Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines
Authors: Theresa A Lawrie
Andrew Bryant
Tony C Tham
Sarah R Hill
Edmund J Fordham
Scott Mitchell
Therese Dowswell
Journal: American Journal of Therapeutics (2021)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Repurposed medicines; SARS-CoV-2 virus; ivermectin; clinical trials; mortality reduction
Affiliations: Population Health Sciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom., Evidence-based Medicine Consultancy, Bath, United Kingdom., Emergency Department, Princess Elizabeth Hospital, Guernsey, United Kingdom; and., Division of Gastroenterology, Ulster Hospital, Dundonald, Belfast, Northern Ireland, United Kingdom.

Abstract:  Background: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. Areas of uncertainty: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. Data sources: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. Therapeutic advances: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. Conclusions: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally. 

Retracted: No

PubPeer comments:
 https: twitter.com GidMK status 1407140602009985025 , 
 Published since this meta-analysis: [Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial] [Ivermectin is the new hydroxychloroquine, take 4: Fraud, incompetence, or both?] [Is Ivermectin for Covid-19 Based on Fraudulent Research?] [Huge study supporting ivermectin as Covid treatment withdrawn over ethical concerns] Opinion pieces published by one of the authors (Edmund Fordham): [Scandal of the suppressed case for ivermectin] [The doctor whou2019s curing Covid-19 with zinc and hydroxychloroquine] [Why wonu2019t these medical journals tell the truth about hydroxychloroquine?] [ You need remember only this: if a cheap, safe, existing medicine works as prophylaxis, we donu2019t need a vaccine. ] , 
 Some questions for the authors: u2014 Now that one of the preprints included ( [Efficacy and Safety of Ivermectin for Treatment and prophylaxis of COVID-19 Pandemic]  ) has been withdrawn, will the authors publish a Correction to exclude this from their meta-analysis? How would this affect the results and conclusions? u2014 Are the authors confident that the others studies included are sound? For example, [serious concerns] have been raised about the Niaee et al preprint ( This raises serious questions about whether the trial was conducted as described, and whether random allocation with concealment genuinely occurred. In the absence of a good explanation these results should be interpreted with extreme caution, this study should be considered at very high risk of bias, and, in my opinion, should not be included in meta-analyses ). In light of these concerns, should this study have been excluded from the meta-analysis? If so, how would this have affected the results and conclusions? u2014 Tess Lawrie is listed as a key supporter of the [BIRD Group] and Edmund Fordham is a member of the BIRD Recommendation Development Panel. The BIRD Group is  a non-profit organisation campaigning for the safe medicine ivermectin to be approved to prevent and cure covid-19 around the world . Edmund Fordham is a member of [HART] ), which [recommends stopping all mask mandates among other steps] . Both [BIRD] and [HART] appear to advocate for Ivermectin-based treatment protocols. BIRD has this statement on their website:  Bird is a campaign managed through EbMCsquared, a not-for-profit Community Interest Company. It means 100% of profits after tax are reinvested into the business or to the advancement of our social purpose, for example to work on projects such as the Ivermectin campaign. Tess Lawrie is Director of EbMCsquared and an author of the meta-analysis. The authors have been transparent about their inclusion criteria, but they do not appear to have been transparent about their relationship involvement with HART and BIRD. As this meta-analysis is being used in support of these campaigns, would it be appropriate for the authors to disclose their involvement with these groups campaigns? u2014 The authors state:  This updated version was funded by the crowdfunding initiative https: www.gofundme.com f help-us-get-lifesaving-drug-approved-for-covid19. They also say [elsewhere] that  Our appeal video has been taken down by Vimeo, YouTube and Dailymotion . Could the authors comment on the reasons why the fundraising video has been removed from these platforms? u2014 Edmund Fordham s affiliation is given as  Evidence-based Medicine Consultancy, Bath, United Kingdom , but does not appear to have published with this affiliation previously. Their [website] lists Lawrie and Dowswell but not Fordham. Could the authors clarify whether (and in what way) Fordham is employed by or otherwise affiliated with  Evidence-based Medicine Consultancy (Bath)? , 
 https: twitter.com GidMK status 1416290819565244424 , 
 https: twitter.com GidMK status 1417653874589007874 Relates to Petkov 2021, included in the Bryant et al meta-analysis. Petkov 2021, Elgazzar 2020, and Niaee 2020 all have serious question marks, and appear to be unsuitable at this point for inclusion in a meta-analysis. Could the authors respond explain whether they stand by these studies and the conclusions of their meta-analysis? Readers are also referred to: [Ivermectin is the new hydroxychloroquine, take 2] , especially subsection  The BIRD Group u201cmeta-analysisu201d: Bad science and undisclosed conflicts of interest  ...At worst, itu2019s a biased piece of **scientific hackery**...  **One canu2019t help but wonder whether the known bias of an organization dedicated to promoting COVID-19 treatments like ivermectin crept into this meta-analysis.** The first author Andrew Bryant, Tess Lawrie, and the most of the authors are affiliated with the Bird Group... , 
 The authors are fundraising again, this time by launching the  Ivermectin Buyers Club https: mobile.twitter.com BIRDGroupUK status 1419382818837250049 But  The authors have no conflicts of interest to declare. , 
 https: twitter.com CochraneLibrary status 1420365263690686467?s=20 , 
 Several authors are members of BIRD Group, who not only run the  Ivermectin Buyers Club but also sell ivermectin merchandise:  Remember that the authors  have no conflicts of interest to declare . Meanwhile, the meta-analysis by Andrew Hill and colleagues is [being retracted] :  Subsequently, we and the authors have learned that one of the studies on which this analysis was based has been withdrawn due to fraudulent data. The authors will be submitting a revised version excluding this study, and the currently posted paper will be retracted. Are the authors of the present study taking steps to retract it? , 
 The authors state:  with respect to ivermectin prophylaxis of frontline workers and those at risk, controlled observational studies from Bangladesh and Argentina (the latter which involved 1195 health care workers) have shown apparent reductions in COVID-19 transmission with ivermectin prophylaxis, including in some reports total protection (zero infections) where infection rates in the control group exceeded 50% But the study from Argentina has been called into question:  [Ivermectin Is Anti-Vaxxersu2019 Latest COVID Drug Of Choice. A Study Promoting It Has Suspect Data]  and  [Is Ivermectin for Covid-19 Based on Fraudulent Research? Part 3]  Several studies reporting results on ivermectin are openly being called fraudulent, including one from Egypt used in this meta-analysis.  So far the authors haven t provided a response to the numerous concerns about their work and the studies they have included. , 
  Bryant et al pooled heterogeneous patient populations, interventions, comparators and outcomes. In other words, they compare apples and oranges, serving a large bowl of a colourful fruit salad. [...]  Evidence syntheses must be pieces of the highest trustworthiness. However, reliability is at risk when researchers publish problematic trials or misuse established evidence assessment tools as a guise for quality of evidence synthesis in general, but especially during a pandemic, by trying to create **pseudotrustworthiness** for substances that cannot be considered effective and safe treatment options nor game changers, at this stage. From  [Evidence on the efficacy of ivermectin for COVID-19: another story of apples and oranges]  Bryant, Lawrie and Fordham have responded via a  letter to the editor [posted as a preprint] to OSF Preprints. They speciously argue that there is an  existing large body of evidence showing that ivermectin provides benefit in a variety of important clinical outcomes . But their references in support of this claim are: 1) Their own deeply problematic meta-analysis and systematic review, which includes studies that are unreliable, deeply flawed, and probably fraudulent (see comments above). 2) The Kory et al review, also published in the American Journal of Therapeutics, which [Frontiers rejected] , saying:  the article made a series of strong, unsupported claims based on studies with insufficient statistical significance, and at times, without the use of control groups. Further, the authors promoted their own specific ivermectin-based treatment which is inappropriate for a review article... 3) A meta-analysis that the authors have retracted: https: twitter.com DrAndrewHill status 1427279978673197059 Curiously this letter to the editor isn t signed by four of the original authors. Does this imply that Dowswell, Mitchell, Hill, and Tham disagree with Bryant, Lawrie and Fordham s arguments in support of the original meta-analysis systematic review? , 
 Three of the authors have published another letter to the editor in the original journal: 10.1097 MJT.0000000000001442 Do the authors of the original paper who haven t authored this letter to the editor continue to stand by its findings? In the letter to the editor, the authors state:  The authors have no conflicts of interest to declare. How is that consistent with their involvement with the Ivermectin Buyers Club?   In their letter to the editor about this paper, the authors state:  With regard to the authorship of the original article (and the present Letter), all authors except Dr. Dowswell attended the BiRD (British Ivermectin Recommendation Development) meeting comprised of medical doctors, healthcare professionals and other stakeholders, with international representation, which was convened for an u201cEvidence to Decisionu201d framework event on 20 February 2021. A. Bryant and T. A. Lawrie were members of the Steering Group and did not vote on the decisions. E. J. Fordham, Hill, Mitchell and Tham were ordinary members of the panel. The panel voted to recommend the deployment of ivermectin for the treatment and prevention of Covid-19, upon an evidence base comprising an earlier version of the meta-analysis as published in Am. J. Therap., plus additional supporting evidence. BiRD remains an unincorporated, not-for-profit, ad hoc association with no financial or material interests in ivermectin or any other medicine or any other product. Its continuing activities are transparently managed through EbMCsquared, a not-for-profit Community Interest Company. E. J. Fordham is a member of HART (Health Advisory and Recovery Team) a British not-for-profit, unincorporated membership association, wherein all consulting members collaborate on an entirely voluntary (unpaid) basis for research on multiple aspects of public health policy relating to Covid-19. HART has no material or financial interests in ivermectin or any other medical product. E. J. Fordham is not a member of its Executive Committee. HART bulletins are circulated to UK Parliamentarians but it remains firmly non-party political. Given these **extensive conflicts of interest**, why weren t they declared originally? One of the authors of the original paper was  Mitchell, Scott MBChB, MRCS . Is that this Scott Mitchell?  The Scott Mitchell who is an FLCCC clinical advisor? As FLCCC have a very clear agenda, why wasn t this declared by the authors, in the original paper or the letter to the editor? Reactions to the letter of the editor can be found here: https: twitter.com jamesheathers status 1435713457781764096 And here: https: twitter.com GidMK status 1435840375818649600 Could the authors respond to these questions concerns? , 
 See  [The lesson of ivermectin: meta-analyses based on summary data alone are inherently unreliable]  by Lawrence et al https: twitter.com K_Sheldrick status 1440626445013774345 , 
 Authors Bryant, Lawrie, Fordham, Hill, Mitchell, and Tham are BIRD Group members. On 30 September 2021, BIRD Group s Twitter account was suspended for violating Twitter s rules.  , 
 Published October 7, [Is Ivermectin For Covid-19 Based On Fraudulent Research? Part 4] , outlines serious concerns about Raad 2021 included in this meta-analysis:  the corresponding author on the study asked me to send him $1,500 USD for access to the data [...]  the dataset that was emailed to several people is quite clearly not data from a real randomized trial [...]  Dr. Eid, a co-author on the research who had not been involved with data collection, agreed that whether or not there was some real data from the research, it was clear that the study itself was based on fake numbers and should be retracted Also published October 7, [Ivermectin: How false science created a Covid miracle drug] (BBC):  The BBC can reveal that more than a third of 26 major trials of the drug for use on Covid have serious errors or signs of potential fraud. None of the rest show convincing evidence of ivermectin s effectiveness. Dr Kyle Sheldrick, one of the group investigating the studies, said they had not found  a single clinical trial claiming to show that ivermectin prevented Covid deaths that did not contain  either obvious signs of fabrication or errors so critical they invalidate the study . [...]  The largest and highest quality ivermectin study published so far is the Together trial at the McMaster University in Canada. It found no benefit for the drug when it comes to Covid. [...] Author of the meta-analysis Tess Lawrie  has called for a pause to the Covid-19 vaccination programme and has made unsubstantiated claims implying the Covid vaccine had led to a large number of deaths based on a common misreading of safety data. When asked during an online panel what evidence might persuade her ivermectin didn t work she replied:  Ivermectin works. There s nothing that will persuade me.  It is apparent that a number of studies included in the authors meta-analysis do not stand up to scrutiny (such as Elgazzar 2020, Niaee 2020, Raad 2021): is there now clear evidence that the findings of the meta-analysis are unreliable? If the authors won t address these multiple concerns, perhaps the American Journal of Therapeutics will? , 
 Dr Hill and colleagues have posted a new preprint, relevant to this meta-analysis and systematic review: [Ivermectin for COVID-19: addressing potential bias and medical fraud]  We present a sub-group analysis, to assess the effects of stratifying by trial quality on the overall results. The stratification is based on the Cochrane Risk of Bias measures (RoB 2) and analysis of raw data where possible. The results suggest that the significant effect of ivermectin on survival was dependent on largely poor quality and potentially fraudulent studies. This highlights the need for rigorous quality assessments, the need for authors to share patient level data and efforts to continue to avoid publication bias for registered studies. These steps are vital to facilitate accurate conclusions on any clinical treatment. (...)  In July 2021, after the potentially fraudulent studies were identified, we retracted our published meta-analysis and began working on an updated analysis, assessing the effects of stratifying by trial quality on the overall results. (...)  On excluding the potentially fraudulent Elgazzar study, ivermectin results in a borderline significant 38% increase in survival (p=0.05). On excluding the high risk of bias studies, ivermectin results in a non-significant 10% increase in survival (p=0.66). Lastly, on excluding studies with some concerns of bias, ivermectin results in a non-significant 4% increase in survival (p=0.90) (Figure 1). These observations demonstrate that the significant effect of ivermectin on survival was dependent on the inclusion of studies with a high risk of bias or potential medical fraud. The [Niaee preprint] now has an Editorial Note of Concern:  25 October 2021: This study describes the results of a double-blind, randomized controlled trial for the use of ivermectin to treat mild to severe COVID-19 infection in 180 patients. The researchers indicated that the treatment resulted in reduced mortality, improved oxygen saturation, and improvement on a number of other clinical parameters. On 8 October 2021 and 9 October 2021, two articles were published by subject-matter experts outlining concerns about various aspects of the study and, in particular, calling into question the randomization of participants. The authors and publishing journal have been alerted to these issues, and this note will be updated with any new information related to the publication. Do all the authors of the Bryant et al meta-analysis systematic review still have confidence in its conclusions? What steps are the authors taking to correct the scientific record? , 
 From Retraction Watch, concerning the Raad study: [Ivermectin-COVID-19 study retracted; authors blame file mixup] New results emerging from Malaysia: https: twitter.com Khairykj status 1455834757867048961 , 
 Expression of concern. h t [Retraction Watch] .  ,