The many problems of the Ivermectin study in the NEJM

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:

Data issues:

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:

covid19criticalcare.com
doyourownresearch.substack.com (D),
longhaulwiki.com,
stevekirsch.substack.com,
trialsitenews.com,
twitter.com (W),
twitter.com (X),
twitter.com (Y), twitter.com (Z)].
Protocols, approvals, and statistical analysis plans can be found here [togethertrial.com (C)].

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.

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!

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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.

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