 [0.53, 1.69) 
1.11 {0.69, l.98l 
2.03 [1.44, 2 .86] 
1.45 {0.95, 2.23) 
3.67 [1.17, 11.52J 
1.08 [0.87, 1.34! 
0.99{0.57, 1.721 
1.44 [1.00, 2.091 
1.26 (0.92, 1.71] 
1.35 (1.05, 1.75] 
Risk Ratio 
IV, Random, 95% Cl 
---+= -
T 
l --
j 
r 
• 
0.01 
0.1 
1 
10 
100 
Favours Control Favours lvermec:tin 
44 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 133 of 141

Figure lC 
1C) 
lvermectin Control 
Mean Difference 
Study or Subgroup 
Mean Difference 
SE 
Total 
Total Weight IV, Random, 95% Cl 
2.4.l Single-day dosing 
Bangladesh Chowdhury et al 
Bangladesh Podder et al 
India Mohan et al 0.2mg/kg 
India Mohan et al 0.4mg/kg 
!ran Rezai et a! 
Subtotal (95% Cl) 
-1 
., l 
0.2 
-0.3 
-1.1 
0.31 
60 
0.88 
30 
0.58 
40 
0.61 
40 
0.44 
35 
205 
Heterogeneity: Tau'"' 0.04; Chi' ""4.57, df "'4 (P"" 0.33); f "" 12% 
Test for overall effect: 2 ,,., 3.22 (P"' 0.001) 
2.4.2 Multi-day dosing 
Colombia Lopez Medina et al 
"'2 1.53 
200 
Iraq Hashim et a! 
7.3 L03 
70 
Subtotal (95% Cl) 
270 
Heterogeneity: Tau' = 12.34; Chi' = 8.26, df = 1 (P = 0.004); I'= 88% 
Test for overall effect; Z "' l.80 (P = 0.07) 
Total (95% Cl) 
475 
Heterogeneity: Tau 2 = 2.14; Chi'"" 43.40, df ~ 6 (P < 0.00001); 1z"" 86% 
Test for overall effect: l"" 2.52 (P"' 0.01) 
Test for subqroup differences: Chi2 "' 2.28, df"' 1 (P .. 0.13}, 1' = 56.2% 
56 
17.5% ··l.00 H.61. -0.39] 
32 
13.4% 
··LOO H.72, 0.72) 
45 
15.8% 
0.20 [-0.94, 1.34] 
45 
15.6% 
-0.30 [-1.50, 0.90] 
34 
16.8% -1.10 !-1.96, -0.24J 
212 
79.0% -0.7S [-1.21, -0.30J 
198 
8,7% 
··2.00 H.00, LOOJ 
70 
12.2% ••7.30 [-9.32, -5.28! 
268 
21.0% 
-4.77 Hl-96, 0.42J 
480 10(!.0% -1.58 [-2.80, -0.351 
Mean Oifferenc:e 
IV, Random, 95% Cl 
l 
~I 
t··---··- · · ·•··•··➔-···•• 
j.. 
....... 
·+-.... ,·-- ... ·---• 4 
-10 
.. 5 
0 
5 
10 
favours lvermectin favours Control 
45 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 134 of 141

Figure 1D 
10) 
Experimental 
Control 
Study or Subgroup 
Events 
Total Events Total Weight 
2.1.1 Multi-day Dosing 
Argentina Chahla et al 
108 
llO 
124 
144 
19.4% 
Bangladesh Chac:har et al 
16 
25 
15 
25 
6.6% 
Bulgaria Petkov et al 
10 
50 
7 
50 
2.1% 
Colombia Lopez-Medina et al 
164 
200 
156 
198 
18.5% 
Egypt Elgazzar Moderate 
99 
100 
74 
100 
17.7% 
Egypt Elgazzar Severe 
94 
100 
50 
100 
14.1% 
Turkey Okumus et al 
22 
30 
16 
30 
7.4% 
Subtotal (95% Cl) 
615 
647 
85.9% 
Total events 
513 
442 
Heterogeneity: Taut = 0.03; Chi' "' 33.03, df"" 6 {P < 0.0001}; 12 = 82% 
Test for overall effect: Z"" 3.17 (P"" 0.002) 
2.1.2 Single-day dosing 
Bangladesh Mahmud et al 
Subtotal (95% Cl) 
111 
Total events 
111 
Heterogeneity: Not applicable 
Test for overall effect: Z = 3.04 (P = 0.002) 
Total (95% Cl) 
183 
UB 
798 
80 
180 
14.1% 
180 
14.1% 
80 
827 100.0% 
Total events 
624 
522 
Heterogeneity: Tau' = 0.02; Chi' .. 34.88, df""' 7 (P < 0.0001}; I' = 80% 
Test for overall effect: Z"' 3.65 (P"" 0.0003} 
Test for subqroup differences: Chi2 = 0.27, df"' 1 (P"' 0.60), 11 = 0% 
Risk Ratio 
IV, Random, 95% Cl 
1.14 11.06, 1.22} 
1.07 [0.69, 1.65] 
1.43 [0.59, 3.45J 
1.04 [0.94, 1.15] 
1.34 [1.19, 1.51] 
1.88 [1.54, 2.30} 
1.38 {0.92, 2.05) 
1.28 [1.10, 1.481 
1.36 {1.12, 1.67] 
1.36 (1.12, 1.671 
1.29 [1.12, 1.47J 
Risk Ratio 
IV, Random, 95% Cl 
....... 
·-· - __ _, . .,.-·~· 
,.., 
• 
l 
1.5 
2 
Favours Control Favours lvermectin 
46 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 135 of 141

Figure lE 
1E) 
lvermectin 
Control 
Study or Subgroup 
Mean 
SD Total Mean SD Total Weight 
6.2.l Multi-day dosing 
Ahmed et al IVM Sdays 
9.6 
s 
24 
9.7 
4 
24 
16.2% 
Egypt Abd-Elsalarn et al 
8.8 4.9 
82 10.97 5.2 
82 
16.8% 
Egypt Elgazzar Moderate 
s 
1 
100 
15 
8 
100 
16.8% 
Egypt Elgazzar Severe 
6 
1 
100 
18 
8 
100 
16.8% 
Subtotal (95% Cl) 
306 
306 
66.7% 
Heterogeneity: Tau2 = 30.04; Chi'= 117.60, df = 3 (P < 0.00001); 11 "' 97% 
Test for overall effect: Z "' 2.20 (P"" 0.03) 
6.2.2 Single-day dosing 
Ahmed et al !VM+Doxy 
10.l 
4 
24 
9.7 
4 
24 
Iran Rezai et al 
6.9 3.1 
34 
8.4 3.3 
35 
Subtotal (95% Cl) 
58 
59 
Heterogeneity: Tau 2 ,,, 0.84; Chi' = l.87, df = 1 (P "' 0.17); 12 "' 4 7% 
Test for overall effect: Z "' 0.80 (P "' 0.42) 
16.4% 
16.9% 
33.3% 
Total (95% Cl) 
364 
365 100.0% 
Heterogeneity: Tau1 "' 28.42; Chi1 "" 183.11, df = 5 (P < 0.00001); I'= 97% 
Test for overall effect: l = 1.93 (P"" 0.05) 
Test for subgroup differences: Chi2 = 3.36, df = 1 (P"" 0.07}, !2 "' 70.2% 
Mean Difference 
IV, Random, 95% Cl 
-0.10 [-2.66, 2.46] 
-2.17 f-3.72, -0.621 
-10.00 [-11.58, -8.421 
-12.00 [-13.58, -10.42) 
-6.12 [-11.57, -0.67] 
0.40 [-1.86, 2.661 
-1.50 [-3.01, 0.011 
-0.74 [-2.57, 1.08) 
-4.27 Ht60, o.o6J 
Mean Difference 
IV, Random, 95% Cl 
. , .. _J ·••····· 
-
~ 
-~, ..... rr-
·-· 
-10 
-5 
0 
5 
10 
Favours lvermectin Favours Control 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 136 of 141

Figure 1F 
1F) 
Study or Subgroup 
Bangladesh Chowdhury et al 
Colombia Lopez-Medina et al 
Israel Schwartz et al 
Lebanon Raad et al 
Total (95% Cl) 
lvermectin 
Events Total 
0 
60 
4 
200 
0 
49 
0 
50 
359 
Control 
Events Total 
2 
56 
6 
198 
3 
45 
3 
50 
Weight 
11.2% 
65.2% 
11.8% 
11.8% 
349 100.0% 
Total events 
4 
14 
Heterogeneity: Tau 2 = 0.00; Chi 2 "' 1.88, df"' 3 (P"" 0.60); 12 "" 0% 
Test for overall effect: Z = 1.80 (P = 0.07) 
Risk Ratio 
IV, Random, 95% Cl 
0.19 [0.01, 3.81} 
0.66 [0.19, 2.30] 
0.13 [0.01, 2.48] 
0.14 [0.01, 2.70J 
0.40 [0,14, 1.08] 
Risk Ratio 
IV, Random, 95% Cl 
----------------,-4--
0.005 
0.1 
1 
10 
200 
Favours lvermectin Favours Control 
48 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 137 of 141

Figure 1G 
1G) 
lvetmectin 
Control 
Risk Ratio 
Study or Subgroup 
·-·-- EY!:ri_ts . I~t-~--Events __ To~al ___ Weight IV, Ran<l_om, 95% Cl 
4.3.1 Severe · 
· 
· 
Brazil Fonseca et al 
Egypt Elgazzar Severe 
Mexico Gonzalez et al 
Turkey Okumus et al 
Subtotal (95% Cl) 
12 
2 
5 
6 
53 
25. 
100 
20 
36 
6 
30 
9 
219 
Total events 
2 5 
60 
115 
18.4% 
100 
9.4% 
37 
12.5% 
30 
14.7% 
282 
SS.0% 
Heterogeneity: Tau2 = 0.45; Chi'=- 8.90, df = 3 (P = 0.03); I'= 66% 
Test for overall effect: Z = 1.30 (f' ~ 0.19) 
4.3.2 Mild/moderate 
Bangladesh Mahmud et al 
0 
183 
3 
180 
3.2% 
Colombia Lopez-Medina et al 
0 
200 
198 
2.8% 
Egypt Abd-E!salam et al 
3 
82 
4 
82 
9.1% 
Egypt Elgazzar Moderate 
0 
100 
4 
100 
3.2% 
India Kirti et al 
0 
55 
4 
57 
3.3% 
Iran Niaee et al 
4 
120 
11 
60 
12.4% 
Iran Rezai €! al 
l 
35 
0 
34 
2.8% 
Iraq Hashim et al 
2 
70 
6 
70 
8.4% 
Subtotal (95% Cl) 
845 
781 
45.0% 
Total events 
10 
33 
Heterogeneity: Tauz = 0.00; Chi' = 5.42, df ~ 7 (P ~ 0.61); I' ~ 0% 
Test for overall effect: Z "" 3.57 (P = 0.0004) 
Total (95% Cl) 
1064 
1063 100.0% 
Total events 
35 
93 
Heterogeneity: Tau2 = 0.35; Chi2 "' 19.24, df = 11 (P = 0.06); I'= 43% 
Test for overall effect: Z = 2.85 {P"' 0.004) 
Test for subgroup differences: Chi'= 1.54, df'" l (P"' 0.21), !' = 35.1% 
1.04 [0.57, 1.911 
0.10 {0.02, 0.42] 
0.86 [0.29, 2.56] 
0.67 [0.27, l.64J 
0.58 {0.25, 1.321 
0.14 [0.01, 2.70) 
0.33 f0.Gl, 8.0SJ 
0.75 [0.17, 3.25] 
0.11 [0.0 l, 2.04] 
0.12 f0.01, 2.091 
0.18 [0.06, 0.55) 
2.92 [0.12, 69.20) 
0.33 [0.07, 1.60] 
0.30 10.15, 0.58! 
0,44 !0.25, 0.77! 
-l 
·•··"·-·•··••·~······· ~~-
--~-,.+---
··-·••···•·••,- ...j ·• 
.... ~-···- t 
0 
0.01 
0.1 
1 
10 
100 
favours lvermectin favours Control 
49 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 138 of 141

Figure lH 
1H} 
lvermectin 
Control 
Study or Subgroup 
Events Total Events Total Weight 
Argentina Krolewiecki et al 
1 
30 
0 
15 
3.0% 
Brazil Fonseca et al 
12 
53 
24 
115 
78.5% 
Egypt Abd-Elsalam et al 
3 
82 
3 
82 
11.9% 
India Kirti et al 
1 
55 
5 
57 
6.6% 
India Mohan et al 
0 
100 
0 
52 
Total (95% Cl) 
320 
321 100.0% 
Total events 
17 
32 
Heterogeneity: Tau 2 = 0.00: Chi 2 == 2.26, df = 3 (P:::: 0.52); 12 = 0% 
Test for overall effect Z = 0.10 (P == 0.92) 
Risk Ratio 
IV, Random, 95% Cl 
1. 5 5 [0.07, 35 .89} 
1.08 [0.59, 2.00} 
1.00 [0.21, 4.81] 
0.21 [0.03. 1.721 
Not estimable 
0.97 [0.57, 1.67] 
Risk Ratio 
IV, Random, 95% Cl 
0.01 
0.1 
1 
10 
Favours lvermectin Favours Control 
100 
50 
0 ::, 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 139 of 141

People in Bolivia and elsewhere have been buying ivermectin as protection against COVID-19, 
FLAWED PREPRINT 
HIGHLIGHTS CHALLENGES 
OF COVID DRUG STUDIES 
Paper's withdrawal from online platform deals blow 
to an anti-parasite drug's promise to treat COVID-19. 
By Sara Reardon 
T
hroughout the pandemic, the anti· 
parasite drug ivermectin has attracted 
much attention, particularly in Latin 
America, as a potential way to treat 
COVID-19. But scientists say that 
recent, shocking revelations of widespread 
flaws in the data of a preprint study reporting 
that the medication greatly reduces COVID-19 
deaths have dampened ivermectin's promise 
-and highlightthechallenges ofinvestigating 
drug efficacy during a pandemic. 
"I was shocked, as everyone in the scientific 
community probably were;' says Eduardo 
Lopez-Medina, a paediatrician at the Centre 
for the Study of Paediatric Infections in Cali, 
Colombia, who was not involved with the study 
and who has investigated whetherivermectin 
can improve COVID-19 symptoms. "It was one 
of the first papers that led everyone to get into 
the idea iverrnectin worked" in a clinical-trial 
setting, he adds. 
The paper summarized the results of a din-
ica I trial seeming to show that ivermectin can 
reduce COVID• 19 death rates by more than 
90% (ref. I) -among the largest studies of the 
drug's ability to treat COVID-19 so far. But on 
14 July, after Internet sleuths raised concerns 
about plagiarism and data manipulation, the 
preprint server Research Square withdrew the 
paper because of"ethical concerns". 
Ahmed Elgazzar at Benha University in 
Egypt, who is one of the authors of the paper, 
told Nature he was not given a chance to 
defend his work before it was removed. 
Early in the pandemic, scientists showed 
that ivermectin could inhibit the coronavirus 
SARS·CoV-2 in cells in laboratory studies2• But 
data on ivermectin's efficacy against COVID-19 
in people are still scarce, and study conclu-
sions conflict greatly, making the withdrawal 
of a major trial particularly noteworthy. 
Although the World Health Organization 
advisesagainsttakingivermectinasa COVlD-19 
treatment outside clinical trials, the over-the-
counter drug has become popular in some 
regions of the world. Some view it as a stop· 
gap until vaccines become available in their 
areas, even though it has not yet been proved 
effective. Scientists worry that it will also be 
seen as an alternative to vaccines, which are 
highly effective. 
The paper's irregularities came to light when 
Jack Lawrence, a master's student at the Uni-
versity oftondon, was reading it for a class 
assignment and noticed that some phrases 
were identical to those in other published 
© 2021 Springer Nature Limited. All rights reserved. 
work. When he contacted researchers who 
specialize in detecting fraud in scientific pub· 
Ii cations, the group found other causes for 
concern, including dozens of patient records 
that seemed to be duplicates, inconsistencies 
between the raw data and the information in 
the paper, patients whose records indicate 
they died before the study's start date, and 
numbers that seemed to be too consistent to 
have occurred by chance. 
In an editorial note, Research Square said 
that it has launched a formal investigation into 
the concerns raised by Lawrence and his col-
leagues. According to the Egyptian newspaper 
Al·Sharouk, Egypt's minister of higher educa· 
tion and scientific research is also examining 
the allegations. 
The paper was "withdrawn from the 
Research Square platform without informing 
or asking me", Elgazzar wrote in an e-mail to 
Nature. He defended the paper, and said of the 
plagiarism allegations that "often phrases or 
sentences are commonly used and referenced" 
when researchers read one another's papers. 
Ripple effects 
Although dozens of ivermectin clinical trials 
have been launched over the past year3, the 
Elgazzar paper was notable for announcing 
one of the first positive results, as well as for 
its size - it included 400 people with symp• 
toms ofCOVID-19-and the magnitude of the 
drug's effect. few therapies can claim such an 
impressive reduction in death rates. "It was a 
significant difference, and that stood out;' says 
Andrew Hill, who studies repurposed drugs at 
the University of Liverpool, UK. "It should have 
raised red flags even then." 
Before its withdrawal, the paper was 
viewed more than 150,000 times, cited more 
than 30 times and included in a number of 
meta-analyses that collect trial findings into 
a single, statistically weighted result. In one 
meta-analysis in the American Journal of 
Therapeutics that found ivermectin greatly 
reduced COVID· 19 deaths4, the Elgazzar paper 
accounted for 15.5% of the effect. 
One of the authors of the meta-analysis, 
statistician Andrew Bryant at Newcastle Uni· 
versity, UK, says that his team corresponded 
with E!gazzar before publishing the work to 
clarify some data. "We had no reason to doubt 
the integrity ofElgazzar ;' he said in an e-mail. 
He added that in a pandemic setting, no one 
can reanalyse all of the raw data from patient 
records when writing a review. Bryant went on 
to say that his group will revise the conclusion 
ifinvestigations find the study to be unrelia-
ble. However, even if the study is removed, the 
meta-analysis would still show that ivermec· 
tin causes a major reduction in deaths from 
COVID-19, he says. 
The paper's withdrawal is not the first scan-
dal to dog studies ofivermectin and COVID• 19. 
Hill thinks many of the other ivermectin trial 
Nature I Vol 596 I 12 August 2021 I 173 
EXHIBITN 
Case 3:22-cv-00184   Document 12-27   Filed on 08/08/22 in TXSD   Page 140 of 141

News in focus 
papers that he has scanned are likely to be 
flawed or statistically biased. Many rely on 
small sample sizes or were not randomized or 
well controlled, he says. And in 2020, an obser-
vational study of the drug was withdrawn after 
scientists raised concerns about it and a few 
other papers using data by the company Sur-
gisphere in Chicago, Illinois, that investigated 
a range ofrepurposed drugs against COVID-19. 
"We've seen a pattern of people releasing infor-
mation that's not reliable;' says Hill. "It's hard 
enough to do work on COVID and treatment 
without people distorting databases." 
Carlos Chaccour, a global-health researcher 
at the Barcelona Institute for Global Health 
in Spain, says it has been difficult to conduct 
rigorous studies on ivermectin. That's partly 
because funders and academics in wealthy 
countries haven't supported them, and, he 
suspects, have often dismissed trials of iver-
mectin because most of them have been done 
in lower-income countries. furthermore, says 
RodrigoZoni, a cardiologist at the Corrientes 
Cardiology Institute in Argentina, it is difficult 
to recruit participants because many people 
- particularly in Latin America - are already 
taking the widely available drug in an attempt 
to prevent COVID-19. 
Adding to the difficulty are conspiracy the· 
ories holding that ivermectin has been proved 
to work and that drug companies are depriving 
the public of a cheap cure. Chaccour says he 
has been called 'genocidal' for doing research 
on the drug rather than just endorsing it. 
Although the jury is still out on ivermectin, 
many say the retraction speaks to the difficulty 
of assessing research during a pandemic. "I 
personally have lost all faith in the results of 
(ivermectin] trials published to date," says 
Gideon Meyerowitz-Katz, an epidemiologist 
at the University of Wollongong in Australia 
who helped Lawrence to analyse the Elgazzar 
paper. It's not yet possible to assess whether 
ivermectin works against COVID-19, because 
the data currently available are not of suffi-
ciently high quality, he says. 
Chaccour and others studying ivermectin 
say that proof of whether the drug is effective 
against COVID-19 rests on a handful oflarge, 
ongoing studies, including a trial in Brazil with 
more than 3,500 participants. By the end of 
2021, says Zoni, around 33,000 people will 
have participated in some kind of ivermectin 
trial. 
"I think it is our duty to exhaust all potential 
benefits;' says Chaccour, particularly given 
that most countries still do not have wide-
spread access to vaccines. "Ultimately if you 
do a trial and it fails, fine, but at least we tried." 
1. 
Elgaz:zar, A. et al. Preprint at Research Square hnps,//doi. 
org/10.21203/rs.3.rs-100956jv3 (2020). 
2. Caly, L., Oruce, J. D., Catton, M. G., Jans. D. A. & 
Wagstaff, K. M. Antiviral Res. 178, 104787 (2020). 
3-
Popp, M. et al. Cochrane Data. System. Rev. httpsJ/doi. 
org/10.1002/14651858.C0015017.pub2 (2021). 
4-
Bryant, A. et al. Am. J. Ther. 28, e434-e460 (2021). 
174 I Nature I Vol 596 I 12 August 2021 
BIDEN URGED TO BLOCK 
POLITICAL MEDDLING 
IN US SCIENCE 
White House science office expected to deliver a 
review of scientific-integrity policies next month. 
By Nidhi Subbaraman 
U 
S researchers and science groups 
appealed to President Joe Biden's 
administration last month to protect 
government science from political 
interference and to empower 
federal scientists to speak to the media and 
public. They made this request during public 
listening sessions hosted by the White House 
Office of Science and Technology Policy 
(OSTP) - the first such sessions held since 
the science office kicked off a massive project 
to bolster scientific integrity in the federal 
government. 
After four years in which former president 
Donald Trump's administration sidelined 
science and scientists in government 
decisions, researchers were hopeful that 
Biden would safeguard independent 
scientific work and communication. In 
January, he made moves in this direction 
when he instructed the OSTP to review 
rules at all US agencies, with the goal of 
ensuring the existence of policies that 
"ban improper political interference in the 
conduct of scientific research". The OSTP 
convened a task force in May, comprising 
nearly 50 representatives from several US 
agencies, to tackle the issue. The group has 
so far met in closed·door sessions and with 
scientific-integrity experts. 
"This level of engagement has not really 
happened before in the federal government 
around the issue of scientific integrity;• says 
Alondra Nelson, the OSTP's deputy director 
for science and society, who co-chairs the task 
force. 
The current effort expands on a push 
to protect scientific integrity that former 
president Barack Obama began a decade ago. 
Policies at US science agencies were the focus 
of that OSTP•led drive, Nelson tells Nature, 
but Bid en's project further aims to guide the 
use of evidence at all government agencies. 
Speaking up 
During three public listening sessions In 
July, attendees urged government agencies 
to be transparent about how science is used 
in policy and regulation, and recommended 
that scientists be enabled to pursue their work 
without political interference- and be free to 
speak about it. 
Andrew Rosenberg, director of the Center 
for Science and Democracy at the Union of 
Researchers have urged the White House to safeguard science against political interference. 
© 2021 Springer Nature Limited. All rights reserved. 
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