The many problems of the Ivermectin study in the NEJM

Posted on by Jesse Santiano, M.D.

The esteemed New England Journal of Medicine published an ivermectin study, Effect of Early Treatment with Ivermectin among Patients with Covid-19 in March 2022.

The second paragraph of the abstract lays out the design of the study to make it sound like it is a well-made, unbiased, and a scientific study:

METHODS

We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2–positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo.

Many readers will understandably go straight to the conclusion part and will see this:

Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.)

NEJM March 30, 2022 and updated April 5, 2022

Many read that and will move on with the knowledge that ivermectin is not effective. But that is not so. Below is the result of the same study.

The graph shows that ivermectin works better than the placebo in almost all the categories and yet the authors did not find a statistically significant difference among them. (See what a statistician thinks about that below.)

There are other issues with the paper. c19ivermectin.com has a whole webpage of analysis, comments, and criticism about the study. The people at c19ivermectin have tried to reach the authors but they have not responded. All the links below direct to c19ivermectin.com/togetherivm.html#ref_marinos. Here are the issues.

Protocol issues:

  1. blinding failures
  2. unequal randomization
  3. significant confounding
  4. unknown onset patients included
  5. widespread community use
  6. DSMC not independent
  7. extreme conflicts of interest
  8. vaccine inclusion changes
  9. analysis company works closely with Pfizer
  10. designed by Cytel
  11. change in viral load not reported
  12. per-protocol conflict vs. fluvoxamine
  13. multiple conflicting randomization protocols
  14. conflicting dosing
  15. plasma concentration below known effective
  16. primary outcome easy to game
  17. conflicting target enrollment
  18. futility
  19. threshold inconsistent
  20. subgroup analysis
  21. missing analysis
  22. missing outcomes
  23. mid-trial protocol changes
  24. imputation protocol violation
  25. single-dose recruiting continued after change
  26. funding list incorrect
  27. SAP after trial start
  28. single dose results not reported
  29. placebo unspecified

Data issues:

  1. unexplained delay
  2. no response to data request
  3. 3 different death counts
  4. patient count mismatch
  5. conflicting placebo arm counts
  6. unknown onset results dramatically better
  7. low active arm side-effects
  8. incorrect conclusion
  9. conflicting comorbidity counts
  10. conflicting adverse event counts
  11. screening to treatment delay
  12. missing age information
  13. mean delay likely excluding unknown onset
  14. two different per-protocol counts
  15. 3-dose placebo much more effective
  16. dominated by Gamma variant
  17. no discussion

April 5:

 The paper was updated, with no indication or explanation of the changes. Changes include age range, placebo description, per-protocol count, and death counts (details below). 

April 20: 

The authors have still not responded to the data request. There is still no explanation for the Apr 5 changes. Data in this trial appears to be unreliable.

Delayed >6 months. 

The paper was delayed for over 6 months with no explanation. The companion fluvoxamine arm, completed at the same time, was published on Aug 23, 2021. The paper was submitted to NEJM in Sep 2021 [vimeo.com (B)]. COI forms suggest that additional authors were added after submission and the corresponding author changed from Prof. Mills to Dr. Rayner, [doyourownresearch.substack.com] whose conflicts include Pfizer, Merck, the Gates Foundation, and the Australian Government.

No response to the data request. 

The trial registration states that data was to be available at termination and upon request [clinicaltrials.gov], however, the authors have not responded to a request for the data. Requests can be sent to thetogethertrial@gmail.com, let us know the outcome.

Conflicts of interest are the reason why this study sucks. Again. From c19ivermectin.

Possibly the largest financial conflict of interest of any trial to date. 

Disclosed conflicts of interest include Pfizer, Merck, Bill & Melinda Gates Foundation, Australian Government, Rainwater Charitable Foundation, Fast Grants, Medicines Development for Global Health, Novaquest, Regeneron, AstraZeneca, Daichi Sankyo, Commonwealth Science and Research Organization, and Card Research. Many conflicts of interest appear unreported. For example, Unitaid is a sponsor [Harper, togethertrial.com (B)].

Analysis done by a company that receives payment from and works closely with Pfizer. 

All analyses were done by Cytel. Cytel is a statistical modeling company that helps pharmaceutical companies get approval — they work very closely with Pfizer [cytel.com]. Cytel’s software and services are used by the top 30 pharmaceutical companies [cytel.com (B)].

A co-principal investigator works for Cytel and the Gates Foundation [empendium.com]: “The majority of the time I work for a company called Cytel, where I design clinical trials, predominantly for the Bill & Melinda Gates Foundation”.

The Gates Foundation is a founding partner of GAVI, which took out Google ads telling people not to use ivermectin [twitter.com (U)], and a major funder of Unitaid, which may have modified the results of the Hill meta-analysis in a way that prevented adoption. [c19ivermectin.com, c19ivermectin.com (B), twitter.com (C)].

Associated with MMS Holdings. 

The trial is associated with MMS Holdings [dcricollab.dcri.duke.edu], whose mission includes helping pharmaceutical companies get approval and designing scientific studies that help them get approval. One of their clients is Pfizer [mmsholdings.com].

Certara

One of the senior investigators was Dr. Craig Rayner, President of Integrated Drug Development at Certara – another company with a similar mission to MMS Holdings. They state on their website that: “Since 2014, our customers have received over 90% of new drug and biologic approvals by the FDA.” One of their clients is Pfizer. [certara.com].

Funding conflict

The paper does not include the Bill and Melinda Gates Foundation or Unitaid as funders, however the Mar 25, 2021 protocol shows the Gates Foundation [static1.squarespace.com], and the website shows Unitaid. [togethertrial.com (B)].

For additional issues see: 

In an article by Steve Kirsch, he quoted Ed Mills. Co-principal investigator of the Together Trial.

“There is a clear signal that IVM works in COVID patients.. that would be significant if more patients were added.. you will hear me retract previous statements where I had been previously negative” 

 [stevekirsch.substack.com]

Below is a quote from a Vimeo of this study from From Frank Harrell

Anytime I hear the phrase that there was no significant difference between two treatments, my hair raises on the end because that is not really not a good way to summarize the results. It doesn’t actually mean anything and it can’t give you evidence in favor of the nul.

Ed raised the important point when you have a confidence interval that goes all the way down to a 30% reduction in relative risk the question of whether the study was stopped too early in light of the political ramifications of needing to demonstrate that the efficacy is really unimpressive it really could be raised as a logical question.

I don’t know what’s valuable to know in terms of how much money is worth or time is worth to find out more but because of the political ramifications. The points at which this study was stopped I think could be debated.

Ed Mills: I totally agree with Frank

Grand Rounds Rethinking Clinical Trials 03-18-2022

If you want to see the universe of ivermectin studies on COVID-19, take a look at the image below as of today April 22, 2022.

https://c19ivermectin.com/

Bottom line:

The ivermectin study on the March 2022 edition of the NEJM is fraught with protocol violations. Some may be surprised that NEJM published it. but to me after the Surgisphere scandal, I read all medical journals with suspicion.

According to at least one of the principal authors of the study (Ed Mills), ivermectin works and the study would have shown it if only it was prolonged.

And that my dear readers are what happens when agenda and politics are mixed with medicine.

 

Truth heals, Lies kill. Don’t Get Sick!

Knowledge about Covid-19 is rapidly evolving. Stay current by subscribing. Feel free to share and like.

If you find value in this website, please consider donating to show your support.

 

Related:

  1. Japanese company announces Ivermectin has antiviral properties
  2. City-wide use of Ivermectin lowered COVID-19 cases, hospitalizations and deaths in Itajaí, Brazil
  3. What makes Ivermectin a kick-ass antiviral?
  4. Where to Get Ivermectin
  5. How to get Ivermectin
  6. Ivermectin is effective against the Influenza and a Cold Virus In Vitro
  7. Bayes Theorem Confirms Meta-analysis of Ivermectin’s Effectivity against COVID-19
  8. News that ivermectin overdose is clogging up hospitals is not true
  9. Ivermectin vs Remdesivir for COVID-19
  10. Solved! The Ivermectin African Enigma
  11. IVMMETA.COM: A website of studies on Ivermectin’s efficacy
  12. Ivermectin is effective against the Influenza and a Cold Virus In Vitro

Reference:

Reis G, Silva EASM, Silva DCM, Thabane L, Milagres AC, Ferreira TS, Dos Santos CVQ, Campos VHS, Nogueira AMR, de Almeida APFG, Callegari ED, Neto ADF, Savassi LCM, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Forrest JI, Ruton H, Sprague S, McKay P, Guo CM, Rowland-Yeo K, Guyatt GH, Boulware DR, Rayner CR, Mills EJ; TOGETHER Investigators. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med. 2022 Mar 30:NEJMoa2115869. doi: 10.1056/NEJMoa2115869. Epub ahead of print. PMID: 35353979; PMCID: PMC9006771.

© 2018 – 2022 Asclepiades Medicine, L.L.C. All Rights Reserved
DrJesseSantiano.com does not provide medical advice, diagnosis, or treatment

As an Amazon Associate, I earn from qualifying purchases.