Ivermectin meta-analysis by Dr. Andrew Hill; and criticisms

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Research Square

This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Systematic Review

Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection

Andrew Hill, Ahmed Abdulamir, Sabeena Ahmed, Asma Asghar, Olufemi Emmanuel Babalola, Rabia Basri, Carlos Chaccour, Aijaz Zeeshan Khan Chachar, Abu Tauib Mohammed Chowdhury, Ahmed Elgazzar, Leah Ellis, Jonathan Falconer, Anna Garratt, Basma Hany, Hashim A Hashim, Wasim Ul Haque, Arshad Hayat, Shuixiang He, Ramin Jamshidian, Wasif Ali Khan, Ravi Kirti, Alejandro Krolewiecki, Carlos Lanusse, Jacob Levi, Reaz Mahmud, Sermand Ahmed Mangat, Kaitlyn McCann, Anant Mohan, Mortezza Shakshi Niaee, Nurullah Okumus, Victoria Pilkington, Chinmay Saha Podder, Ambar Qavi, Houssam Raad, Mohammaed Sadegh Rezai, Surapaneni Sasank, Veerapaneni Spoorthi, Tejas Suri, Junzheng Wang, Hannah Wentzel

Abstract

EDITORIAL NOTE:

Editorial Note: On July 6, 2021, Open Forum Infectious Diseases published a version of this preprint. The authors subsequently learned that one of the studies on which this analysis was based had been withdrawn due to fraudulent data. An expression of concern was issued on August 9, 2021. The authors will be submitting a revised version excluding the problematic study, and the originally published paper will be retracted. This note will be updated with the link to the revised version once it is published.

Ivermectin is an antiparasitic drug being investigated for repurposing to SARS-CoV-2. In-vitro, ivermectin showed limited antiviral activity and a COVID-19 animal model demonstrated pathological benefits but no effect on viral RNA. This meta-analysis investigated ivermectin in 18 randomized clinical trials (2282 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. In six randomized trials of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-0.52]; p=0.0002); 14/650 (2.1%) deaths on ivermectin; 57/597 (9.5%) deaths in controls) with favorable clinical recovery and reduced hospitalization. Many studies included were not peer reviewed and meta-analyses are prone to confounding issues. Ivermectin should be validated in larger, appropriately controlled randomized trials before the results are sufficient for review by regulatory authorities.

https://www.researchsquare.com/article/rs-148845/v1

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FranceSoir

Ivermectin: the BonSens.org association attacks Dr Hill’s meta-analysis as fraudulent science

Publié le 27/03/2021 à 12:07 – Mise à jour à 12:08

Auteur(s): FranceSoir A+A

The BonSens Association demands the withdrawal of Dr Andrew Hill’s meta-analysis.

As part of its commitment to defend the health of its members and the health of citizens in countries throughout Europe and the world,  BonSens.org announced today that it had sent a letter to senior academic leaders at the University of Liverpool about the preprint paper ‘Preliminary meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection’ by Dr Andrew Hill and his project team.

BonSens.org is currently participating in the forthcoming legal action to secure an emergency use authorisation for ivermectin in the treatment of COVID-19 patients in France. The letter highlights the serious concerns about the scientific credibility of Dr Hill’s paper, following concerns raised by professional colleagues of Dr Hill, who are also participating in ivermectin research.

A member of the Association’s office confirms that:

We are concerned about unethical scientific interference in the production of Dr Hill’s preprint paper, by the project’s promoters Unitaid or other as yet unidentified actors.”

On Monday (22/3/21), the European Medicines Agency advised against the use of ivermectin in the treatment of COVID-19 patients, outside of clinical trials.  The Association questions whether the purpose of this scientific interference in Dr Hill’s meta-analysis, “is to delay emergency authorizations for the use of ivermectin in the treatment of COVID-19 patients, in France and throughout the world“.

The Association commissioned a forensic communication consultant to assess the paper. Arising from this work, an email was sent to Dr Hill on 18 March 2021 seeking further information or explanation in respect of 23 important questions about the paper. Dr Hill has not yet responded to this email of any of the issues raised in it.

The Association’s office has confirmed that BonSens.org has “requested the immediate withdrawal of this study , pending a full investigation of the concerns we have raised and the concerns about Dr Hill’s paper already in the public domain.”

https://www.francesoir.fr/societe-science-tech-politique-monde/ivermectin-bonsensorg-association-attacks-dr-hills-meta

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TrialSite News

News Roundup | Scientific Misconduct Accusation with Dr. Andrew Hill’s Ivermectin Meta-Analysis

TrialSite Staff April 5, 2021

Scientific Misconduct Associated with Ivermectin Meta Analysis:The ivermectin situation continues in controversy as a new French civic group known as the BonSens Association makes allegations of scientific misconduct associated with the ivermectin meta-analysis authored by Dr. Andrew Hill and a group of researchers affiliated with the University of Liverpool and Unitaid. TrialSite has gained insight on this imbroglio from a series of conversations with relevant and associated parties, some that wish to remain anonymous that have shared that in fact this study was modified separate and apart from the investigator. According to some ivermectin proponents, at stake here is more than just issues of scientific integrity but importantly, the health of hundreds of millions of people and the operation of free markets, which depend on the rule of law, scientific transparency, and rational actions by government health authorities and regulatory bodies.

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News Roundup | Scientific misconduct accusation with Dr. Andrew Hill’s Ivermectin Meta-Analysis…

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Nature

  • 02 August 2021

Flawed ivermectin preprint highlights challenges of COVID drug studies

The study’s withdrawal from a preprint platform deals a blow to the anti-parasite drug’s chances as a COVID treatment, researchers say.

Throughout the pandemic, the anti-parasite drug ivermectin has attracted much attention, particularly in Latin America, as a potential way to treat COVID-19. But scientists say that recent, shocking revelations of widespread flaws in the data of a preprint study reporting that the medication greatly reduces COVID-19 deaths dampens ivermectin’s promise — and highlights the challenges of investigating drug efficacy during a pandemic.

“I was shocked, as everyone in the scientific community probably were,” says Eduardo López-Medina, a paediatrician at the Centre for the Study of Paediatric Infections in Cali, Colombia, who was not involved with the study and who has investigated whether ivermectin can improve COVID-19 symptoms. “It was one of the first papers that led everyone to get into the idea ivermectin worked” in a clinical-trial setting, he adds.

The paper summarized the results of a clinical trial seeming to show that ivermectin can reduce COVID-19 death rates by more than 90%1 — among the largest studies of the drug’s ability to treat COVID-19 to date. But on 14 July, after internet sleuths raised concerns about plagiarism and data manipulation, the preprint server Research Square withdrew the paper because of “ethical concerns”.

Ahmed Elgazzar at Benha University in Egypt, who is one of the authors on the paper, told Nature he was not given a chance to defend his work before it was removed.
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Ripple effects

The paper’s irregularities came to light when Jack Lawrence, a master’s student at the University of London, was reading it for a class assignment and noticed that some phrases were identical to those in other published work. When he contacted researchers who specialize in detecting fraud in scientific publications, the group found other causes for concern, including dozens of patient records that seemed to be duplicates, inconsistencies between the raw data and the information in the paper, patients whose records indicate they died before the study’s start date, and numbers that seemed to be too consistent to have occurred by chance.
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Although dozens of ivermectin clinical trials have been launched over the past year3, the Elgazzar paper was notable for announcing one of the first positive results, as well as for its size — it included 400 people with symptoms of COVID-19 — and the magnitude of the drug’s effect. Few therapies can claim such an impressive reduction in death rates. “It was a significant difference, and that stood out,” says Andrew Hill, who studies repurposed drugs at the University of Liverpool, UK. “It should have raised red flags even then.”

Lawrence agrees. “I was absolutely shocked that no one had uncovered it,” he says.
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One of the authors of the meta-analysis, statistician Andrew Bryant at Newcastle University, UK, says that his team corresponded with Elgazzar before publishing the work to clarify some data. “We had no reason to doubt the integrity of [Professor] Elgazzar,” he said in an e-mail. He added that in a pandemic setting, no one can reanalyse all of the raw data from patient records when writing a review. Bryant went on to say that his group will revise the conclusion if investigations find the study to be unreliable. However, even if the study is removed, the meta-analysis would still show that ivermectin causes a major reduction in deaths from COVID-19, he says.

Reliable data needed

The paper’s withdrawal is not the first scandal to dog studies of ivermectin and COVID-19. Hill thinks many of the other ivermectin trial papers that he has scanned are likely to be flawed or statistically biased. Many rely on small sample sizes or were not randomized or well controlled, he says. And in 2020, an observational study of the drug was withdrawn after scientists raised concerns about it and a few other papers using data by the company Surgisphere that investigated a range of repurposed drugs against COVID-19. “We’ve seen a pattern of people releasing information that’s not reliable,” says Hill. “It’s hard enough to do work on COVID and treatment without people distorting databases.”

Carlos Chaccour, a global-health researcher at the Barcelona Institute for Global Health in Spain, says it has been difficult to conduct rigorous studies on ivermectin. That’s partly because funders and academics in wealthy countries haven’t supported them, and, he suspects, have often dismissed trials of ivermectin because most of them have been done in lower-income countries. Furthermore, says Rodrigo Zoni, a cardiologist at the Corrientes Cardiology Institute in Argentina, it is difficult to recruit participants because many people — particularly in Latin America — are already taking the widely available drug in an attempt to prevent COVID-19.

Adding to the difficulty are conspiracy theories holding that ivermectin has been proven to work and that drug companies are depriving the public of a cheap cure. Chaccour says he has been called ‘genocidal’ for doing research on the drug rather than just endorsing it.
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Nature 596, 173-174 (2021)

doi: https://doi.org/10.1038/d41586-021-02081-w

References

  1. 1.Elgazzar, A. et al. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-100956/v3 (2020).
  2. 2.Caly, L., Druce, J. D., Catton, M. G., Jans, D. A. & Wagstaff, K. M. Antiviral Res. 178, 104787 (2020).PubMed  Article  Google Scholar 
  3. 3.Popp, M. et al. Cochrane Data. System. Rev. https://doi.org/10.1002/14651858.CD015017.pub2 (2021).Article  Google Scholar 
  4. 4.Bryant, A. et al. Am. J. Ther. 28, e434–e460 (2021).PubMed  Article  Google Scholar

https://www.nature.com/articles/d41586-021-02081-w

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