Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial | Infectious Diseases | JAMA | JAMA Network
[Skip to Navigation]
Sign In
Visual Abstract. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19
Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19
Figure 1.  Enrollment, Randomization, and Treatment Assignment
Enrollment, Randomization, and Treatment Assignment

RT-PCR indicates reverse transcriptase–polymerase chain reaction.

aPatients with mild disease were at home or hospitalized but not receiving high-flow nasal oxygen or mechanical ventilation (invasive or noninvasive). Patients with severe pneumonia were receiving high-flow nasal oxygen, mechanical ventilation (invasive or noninvasive), or extracorporeal membrane oxygenation.

bThe numbers of patients with these exclusion criteria were not collected.

cAspartate aminotransferase and alanine aminotransferase.

dEight patients used ivermectin within 5 days prior to randomization, 1 had a positive pregnancy test, 1 was asymptomatic, 1 lived in an inaccessible area, and 1 had onset of symptoms 8 days prior to randomization.

ePatient was asymptomatic and was randomized to receive placebo but received ivermectin.

fUse of ivermectin before randomization.

gIncludes deaths and recoveries.

Figure 2.  Time to Resolution of Symptoms in the Primary Analysis Population
Time to Resolution of Symptoms in the Primary Analysis Population

The cumulative rate of symptom resolution is the percentage of patients who experienced their first day free of symptoms. All patients were followed up for 21 days.

Table 1.  Demographic and Clinical Characteristics of the Patients at Baseline and Medications Initiated Since Symptom Onset in the Primary Analysis Population
Demographic and Clinical Characteristics of the Patients at Baseline and Medications Initiated Since Symptom Onset in the Primary Analysis Population
Table 2.  Outcomes in the Primary Analysis Population
Outcomes in the Primary Analysis Population
Table 3.  Summary of Adverse Events During the 21-Day Follow-up Period in the Primary Analysis Population
Summary of Adverse Events During the 21-Day Follow-up Period in the Primary Analysis Population
1.
Omura  S.  Ivermectin: 25 years and still going strong.   Int J Antimicrob Agents. 2008;31(2):91-98. doi:10.1016/j.ijantimicag.2007.08.023 PubMedGoogle ScholarCrossref
2.
Yang  SNY, Atkinson  SC, Wang  C,  et al.  The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer.   Antiviral Res. 2020;177:104760. doi:10.1016/j.antiviral.2020.104760 PubMedGoogle Scholar
3.
Wagstaff  KM, Sivakumaran  H, Heaton  SM, Harrich  D, Jans  DA.  Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus.   Biochem J. 2012;443(3):851-856. doi:10.1042/BJ20120150 PubMedGoogle ScholarCrossref
4.
Mastrangelo  E, Pezzullo  M, De Burghgraeve  T,  et al.  Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug.   J Antimicrob Chemother. 2012;67(8):1884-1894. doi:10.1093/jac/dks147 PubMedGoogle ScholarCrossref
5.
Tay  MY, Fraser  JE, Chan  WK,  et al.  Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5: protection against all 4 DENV serotypes by the inhibitor Ivermectin.   Antiviral Res. 2013;99(3):301-306. doi:10.1016/j.antiviral.2013.06.002 PubMedGoogle ScholarCrossref
6.
Frontline Covid-19 Critical Care Alliance. Accessed December 19, 2020. https://covid19criticalcare.com/
7.
US Senate Committee on Homeland Security & Governmental Affairs. Early outpatient treatment: an essential part of a COVID-19 solution, part II. Accessed December 19, 2020. https://www.hsgac.senate.gov/early-outpatient-treatment-an-essential-part-of-a-covid-19-solution-part-ii
8.
Caly  L, Druce  JD, Catton  MG, Jans  DA, Wagstaff  KM.  The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro.   Antiviral Res. 2020;178:104787. doi:10.1016/j.antiviral.2020.104787 PubMedGoogle Scholar
9.
de Melo  GD, Lazarini  F, Larrous  F,  et al.  Anti-COVID-19 efficacy of ivermectin in the golden hamster.   bioRxiv. Preprint posted November 22, 2020. doi:10.1101/2020.11.21.392639Google Scholar
10.
Arévalo  A, Pagotto  R, Pórfido  J,  et al.  Ivermectin reduces coronavirus infection in vivo: a mouse experimental model.   bioRxiv. Preprint posted November 2, 2020. doi:10.1101/2020.11.02.363242 Google Scholar
11.
Ministerio de Salud, República del Perú. Resolución ministerial No. 270-2020-MINSA. Accessed December 19, 2020. https://cdn.www.gob.pe/uploads/document/file/694719/RM_270-2020-MINSA.PDF
12.
Rodriguez Mega  E. Latin America’s embrace of an unproven COVID treatment is hindering drug trials. Nature. Accessed December 19, 2020. https://www.nature.com/articles/d41586-020-02958-2
13.
Ministerio de Salud, Gobierno del Estado de Bolivia. Resolución ministerial No. 0259. Accessed December 19, 2020. https://www.minsalud.gob.bo/component/jdownloads/?task=download.send&id=425&catid=27&m=0&Itemid=646
14.
Molento  MB.  COVID-19 and the rush for self-medication and self-dosing with ivermectin: a word of caution.   One Health. 2020;10:100148. doi:10.1016/j.onehlt.2020.100148 PubMedGoogle Scholar
15.
Siddiqi  HK, Mehra  MR.  COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal.   J Heart Lung Transplant. 2020;39(5):405-407. doi:10.1016/j.healun.2020.03.012 PubMedGoogle ScholarCrossref
16.
Mahajan  UV, Larkins-Pettigrew  M.  Racial demographics and COVID-19 confirmed cases and deaths: a correlational analysis of 2886 US counties.   J Public Health (Oxf). 2020;42(3):445-447. doi:10.1093/pubmed/fdaa070 PubMedGoogle ScholarCrossref
17.
Karaca-Mandic  P, Georgiou  A, Sen  S.  Assessment of COVID-19 hospitalizations by race/ethnicity in 12 states.   JAMA Intern Med. 2021;181(1):131-134. doi:10.1001/jamainternmed.2020.3857 PubMedGoogle ScholarCrossref
18.
Cao  B, Wang  Y, Wen  D,  et al.  A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19.   N Engl J Med. 2020;382(19):1787-1799. doi:10.1056/NEJMoa2001282 PubMedGoogle ScholarCrossref
19.
Beigel  JH, Tomashek  KM, Dodd  LE,  et al; ACTT-1 Study Group Members.  Remdesivir for the treatment of COVID-19: final report.   N Engl J Med. 2020;383(19):1813-1826. doi:10.1056/NEJMoa2007764 PubMedGoogle ScholarCrossref
20.
Spinner  CD, Gottlieb  RL, Criner  GJ,  et al; GS-US-540-5774 Investigators.  Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial.   JAMA. 2020;324(11):1048-1057. doi:10.1001/jama.2020.16349 PubMedGoogle ScholarCrossref
21.
World Health Organization. WHO R&D blueprint: novel coronavirus: COVID-19 therapeutic trial synopsis. Accessed December 20, 2020. https://www.who.int/blueprint/priority-diseases/key-action/COVID-19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf
22.
US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Published November 27, 2017. Accessed December 20, 2020. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf
23.
Wu  Z, McGoogan  JM.  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648 PubMedGoogle ScholarCrossref
24.
Mitjà  O, Corbacho-Monné  M, Ubals  M,  et al; BCN PEP-CoV-2 RESEARCH GROUP.  Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial.   Clin Infect Dis. 2020;ciaa1009.PubMedGoogle Scholar
25.
Bray  M, Rayner  C, Noël  F, Jans  D, Wagstaff  K.  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;178:104805. doi:10.1016/j.antiviral.2020.104805 PubMedGoogle Scholar
26.
Momekov  G, Momekova  D.  Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens.   Biotechnol Biotechnol Equipment. 2020;34:469-74. doi:10.1080/13102818.2020.1775118 Google ScholarCrossref
27.
Rajter  JC, Sherman  MS, Fatteh  N, Vogel  F, Sacks  J, Rajter  JJ.  Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ICON Study.   Chest. Published online October 12, 2020. doi:10.1016/j.chest.2020.10.009Google Scholar
28.
Ahmed  E, Hany  B, Abo Youssef  S,  et al  Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic.   Research Square. Preprint posted November 17, 2020. doi:10.21203/rs.3.rs-100956/v1Google Scholar
29.
Hashim  HA, Maulood  MF, Rasheed  AM, Fatak  DF, Kabah  KK, Abdulamir  AS.  Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq.   medRxiv. Preprint posted October 27, 2020. doi:10.1101/2020.10.26.20219345Google Scholar
30.
Niaee  MS, Gheibi  N, Namdar  P,  et al.  Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical trial.   Research Square. Preprint posted November 24, 2020. doi:10.21203/rs.3.rs-109670/v1Google Scholar
31.
Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection. Accessed December 21, 2020. https://clinicaltrials.gov/ct2/show/results/NCT04523831
32.
Schmith  VD, Zhou  JJ, Lohmer  LRL.  The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19.   Clin Pharmacol Ther. 2020;108(4):762-765. doi:10.1002/cpt.1889 PubMedGoogle ScholarCrossref
33.
Diazgranados-Sanchez  JA, Mejia-Fernandez  JL, Chan-Guevara  LS, Valencia-Artunduaga  MH, Costa  JL.  Ivermectin as an adjunct in the treatment of refractory epilepsy [article in Spanish].   Rev Neurol. 2017;65(7):303-310.PubMedGoogle Scholar
34.
Smit  MR, Ochomo  EO, Aljayyoussi  G,  et al.  Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial.   Lancet Infect Dis. 2018;18(6):615-626. doi:10.1016/S1473-3099(18)30163-4 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    14 Comments for this article
    EXPAND ALL
    Study Endpoint
    Peter Yim, PhD | Virtual Scalpel, Inc.
    After initiation of the study the primary endpoint, "worsening by 2 points on the 8-category ordinal scale," was "substantially lower" than expected. At that point the primary study endpoint was modified to be "time from randomization to complete resolution of symptoms". Two questions to the authors:

    1. Did the authors consider the following modification to the primary endpoint: "worsening by 1 point on the 8-category ordinal scale"?

    2. Did the authors consider using one of the original secondary endpoints as the primary endpoint?

    And, the title of the study protocol uses the term
    "D11AX22 Molecule" instead of "ivermectin." Did the informed consent form also use "D11AX22 Molecule" to refer to ivermectin? 
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Questions
    Eric Osgood, MD | St. Francis Medical Center
    1. "Having received ivermectin within the previous 5 days," was an exclusion criterion. Thee drug is used prophylactically monthly or every 2 weeks. Do we know if participants used it during a window outside the 5 days but recently enough where residual levels could have effects? If it does have benefit, couldn't this explain why deterioration was so much rarer than anticipated based on the literature?

    2. What measures were taken to ensure the placebo arm did not receive active drug prior to 9/29/20? Shouldn't all placebo subjects have had serum ivermectin levels drawn?

    3. Is "total symptom
    resolution" a validated metric?

    4. Why do authors propose initial clinical deterioration rate of 18% was not even close to being met, and only 3.5% in the placebo arm worsened by 2 points? Could an explanation be what I proposed in question 1? With a placebo arm doing this well, would a statistically significant benefit of experimental arm even be mathematically possible?

    5. Bioavailability of ivermectin is much greater if taken with a lipid-rich meal. Why were participants instructed to take it on an empty stomach?

    6. Why was there no virological assessment?
    CONFLICT OF INTEREST: Clinical Advisor to Frontline COVID-19 Critical Care Alliance (FLCCC), which has published an At-Home Outpatient Treatment Protocol with ivermectin
    READ MORE
    Methodological Flaws
    H. Robert Silverstein, MD | Preventive Medicine Center, Hartford
    The article states: "On October 20, 2020, the lead pharmacist observed that a labeling error had occurred between September 29 and October 15, 2020, resulting in all patients receiving ivermectin and none receiving placebo during this time frame. The study blind was not unmasked due to this error. The data and safety monitoring board recommended excluding these patients from the primary analysis but retaining them for sensitivity analysis. The protocol was amended to replace these patients to retain the originally calculated study power. The primary analysis population included patients who were analyzed according to their randomization group, but excluded patients recruited between September 29 and October 15, 2020, as well as patients who were randomized but later found to be in violation of selection criteria. Patients were analyzed according to the treatment they received in the as-treated population (sensitivity analysis)."

    To me this is an error that should have stopped the study. It is my belief, and I suspect that of many others, that the editors erred allowing publication of this article.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Changing Statistical Design
    Binh Ngo, M.D. | Keck USC School of Medicine
    The authors did not acknowledge the most significant limitation of their study: the original power calculation was based on a 20% worsening of 2 points in their ordinal scale.

    "According to the literature, 20% of patients will develop the primary outcome (worsening of 2 or more points in the 7-point ordinal scale). Thus, we will need to include 400 patients (72 total events plus 10% lost events) in order to detect a hazard ratio of 0.5 of ivermectin vs. placebo in time to deterioration, with a power of 80% and alpha of 0.05 "

    In this very young
    population, only 12 patients reached that outcome. So they decided to change the primary outcome parameter to "resolution of symptoms". Yet they retained the original power calculation. So they decided to simply terminate the study if "there was no indication of benefit".

    Their approach is fundamentally flawed. It is clear that all parameters were trending to favor ivermectin at the time they truncated their study. It is of concern that this issue was not highlighted by the reviewers.

    Binh Ngo, M.D.
    Keck USC School of Medicine
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Study Power for Negative Outcome
    Adriaan de Haan, B.Eng | Independent
    Can the authors provide

    - The study power calculations for the updated primary outcome of complete symptom resolution.

    - The Type II error P value; for a negative outcome this value is as important as the Type I error P value normally published for positive outcomes.

    - Information on how it was determined that the placebo arm did not take ivermectin outside of the study confines, either in the weeks leading up to the study or even during the study. It has been widely reported that South America has seen widespread adoption of ivermectin through self-medication and
    that this fact complicated running good studies for Ivermectin, yet I do not see any mechanisms put in place to ensure that placebo arm did not have ivermectin in their system. In fact, it was found that a large percentage was accidentally given ivermectin, casting doubt on whether the same mistake might have been made in other participants.

    Also, in secondary outcomes, the Escalation of Care since Randomization for Ivermectin arm = 4.

    In the Post-Hoc Outcomes, the Escalation of Care occurring >= 12 hours since Randomization for the Ivermectin arm also = 4.

    This would imply that all 4 patients that had Escalation of Care since Randomization in the ivermectin arm occurred >= 12 h after Randomization, hence the same 4 patients would be in both of these analysis.

    However, for some reason the "Duration, median (IQR) d" for these same patients are different in the Secondary Outcomes and Post-Hoc Outcomes.

    For Secondary Outcomes: 13 (3.5-21)
    For Post Hoc Outcomes: 6.5 (4.5-21)

    Can the authors explain how it is possible for the duration of Escalation of Care to be different for these same 4 patients in these two cases?
    CONFLICT OF INTEREST: None Reported
    READ MORE
    My concerns with this Study
    Nick Arrizza, BASc, M.D.(ret'd) | Retrired Physician from Private Practice
    Looking at this study they used "symptom profile" as an outcome, a crude measure in my view as these are variable from start to finish (while also treating "symptoms" of both groups with NSAIDS, steroids, and so on).  A negative PCR test should have been the primary outcome measure and in my view is one of the significant weaknesses of this study. So are we simply looking at the effectiveness of the complementary drugs (present in both groups) to treat 'symptoms' or are we actually seeing the potential effects of ivermectin on disease resolution? In addition there appears to be an imbalance among treatment & placebo groups in the numbers of male and female members which if significant could be confounders.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Findings Seem to Favor Ivermectin
    Kevin Tomera, MD | Beloit Health System
    i find it interesting that viral clearance, hospitalization, fever, time with fever, and clinical deterioration all favor ivermectin.

    To expect total resolution of all covid symptoms within 21 days has not been achieved by any treatment. So why did the authors and editors choose this lofty goal ?
    CONFLICT OF INTEREST: None Reported
    Bias
    Hector Carvallo, Professor of Medicine | Universidad Abierta Interamericana Argentina
    It is no secret that young COVID patients will, fortunately, develop few symptoms (if any) and will recover far sooner than aged ones, not only because of age difference but also because of the lack of co-morbidities. What this trial missed is the chance to investigate viral load in those subjects; if so, they would have found out something important: those young patients surely ceased to provoke contagions. Is it evidence-based medicine or just bias? I foresee we will witness lots of articles like this in the near future.
    CONFLICT OF INTEREST: None Reported
    Absence of Evidence is Not Evidence Against
    Adesuyi Ajayi, MD, PhD | Adjunct Prof Clinical Pharmacology & Medicine, Baylor College of Medicine
    Lopez-Medina et al, conclude ivermectin is ineffective for COVID 19 based on a "soft end point " of a 2 level deterioration in an 8 point questionnaire ordinal scale. This is a grossly inadequate premise as other studies including ours (1) that used "hard end point" RT-PCR for SARS-CoV-2 repeated measurements over 14 days showed significant, dose-dependent virucidal effects of ivermectin to reduce days to COVID 19 negativity by Kaplan-Meir statistics as well as by the treatment effect by 2-way repeated measures ANOVA. There are many confounders to symptomatic amelioration, and measures of virucidal activity is therefore imperative to show efficacy of ivermectin. RT-PCR provides this. Further, symptoms such as hiccups, myalgia, headaches, tiredness, and amnesia may persist after SARS-CoV-2 virological clearance, giving rise to chronic COVID-19 or the lLong haulers syndrome" of COVID-19. The 95% confidence intervals of the symptomatic parameters reported all tend to suggest ivermectin superiority over placebo in the study. There were minimal objective laboratory parameters such as SPO2%, D dimer, cytokine indices, or thrombosis parameters measured to support the conclusion of lack of ivermectin efficacy. This a classic example of the dictum that " Absence of evidence, is not evidence against" as the valid and sensitive end points of anti SARS-CoV-2 efficacy were not employed in the study. Larger international RCTs of sufficient power and hard end points are required to establish the utility of ivermectin in Covid-19 and as a potential broad spectrum antiviral drug against future RNA viruses.

    Reference

    1. Babalola OE, Bode CO, Ajayi AA et al QJM 2021, 114 doi,org /10.1083/qjmed/hcab035
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Ivermectin-Typical AEs in Placebo Group
    David Scheim, PhD (MIT) | U.S. Public Health Service, Commissioned Corps, Inactive Reserve
    The Lopez-Medina et al. study reported a striking anomaly: adverse effects that are characteristic of ivermectin (IVM), described in the study protocol as “security parameters” for its cumulative high IVM dose, occurred at almost identical rates in its IVM and placebo arms.

    Most notable of these AEs were blurred vision and dizziness, both characteristic of higher dose IVM use [1, 2] but of limited incidence in COVID-19 [3-5]. These AEs occurred in percentages of 11.3%, 11.6% for blurred vision and 35.6%, 34.3% for dizziness, respectively, of the IVM and placebo groups. These signs of IVM use in controls
    occurred against a backdrop of surging over-the-counter (OTC) sales of IVM in the study region (available without prescription) during the study period to a total of 154,919 units, 1.6 times the number of COVID-19 cases [6].

    The study was in fact lax in protecting boundaries between its IVM and placebo groups. IVM was substituted for placebo for 38 designated control patients, discovered one month after the fact when “the lead pharmacist observed that a labeling error had occurred” (study paper, p. 3; study protocol, p. 43). Blinding was also compromised, since bitter-tasting IVM was easily distinguishable from the 5% dextrose solution received by the first 64 placebo subjects in the study (supplement 2, eFigure 1). For the other 134 controls, a placebo of unspecified composition was then used, with no report provided of having it tested by taste or otherwise.

    These distinctive AEs for IVM in controls, in the context of widespread OTC availability of IVM in the study region during the study period and multiple protocol lapses and deficiencies, seriously compromise the study. Valuable information has nevertheless been gleaned from outcomes for patients in the IVM treatment arm, which had no deaths, generally mild symptoms, and AEs typical for high-dose IVM (replicated in the control group) that were generally mild and transient.

    References

    1. Kamgno J, Gardon J, Gardon-Wendel N, Demanga N, Duke BO, Boussinesq M. Adverse systemic reactions to treatment of onchocerciasis with ivermectin at normal and high doses given annually or three-monthly. Trans R Soc Trop Med Hyg. 2004;98(8):496-504.
    2. Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Chen T, et al. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(6):615-626.
    3. Pardhan S, Vaughan M, Zhang J, Smith L, Chichger H. Sore eyes as the most significant ocular symptom experienced by people with COVID-19: a comparison between pre-COVID-19 and during COVID-19 states. BMJ Open Ophthalmology. 2020;5(1):e000632.
    4. Pinzon RT, Wijaya VO, Buana RB, Al Jody A, Nunsio PN. Neurologic Characteristics in Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis. Frontiers in Neurology. 2020;11(565).
    5. Chen X, Laurent S, Onur OA, Kleineberg NN, Fink GR, Schweitzer F, et al. A systematic review of neurological symptoms and complications of COVID-19. Journal of Neurology. 2021;268(2):392-402.
    6. Scheim DE. Ivermectin sales in Valle del Cauca, Colombia, patterns of AEs, and other background re López-Medina et al. 2021: OSF Preprints; 2021 [Available from: https://doi.org/10.31219/osf.io/6m3ch]. Access date March 11, 2021.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Author Response
    Eduardo Lopez-Medina, MD, MSc | Centro de Estudios en Infectología Pediátrica
    Our study has received several comments. Most of the criticisms were acknowledged in the manuscript, including the lack of virological assessments and ivermectin plasma levels or the fact that the original primary outcome to detect the ability of ivermectin to prevent clinical deterioration was changed 6 weeks into the trial. We also acknowledged that the placebo used in the first 65 patients differed in taste and smell from ivermectin and explained why this limitation did not compromise the study or its conclusions. Of note, we did report that the manufacturer's placebo had similar organoleptic properties to ivermectin. Participants were instructed to take ivermectin on an empty stomach, as recommended by the FDA.

    It is important to highlight that the primary outcome of this trial was the time to resolution of symptoms. Therefore, even in a relatively young and healthy population, if the true HR of ivermectin vs. placebo was 1.4 (as assumed when calculating the sample size), the study had sufficient power to detect that difference. We have also noted that our study may have been underpowered to detect smaller differences and that larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.

    An interesting observation was made concerning the similar proportions of patients in the ivermectin and placebo groups who had side effects that are characteristic of high ivermectin doses (visual disturbances or dizziness), raising concerns that patients in the placebo group were taking ivermectin during the trial. As described in the article, patients were contacted daily for a structured interview that documented the use of any medications outside the study. In addition, we performed an analysis that excluded patients in the placebo group who had visual disturbances or dizziness, in order to restrict the subgroup to patients who were “true placebo." The HRs for recovery were (>1 indicates benefit of ivermectin):

    Ivermectin group vs. patients in the placebo group who
    • did not have dizziness: HR: 0.89 (95% CI: 0.71 to 1.13), P value: 0.35
    • did not have vision changes: HR: 0.96 (95% CI: 0.77 to 1.19), P value: 0.72

    Regarding the question of whether the informed consent form (ICF) used "D11AX22 Molecule" to refer to ivermectin, the answer is yes. This was discussed and approved by the ethics committee and the national regulatory agency. The ICF met all requirements of the International Conference on Harmonization of GCP, including details related to the drug and the possibility to reposition it against COVID-19. The need to use D11AX22 rather than ivermectin in the ICF arose from the extensive use of ivermectin in the city of Cali during the study period, extensive recommendations from some political and medical leaders to use it against COVID-19, and the fact that the initial placebo had a different taste from ivermectin. The only option to maintain the blind and prevent self-medication for participants in the placebo group during the dextrose/saline-placebo period was to use "D11AX22 Molecule" in the ICF.

    Finally, concerns have been raised regarding the allocation of patients to the incorrect treatment group between September 29 and October 15, 2020 and whether the same mistake might have been made in other participants. When the labeling error was detected, the non-blinded study personnel double-checked the entire randomization/labeling/assignment process, confirming that the correct allocation was given to patients in the rest of the study. The study blind was not unmasked due to this error
    CONFLICT OF INTEREST: Institutional grants from Sanofi Pasteur, GlaxoSmithKline, and Janssen and personal fees from Sanofi Pasteur during the conduct of the study
    READ MORE
    Defining Status of Illness at the Beginning of Treatment
    Marianella Herrera-Cuenca, MD, PhD | Universidad Central de Venezuela
    Can you clarify how many days on average elapsed between the diagnosis of COVID-19 and the beginning of treatment with ivermectin? It seems as if 2 "bonus" days are not bad at all. Maybe another statistical assessment?

    This work is very important in context of the low and middle income countries where vaccines might be delayed, so getting more information on ivermectin usage can be of help if demonstrated as an effective and cost-beneficial alternative.
    CONFLICT OF INTEREST: None Reported
    Ivermectin vs Placebo and Time to Symptom Resolution
    Stephen Strum, MD, FACP | Practice of Hematology & Oncology
    I have read every available publication, peer-reviewed & not, on ivermectin (IVM) vs COVID-19. It is amazing to see the spectrum of results from ineffective to highly effective. What is troubling is that some papers do not use PCR positivity at diagnosis of COVID-19 and evidence of PCR negativity for SARS-CoV-2 as an end-point. Others use different doses of IVM, and schedules that are either single dose or multiple doses each day time 5 days or more. Most studies do not have pharmacokinetics, an exception being that of Krolewiecki et al. who showed a response related to plasma IVM of 160 ng/ml or higher (1).

    What is especially disturbing is a lack of cooperation among investigators in getting to the core issue based on a clean protocol design. We hear talk of the importance of collaboration and given the criticality of COVID-19 and the emergence of variants, the physicians & scientists cannot seem to create a task force that would definitively answer questions as to efficacy. Instead, we perpetuate controversy, as we did with hydroxychloroquine and other agents. How about some "resolution-based" collaboration?

    Reference
    1. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3714649
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Early Administration?
    Silvina Alfieri | Farmacéutica, Oficina de Farmacia Privada
    Adult men and non-pregnant or lactating women were eligible if their symptoms started in the previous 7 days and they had mild illness. Can the first days of infection be considered as day 7? Early administration is critical. The dissonance observed between clinical trials and the version reported by patients treated with ivermectin is striking. 
    CONFLICT OF INTEREST: None Reported
    Original Investigation
    March 4, 2021

    Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial

    Author Affiliations
    • 1Centro de Estudios en Infectología Pediátrica, Cali, Colombia
    • 2Department of Pediatrics, Universidad del Valle, Cali, Colombia
    • 3Clínica Imbanaco, Cali, Colombia
    • 4State Health Department, Valle del Cauca, Colombia
    • 5Department of Public Health, Universidad Icesi, Cali, Colombia
    • 6POHEMA (Pediatric Oncologist and Hematologist) Foundation, Cali, Colombia
    • 7Cali’s Cancer Population-based Registry, Cali, Colombia
    • 8Department of Internal Medicine, Universidad del Valle, Cali, Colombia
    • 9Christus Sinergia Salud, Cali, Colombia
    • 10Neurólogos de Occidente, Cali, Colombia
    • 11Clínica de Occidente, Cali, Colombia
    • 12Municipal Health Department, Cali, Colombia
    • 13Caucaseco Scientific Research Center, Malaria Vaccine and Drug Development Center, Cali, Colombia
    • 14Department of Microbiology, Universidad del Valle, Cali, Colombia
    • 15Hemato Oncólogos, Cali, Colombia
    • 16Health Experts Committee, Valle del Cauca, Colombia
    • 17Centro Médico Santuario, Cali, Colombia
    JAMA. 2021;325(14):1426-1435. doi:10.1001/jama.2021.3071
    Visual Abstract. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19
    Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19
    Key Points

    Question  What is the effect of ivermectin on duration of symptoms in adults with mild COVID-19?

    Findings  In this randomized clinical trial that included 476 patients, the duration of symptoms was not significantly different for patients who received a 5-day course of ivermectin compared with placebo (median time to resolution of symptoms, 10 vs 12 days; hazard ratio for resolution of symptoms, 1.07).

    Meaning  The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand effects on other clinically relevant outcomes.

    Abstract

    Importance  Ivermectin is widely prescribed as a potential treatment for COVID-19 despite uncertainty about its clinical benefit.

    Objective  To determine whether ivermectin is an efficacious treatment for mild COVID-19.

    Design, Setting, and Participants  Double-blind, randomized trial conducted at a single site in Cali, Colombia. Potential study participants were identified by simple random sampling from the state’s health department electronic database of patients with symptomatic, laboratory-confirmed COVID-19 during the study period. A total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July 15 and November 30, 2020, and followed up through December 21, 2020.

    Intervention  Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200).

    Main Outcomes and Measures  Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected.

    Results  Among 400 patients who were randomized in the primary analysis population (median age, 37 years [interquartile range {IQR}, 29-48]; 231 women [58%]), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group).

    Conclusion and Relevance  Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.

    Trial Registration  ClinicalTrials.gov Identifier: NCT04405843

    Introduction

    Therapeutic approaches are needed to improve outcomes in patients with COVID-19. Ivermectin, a widely used drug with a favorable safety profile,1 is thought to act at different protein-binding sites to reduce viral replication.2-5 Because of evidence of activity against SARS-CoV-2 in vitro6 and in animal models,7,8 ivermectin has attracted interest in the global scientific community9 and among policy makers.10 Several countries have included ivermectin in their treatment guidelines,11-13 leading to a surge in the demand for the medication by the general population and even alleged distribution of veterinary formulations.14 However, clinical trials are needed to determine the effects of ivermectin on COVID-19 in the clinical setting.

    Viral replication may be particularly active early in the course of COVID-1915 and experimental studies have shown antiviral activity of ivermectin in early stages of other infections.4 The hypothesis of this randomized trial (EPIC trial [Estudio Para Evaluar la Ivermectina en COVID-19]) was that ivermectin would accelerate recovery in patients with COVID-19 when administered during the first days of infection.

    Methods
    Study Design and Patients

    This study was approved by the Colombian Regulatory Agency (INVIMA No. PI-CEP-1390), the independent ethics committees of Corporación Científica Pediátrica, and collaborating hospitals in Cali, Colombia, and conducted in accordance with Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all patients. Full details of the trial can be found in the protocol (Supplement 1).

    This double-blind, randomized trial of ivermectin vs placebo was conducted from July 15 to December 21, 2020, by Centro de Estudios en Infectología Pediátrica in Cali. Study candidates were identified from the state’s health department electronic database of all patients with a positive result from a SARS-CoV-2 reverse transcriptase–polymerase chain reaction or antigen test performed in any of the Colombian National Institute of Health–authorized laboratories in the city of Cali.

    Potential study participants were identified and selected by simple random sampling from the state’s database. Adult men and non–pregnant or breast-feeding women were eligible if their symptoms began within the previous 7 days and they had mild disease, defined as being at home or hospitalized but not receiving high-flow nasal oxygen or mechanical ventilation (invasive or noninvasive). Patients were excluded if they were asymptomatic, had severe pneumonia, had received ivermectin within the previous 5 days, or had hepatic dysfunction or liver function test results more than 1.5 times the normal level. Details of selection criteria can be found in the protocol (Supplement 1). Health disparities by race/ethnicity have been reported in COVID-19 infections.16,17 Hence, information on this variable was collected by study personnel based on fixed categories as selected by the study participants.

    Randomization

    Eligible patients were randomly assigned in a 1:1 ratio to receive either oral ivermectin or placebo in solution for 5 days. Patients were randomized in permuted blocks of 4 in a randomization sequence prepared by the unblinded pharmacist in Microsoft Excel version 19.0 who provided masked ivermectin or placebo to a field nurse for home or hospital patient visits. Allocation assignment was concealed from investigators and patients.

    Interventions

    Study patients received 300 μg/kg of body weight per day of oral ivermectin in solution or the same volume of placebo for 5 days. Ivermectin was provided by Tecnoquímicas SA in bottles of 0.6% solution for oral administration. Patients were asked to take the investigational product on an empty stomach, except on the first study day, when it was administered after screening and randomization procedures took place.

    Up to August 26, 2020, the placebo was a mixture of 5% dextrose in saline and 5% dextrose in distilled water, after which placebo was a solution with similar organoleptic properties to ivermectin provided by the manufacturer. Because blinding could be jeopardized due to the different taste and smell of ivermectin and the saline/dextrose placebo, only 1 patient per household was included in the study until the manufacturer’s placebo was available. Bottles of ivermectin and placebo were identical throughout the study period to guarantee double-blinding.

    Procedures

    A study physician contacted potential study participants by telephone to verify selection criteria for eligibility and obtain informed consent. Patients were then visited at home or in hospital by a study nurse who drew blood for liver enzyme evaluations and performed a urine pregnancy test. Eligible patients were revisited by a study nurse for enrollment, documentation of baseline demographic and clinical information, and dispensing of the investigational product. Investigational product was left with the patient for self-administration on days 2 through 5. Subsequently, patients were contacted by telephone by study staff on days 2 through 5, 8, 11, 15, and 21 for a structured interview. A study physician reviewed medical records of hospitalized patients to obtain the information required by the protocol. After study end (day 21), unused or empty investigational product bottles were collected to certify adherence. Data were entered into an electronic database and validated by the site’s quality management department.

    Outcome Measures

    The primary outcome was the time from randomization to complete resolution of symptoms within the 21-day follow-up period. The 8-category ordinal scale used in this trial has been used in different COVID-19 therapeutic trials18-20 and is recommended by the World Health Organization’s R&D Blueprint.21 It consists of the following categories: 0 = no clinical evidence of infection; 1 = not hospitalized and no limitation of activities; 2 = not hospitalized, with limitation of activities, home oxygen requirement, or both; 3 = hospitalized, not requiring supplemental oxygen; 4 = hospitalized, requiring supplemental oxygen; 5 = hospitalized, requiring nasal high-flow oxygen, noninvasive mechanical ventilation, or both; 6 = hospitalized, requiring extracorporeal membrane oxygenation, invasive mechanical ventilation, or both; and 7 = death. Time to recovery was defined as the first day during the 21 days of follow-up in which the patient reported a score of 0.

    Secondary outcomes included the proportion of patients with clinical deterioration, defined as those with worsening by 2 points (from the baseline score on the 8-category ordinal scale) since randomization. Additional secondary outcomes were the clinical conditions as assessed by the 8-category ordinal scale on days 2, 5, 8, 11, 15, and 21; however, data for days 2 and 15 are not reported here. The proportion of patients who developed fever and the duration of fever since randomization and the proportion of patients who died were also reported. Proportions of patients with new-onset hospitalization in the general ward or intensive care unit or new-onset supplementary oxygen requirement for more than 24 hours were combined into a single outcome called escalation of care. Frequency of incident cases of escalation of care, as well as the duration in both treatment groups, was reported. Evaluation of adverse events (AEs) included solicited AEs, AEs leading to treatment discontinuation, and serious AEs. AEs were classified according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0.22

    Post Hoc Analysis

    Given that some patients’ need for escalation of care was imminent when randomized, the frequency of incident cases of escalation of care occurring 12 or more hours after randomization and the duration up to day 21 in both treatment groups were reported. A comparison of the proportions of patients who required emergency department (ED) or telemedicine consultation was also performed.

    Statistical Analysis

    The primary outcome was originally defined as the time from randomization until worsening by 2 points on the 8-category ordinal scale. According to the literature, approximately 18% of patients were expected to have such an outcome.23 However, before the interim analysis, it became apparent that the pooled event rate of worsening by 2 points was substantially lower than the initial 18% expectation, requiring an unattainable sample size. Therefore, on August 31, 2020, the principal investigator proposed to the data and safety monitoring board to modify the primary end point to time from randomization to complete resolution of symptoms within the 21-day follow-up period. This was approved on September 2, 2020. The original sample size of 400 based on the log-rank test for the new primary end point was kept, using an ivermectin to placebo assignment ratio of 1:1. This would allow the detection of 290 events of interest (symptom resolution), assuming that 75% of patients would have the outcome of interest at 21 days,24 with a 2% dropout rate. This would provide an 80% power under a 2-sided type I error of 5% if the hazard ratio (HR) comparing ivermectin vs placebo is 1.4, corresponding to a 3-day faster resolution of symptoms in patients receiving ivermectin, assuming that time to resolution of symptoms is 12 days with placebo.24 With an HR of 1.4, 75% and 85% of patients in the placebo and ivermectin groups, respectively, would experience the outcome of interest at 21 days.

    On October 20, 2020, the lead pharmacist observed that a labeling error had occurred between September 29 and October 15, 2020, resulting in all patients receiving ivermectin and none receiving placebo during this time frame. The study blind was not unmasked due to this error. The data and safety monitoring board recommended excluding these patients from the primary analysis but retaining them for sensitivity analysis. The protocol was amended to replace these patients to retain the originally calculated study power. The primary analysis population included patients who were analyzed according to their randomization group, but excluded patients recruited between September 29 and October 15, 2020, as well as patients who were randomized but later found to be in violation of selection criteria. Patients were analyzed according to the treatment they received in the as-treated population (sensitivity analysis).

    The primary end point of time from randomization to complete resolution of symptoms with ivermectin vs placebo was assessed by a Kaplan-Meier plot and compared with a log-rank test. The HRs and 95% CIs for the cumulative incidence of symptom resolution in both treatment groups were estimated using the Cox proportional hazards model. The proportional hazards assumption was tested graphically using a log-log plot and the test of the nonzero slope. There was no evidence to reject the proportionality assumption.

    The time to complete resolution of symptoms was assessed after all patients reached day 21. Data for patients who died or lacked symptom resolution before day 21 were right-censored at death or day 21, respectively. Evaluation of the effect of the treatment in each study visit using the 8-point ordinal scale was estimated using the proportional odds ratio (OR) with its respective 95% CI with an ordinal logistic regression. The proportional odds assumption was met according to the Brant test. The 8-point ordinal scale was inverted in its score, where 0 corresponded to death and 7 to a patient without symptoms.

    For sensitivity analysis, primary and secondary end points were compared in the as-treated population.

    Clustered standard errors were estimated to adjust for the correlation between multiple patients from the same household. Statistical significance was set at P < .05, and all tests were 2-tailed. Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory. Statistical analyses were done with Stata version 16.0 (StataCorp). Bootstrapping 95% CIs for differences of medians were calculated with R statistical package version 3.6.3 (The R Foundation).

    Results
    Patients

    Of the 476 patients who underwent randomization, 238 were assigned to receive ivermectin and 238 to receive placebo (Figure 1). Seventy-five patients were randomized between September 29 and October 15, 2020, and were excluded from the primary analysis population but remained in the as-treated population. Three patients were excluded from all analyses because they were identified as ineligible after randomization (1 asymptomatic patient and 2 who received ivermectin within 5 days prior to enrollment). The primary analysis population included 398 patients (200 allocated to ivermectin and 198 to placebo).

    Patients in both groups were balanced in demographic and disease characteristics at baseline (Table 1; eTable 1 in Supplement 2). The median age of patients in the primary analysis population was 37 years (interquartile range [IQR], 29-48), 231 (58%) were women, and 316 (79%) did not have any known comorbidities at baseline. At randomization, the median National Early Warning Score 2 was 3 (IQR, 2-4) and most patients (n = 232, 58.3%) were at home and able to perform their routine activities. The most common symptoms were myalgia (310 patients, 77.9%) and headache (305 patients, 76.6%), followed by smell and taste disturbances (223 [56%] and 199 [50%], respectively) and cough (211 patients, 53%), which was most commonly dry (181 patients, 45.5%) (eTable 2 in Supplement 2).

    Baseline characteristics of the 75 patients who received ivermectin but were excluded from the primary analysis were not significantly different from the 398 remaining patients in the cohort (eTables 1 and 3 in Supplement 2).

    Primary Outcome

    Time to resolution of symptoms in patients assigned to ivermectin vs placebo was not significantly different (median, 10 days vs 12 days; difference, −2 days [IQR, −4 to 2]; HR for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53) (Figure 2 and Table 2). In the ivermectin and placebo groups, symptoms resolved in 82% and 79% of patients, respectively, by day 21 (Table 2).

    The type of placebo that patients received did not affect the results (HR for ivermectin vs dextrose in saline: 1.14 [95% CI, 0.83-1.55]; HR for ivermectin vs manufacturer’s placebo: 1.07 [95% CI, 0.85 to 1.34] (eFigure 1 in Supplement 2).

    Similar results were observed in the as-treated population (eFigure 2 and eTable 4 in Supplement 2).

    Secondary Outcomes

    Few patients had clinical deterioration of 2 or more points in the ordinal 8-point scale, and there was no significant difference between the 2 treatment groups (2% in the ivermectin group and 3.5% in the placebo group; absolute difference, −1.53 [95% CI, −4.75 to 1.69]). The OR for deterioration in ivermectin vs placebo groups was 0.56 (95% CI, 0.16 to 1.93) (Table 2).

    The odds of improving the score in the ordinal scale were not significantly different between both treatment groups, as determined by proportional odds models (eFigure 3 and eTable 5 in Supplement 2).

    There was no significant difference in the proportion of patients who required escalation of care in the 2 treatment groups (2% with ivermectin, 5% with placebo; absolute difference, −3.05 [95% CI, −6.67 to 0.56]; OR, 0.38 [95% CI, 0.12 to 1.24]). The length of time during which patients required escalation of care in the ivermectin vs placebo groups was not significantly different (median difference, 7 days [IQR, −5.0 to 16.5]). The proportions of patients who developed fever during the study period were not significantly different between the 2 treatment groups (absolute difference of ivermectin vs placebo, −2.61 [95% CI, −8.31 to 3.09]; OR, 0.73 [95% CI, 0.37 to 1.45]), nor was the duration of fever (absolute difference of ivermectin vs placebo, −0.5 days [95% CI, −1.0 to 2.0]) (Table 2). One patient in the placebo group died during the study period. No data were missing for the primary or secondary outcomes. See eTables 4 and 6 in Supplement 2 for the results in the as-treated population.

    Post Hoc End Points and Analyses

    After excluding 4 patients who required hospitalization within 12 hours after randomization (median, 3.25 hours [IQR, 2-6]), there were 4 patients (2%) in the ivermectin group and 6 (3%) in the placebo group who required escalation of care (absolute difference, −1.0 [95% CI, −4.11 to 2.05]; OR, 0.65 [95% CI, 0.18 to 2.36]) (Table 2).

    The proportions of patients who sought medical care (ED or telemedicine consultation) were not significantly different between the 2 treatment groups (8.0% in the ivermectin group and 6.6% in the placebo group; absolute difference, 1.43 [95% CI, −3.67 to 6.54]; OR, 1.24 [95% CI, 0.56 to 2.74]) (Table 2). See eTable 4 in Supplement 2 for the results in the as-treated population.

    Adverse Events

    A total of 154 patients (77%) in the ivermectin group and 161 (81.3%) in the placebo group reported AEs between randomization and day 21. Fifteen patients (7.5%) in the ivermectin group vs 5 patients (2.5%) in the placebo group discontinued treatment due to an AE. Serious AEs developed in 4 patients, 2 in each group, but none were considered by the investigators to be related to the trial medication (Table 3; eTable 7 in Supplement 2).

    Discussion

    In this double-blind, randomized trial of symptomatic adults with mild COVID-19, a 5-day course of ivermectin vs placebo initiated in the first 7 days after evidence of infection failed to significantly improve the time to resolution of symptoms.

    Interest in ivermectin in COVID-19 therapy began from an in vitro study that found that bathing SARS-CoV-2–infected Vero-hSLAM cells with 5-μM ivermectin led to an approximately 5000-fold reduction in viral RNA.8 However, pharmacokinetic models indicated that the concentrations used in the in vitro study are difficult to achieve in human lungs or plasma,25 and inhibitory concentrations of ivermectin are unlikely to be achieved in humans at clinically safe doses.26 Despite this, a retrospective study using logistic regression and propensity score matching found an association between 200 μg/kg of ivermectin in a single dose (8% of patients received a second dose) and improved survival for patients admitted with severe COVID-19.27 The contrast with the findings in this trial may be related to differences in patient characteristics, exposures and outcomes that were measured, or unmeasured confounders in the observational study. To our knowledge, preliminary reports of other randomized trials of ivermectin as treatment for COVID-19 with positive results have not yet been published in peer-reviewed journals.28-31

    Daily doses were used in this trial because pharmacokinetic models have shown higher lung concentrations with daily rather than intermittent dosing,32 and have proven to be well tolerated.33,34 In addition, the US Food and Drug Administration–approved dose for the treatment of helminthic diseases (200 μg/kg) showed clinical benefit in an observational study,27 supporting a hypothesis that higher doses could be clinically relevant.

    This study did not find any significant effect of ivermectin on other evaluated measures of clinical benefit for the treatment of COVID-19. Although a numerically smaller proportion of ivermectin-treated patients required escalation of care (2.0% with ivermectin vs 5.0% with placebo), the difference was not statistically significant and was further attenuated in a post hoc analysis after excluding 4 patients who were hospitalized at a median time of 3.25 hours after randomization. In addition, ivermectin did not reduce ED or telephone consultations, further supporting the lack of efficacy for these outcomes. However, the relatively young and healthy study population rarely developed complications, rendering the study underpowered to detect such effects. Therefore, the ability of ivermectin to prevent the progression of mild COVID-19 to more severe stages would need to be assessed in larger trials.

    The study was sufficiently powered to detect faster resolution of symptoms in patients soon after they became apparent, and no significant difference was identified. However, the study population was relatively young, with few comorbidities and with liver enzyme levels less than 1.5 times the normal level, so the findings may be generalizable only to such populations.

    Cumulatively, the findings suggest that ivermectin does not significantly affect the course of early COVID-19, consistent with pharmacokinetic models showing that plasma total and unbound ivermectin levels do not reach the concentration resulting in 50% of viral inhibition even for a dose level 10-times higher than the approved dose.32

    Limitations

    This study has several limitations. First, the study was not conducted or completed according to the original design, and the original primary outcome to detect the ability of ivermectin to prevent clinical deterioration was changed 6 weeks into the trial. In the study population, the incidence of clinical deterioration was below 3%, making the original planned analysis futile. Ultimately, findings for primary and secondary end points were not significantly different between the ivermectin and placebo groups.

    Second, the study was well-powered to detect an HR for resolution of symptoms of 1.4 in the ivermectin vs placebo groups, but may have been underpowered to detect a smaller but still clinically meaningful reduction in the primary end point.

    Third, virological assessments were not included, but the clinical characteristics that were measured indirectly reflect viral activity and are of interest during the pandemic.

    Fourth, the placebo used in the first 65 patients differed in taste and smell from ivermectin. However, patients from the same household were not included until the placebo with the same organoleptic properties was available, and the lack of effect of ivermectin on the primary outcome was similar when compared with either formulation of placebo.

    Fifth, 2 secondary outcomes used an 8-category ordinal scale that in initial stages requires patient self-reporting and thus allows subjectivity to be introduced. Sixth, data on the ivermectin plasma levels were not collected. Seventh, as already noted, the study population was relatively young and results may differ in an older population.

    Conclusions

    Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.

    Back to top
    Article Information

    Corresponding Author: Eduardo López-Medina, MD, MSc, Centro de Estudios en Infectología Pediátrica, Calle 5 B 5 No. 37 BIS-28, Cali, Colombia (eduardo.lopez@ceiponline.org).

    Accepted for Publication: February 18, 2021.

    Published Online: March 4, 2021. doi:10.1001/jama.2021.3071

    Author Contributions: Drs López-Medina and Ramirez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: López-Medina, López, Hurtado, Dávalos, Ramirez, Martínez, Díazgranados, Oñate, Chavarriaga.

    Acquisition, analysis, or interpretation of data: López-Medina, Hurtado, Ramirez, Martínez, Oñate, Chavarriaga, Herrera, Parra, Libreros, Jaramillo, Avendaño, Toro, Torres, Lesmes, Rios, Caicedo.

    Drafting of the manuscript: López-Medina, Hurtado, Dávalos, Chavarriaga, Caicedo.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: López-Medina, Ramirez.

    Obtained funding: López-Medina, López.

    Administrative, technical, or material support: Hurtado, Dávalos, Martínez, Díazgranados, Chavarriaga, Herrera, Parra, Libreros, Jaramillo, Avendaño, Toro, Torres, Lesmes, Rios, Caicedo.

    Supervision: López-Medina, López, Oñate, Rios, Caicedo.

    Conflict of Interest Disclosures: Dr López-Medina reported receiving grants from Sanofi Pasteur, GlaxoSmithKline, and Janssen and personal fees from Sanofi Pasteur during the conduct of the study. Dr López reported receiving grants from Sanofi Pasteur, GlaxoSmithKline, and Janssen and personal fees from Sanofi Pasteur during the conduct of the study. Dr Oñate reported receiving grants from Janssen and personal fees from Merck Sharp & Dohme and Gilead outside the submitted work. Dr Torres reported receiving nonfinancial support from Tecnoquímicas unrelated to this project during the conduct of the study. No other disclosures were reported.

    Funding/Support: This study received an unrestricted grant from Centro de Estudios en Infectología Pediátrica (grant ScDi823).

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Group Information: In addition to the authors, the following collaborators from Centro de Estudios en Infectología Pediátrica participated in the Estudio Para Evaluar la Ivermectina en COVID-19 (EPIC) trial:

    Catalina De La Cruz, MD; Camilo Andrade; Iñigo Prieto, MD, MSc; Viviana Márquez, MD; Mary Luz Hernandez; Carlos Gonzalez, MD; Victoria Aguirre, RN; Gloria Tamayo; Leidy Gomez; Aracelly Romero; Socorro Mutis; Nidia Guaza; Eliana Valencia; James Riascos; Ovidio Maldonado; Laura Victoria, RN; Hilda Giraldo; Lina Solano, RN; Maria F. Collazos, RN; Elizabeth Toro, MD; Carlos Cortés, MD; Alexandra Sierra, MD; Carolina Ospina, MD; Diana P. Mazo, PharmD; Jhon J. Calderón; Jenny Yela, RN; Diego Rivera, RN; and Diana Suárez, PharmD.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: We are grateful to the patients who participated in this trial; Erika Cantor, MSc, from the Institute of Statistics, Universidad de Valparaíso, Valparaíso, Chile, for her contribution during data analysis; Keith Veitch for his writing assistance; and Neal Alexander, PhD, from CIDEIM in Cali, Colombia, and Rodrigo DeAntonio, DrPH, from Cevaxin in Panamá City, Panamá, for their contribution during study planning. Ms Cantor and Mr Veitch received compensation for their roles in the study. Drs Alexander and DeAntonio did not receive compensation for their roles in the study. We thank Tecnoquímicas for its donation of the investigational product and placebo from August 26, 2020, until the end of the trial.

    References
    1.
    Omura  S.  Ivermectin: 25 years and still going strong.   Int J Antimicrob Agents. 2008;31(2):91-98. doi:10.1016/j.ijantimicag.2007.08.023 PubMedGoogle ScholarCrossref
    2.
    Yang  SNY, Atkinson  SC, Wang  C,  et al.  The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer.   Antiviral Res. 2020;177:104760. doi:10.1016/j.antiviral.2020.104760 PubMedGoogle Scholar
    3.
    Wagstaff  KM, Sivakumaran  H, Heaton  SM, Harrich  D, Jans  DA.  Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus.   Biochem J. 2012;443(3):851-856. doi:10.1042/BJ20120150 PubMedGoogle ScholarCrossref
    4.
    Mastrangelo  E, Pezzullo  M, De Burghgraeve  T,  et al.  Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug.   J Antimicrob Chemother. 2012;67(8):1884-1894. doi:10.1093/jac/dks147 PubMedGoogle ScholarCrossref
    5.
    Tay  MY, Fraser  JE, Chan  WK,  et al.  Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5: protection against all 4 DENV serotypes by the inhibitor Ivermectin.   Antiviral Res. 2013;99(3):301-306. doi:10.1016/j.antiviral.2013.06.002 PubMedGoogle ScholarCrossref
    6.
    Frontline Covid-19 Critical Care Alliance. Accessed December 19, 2020. https://covid19criticalcare.com/
    7.
    US Senate Committee on Homeland Security & Governmental Affairs. Early outpatient treatment: an essential part of a COVID-19 solution, part II. Accessed December 19, 2020. https://www.hsgac.senate.gov/early-outpatient-treatment-an-essential-part-of-a-covid-19-solution-part-ii
    8.
    Caly  L, Druce  JD, Catton  MG, Jans  DA, Wagstaff  KM.  The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro.   Antiviral Res. 2020;178:104787. doi:10.1016/j.antiviral.2020.104787 PubMedGoogle Scholar
    9.
    de Melo  GD, Lazarini  F, Larrous  F,  et al.  Anti-COVID-19 efficacy of ivermectin in the golden hamster.   bioRxiv. Preprint posted November 22, 2020. doi:10.1101/2020.11.21.392639Google Scholar
    10.
    Arévalo  A, Pagotto  R, Pórfido  J,  et al.  Ivermectin reduces coronavirus infection in vivo: a mouse experimental model.   bioRxiv. Preprint posted November 2, 2020. doi:10.1101/2020.11.02.363242 Google Scholar
    11.
    Ministerio de Salud, República del Perú. Resolución ministerial No. 270-2020-MINSA. Accessed December 19, 2020. https://cdn.www.gob.pe/uploads/document/file/694719/RM_270-2020-MINSA.PDF
    12.
    Rodriguez Mega  E. Latin America’s embrace of an unproven COVID treatment is hindering drug trials. Nature. Accessed December 19, 2020. https://www.nature.com/articles/d41586-020-02958-2
    13.
    Ministerio de Salud, Gobierno del Estado de Bolivia. Resolución ministerial No. 0259. Accessed December 19, 2020. https://www.minsalud.gob.bo/component/jdownloads/?task=download.send&id=425&catid=27&m=0&Itemid=646
    14.
    Molento  MB.  COVID-19 and the rush for self-medication and self-dosing with ivermectin: a word of caution.   One Health. 2020;10:100148. doi:10.1016/j.onehlt.2020.100148 PubMedGoogle Scholar
    15.
    Siddiqi  HK, Mehra  MR.  COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal.   J Heart Lung Transplant. 2020;39(5):405-407. doi:10.1016/j.healun.2020.03.012 PubMedGoogle ScholarCrossref
    16.
    Mahajan  UV, Larkins-Pettigrew  M.  Racial demographics and COVID-19 confirmed cases and deaths: a correlational analysis of 2886 US counties.   J Public Health (Oxf). 2020;42(3):445-447. doi:10.1093/pubmed/fdaa070 PubMedGoogle ScholarCrossref
    17.
    Karaca-Mandic  P, Georgiou  A, Sen  S.  Assessment of COVID-19 hospitalizations by race/ethnicity in 12 states.   JAMA Intern Med. 2021;181(1):131-134. doi:10.1001/jamainternmed.2020.3857 PubMedGoogle ScholarCrossref
    18.
    Cao  B, Wang  Y, Wen  D,  et al.  A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19.   N Engl J Med. 2020;382(19):1787-1799. doi:10.1056/NEJMoa2001282 PubMedGoogle ScholarCrossref
    19.
    Beigel  JH, Tomashek  KM, Dodd  LE,  et al; ACTT-1 Study Group Members.  Remdesivir for the treatment of COVID-19: final report.   N Engl J Med. 2020;383(19):1813-1826. doi:10.1056/NEJMoa2007764 PubMedGoogle ScholarCrossref
    20.
    Spinner  CD, Gottlieb  RL, Criner  GJ,  et al; GS-US-540-5774 Investigators.  Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial.   JAMA. 2020;324(11):1048-1057. doi:10.1001/jama.2020.16349 PubMedGoogle ScholarCrossref
    21.
    World Health Organization. WHO R&D blueprint: novel coronavirus: COVID-19 therapeutic trial synopsis. Accessed December 20, 2020. https://www.who.int/blueprint/priority-diseases/key-action/COVID-19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf
    22.
    US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Published November 27, 2017. Accessed December 20, 2020. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf
    23.
    Wu  Z, McGoogan  JM.  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648 PubMedGoogle ScholarCrossref
    24.
    Mitjà  O, Corbacho-Monné  M, Ubals  M,  et al; BCN PEP-CoV-2 RESEARCH GROUP.  Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial.   Clin Infect Dis. 2020;ciaa1009.PubMedGoogle Scholar
    25.
    Bray  M, Rayner  C, Noël  F, Jans  D, Wagstaff  K.  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;178:104805. doi:10.1016/j.antiviral.2020.104805 PubMedGoogle Scholar
    26.
    Momekov  G, Momekova  D.  Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens.   Biotechnol Biotechnol Equipment. 2020;34:469-74. doi:10.1080/13102818.2020.1775118 Google ScholarCrossref
    27.
    Rajter  JC, Sherman  MS, Fatteh  N, Vogel  F, Sacks  J, Rajter  JJ.  Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ICON Study.   Chest. Published online October 12, 2020. doi:10.1016/j.chest.2020.10.009Google Scholar
    28.
    Ahmed  E, Hany  B, Abo Youssef  S,  et al  Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic.   Research Square. Preprint posted November 17, 2020. doi:10.21203/rs.3.rs-100956/v1Google Scholar
    29.
    Hashim  HA, Maulood  MF, Rasheed  AM, Fatak  DF, Kabah  KK, Abdulamir  AS.  Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq.   medRxiv. Preprint posted October 27, 2020. doi:10.1101/2020.10.26.20219345Google Scholar
    30.
    Niaee  MS, Gheibi  N, Namdar  P,  et al.  Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical trial.   Research Square. Preprint posted November 24, 2020. doi:10.21203/rs.3.rs-109670/v1Google Scholar
    31.
    Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection. Accessed December 21, 2020. https://clinicaltrials.gov/ct2/show/results/NCT04523831
    32.
    Schmith  VD, Zhou  JJ, Lohmer  LRL.  The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19.   Clin Pharmacol Ther. 2020;108(4):762-765. doi:10.1002/cpt.1889 PubMedGoogle ScholarCrossref
    33.
    Diazgranados-Sanchez  JA, Mejia-Fernandez  JL, Chan-Guevara  LS, Valencia-Artunduaga  MH, Costa  JL.  Ivermectin as an adjunct in the treatment of refractory epilepsy [article in Spanish].   Rev Neurol. 2017;65(7):303-310.PubMedGoogle Scholar
    34.
    Smit  MR, Ochomo  EO, Aljayyoussi  G,  et al.  Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial.   Lancet Infect Dis. 2018;18(6):615-626. doi:10.1016/S1473-3099(18)30163-4 PubMedGoogle ScholarCrossref
    ×