Magazine ‘unpublishes’ study that suggested the effectiveness of proxalutamide against Covid

An article that indicated a 91% reduction in hospitalizations for Covid-19 in men who used proxalutamide has just been retracted – that is, unpublished – by the scientific journal Frontiers in Medicine. According to the journal, the results presented were not “adequately supported by the methodology of the study”.

Before the final decision, the magazine had already released a public note that warned of potential serious problems in the work, carried out in two hospitals in Brasília. Another article by the same group, this time in the British Medical Journal, received the “expression of concern” label and is undergoing a review process.

Soon after the publication of the work in Frontiers in Medicine, in July 2021, scientists from Brazil and abroad began to openly criticize several points of the research, from the reliability of the data to the ethical aspects of the experiment.

Faced with questions from the scientific community, the journal hired an independent investigation. The opinion that analyzed the study devastated the methodology, especially the randomization of patients.

According to the methodological design, the trial was double-blind and randomized: when participants are randomly divided, without the volunteers or researchers knowing who used placebo or medication. According to the opinion, however, this is not what happened.

Based on information about the order in which the study volunteers were allocated, the person responsible for the opinion says that he submitted the data to a statistical analysis, the well-known Wald–Wolfowitz test, a procedure that analyzes the occurrence of similar events and indicates whether they were randomly generated.

According to the opinion, the probability of having sequences in which consecutive people are allocated to the same group, as happened in the proxalutamide study, is much less than the chance of someone being hit by lightning in the head during a year.

The referee –whose name was not revealed by the editors of the scientific journal– states that the justifications presented by the authors are weak. “In summary, the results show overwhelming evidence that the allocation process for treatment and control was not random. Therefore, the conclusions drawn from the study cannot be defended”, reads the excerpt from his opinion.

The content of the opinion and of all correspondence with the editors of Frontiers in Medicine was disclosed by the authors of the study, who did not agree with the retraction and dispute all the criticisms.

Coordinator of the experiment, Flávio Cadegiani, a doctor in endocrinology, questions the fairness of the review process and says that the authors suspect that the person responsible for the opinion has a personal interest in the retraction of the article.

“We were completely ignored, in our view, because there are no plausible answers. We offer multiple chances for answers. [a crítica] was completely anonymous, with absolutely no statements made in the first person. That is, decisions were always based on third-party opinions, which were never revealed,” she said in an emailed response to the report.

According to Cadegiani, the magazine ignored “additional independent analyses” that would show analytical flaws in the report presented.

Several Brazilian scientists, however, publicly stated that they considered the “unpublishing” of the article to be adequate.

“The retraction of an article happens, in science, when the peer review process has somehow failed, and evidence of errors begins to appear”, explains Leandro Tessler, professor at the Institute of Physics at Unicamp (State University of Campinas), who has already been part of commissions to investigate problem papers.

According to Tessler, when a scientific journal flags a study as potentially problematic and appoints experts to investigate it, that work is much more thorough than the normal review of articles.

“What doesn’t make sense is for the authors of the study to act as if there were some kind of worldwide plot against a work”, he adds.

Doctor in pulmonology, intensive care physician Ana Carolina Peçanha has in her curriculum several training courses in the elaboration and analysis of clinical trials. “The retraction of the work was due to methodological issues, which were really very weak. The decision did not even have to go into the ethical part, which was much worse”, she evaluates.

The criticism on ethical aspects refers to accusations of misconduct in trials with proxalutamide in hospitals in several cities in Brazil. The drug was nicknamed “the new chloroquine” because it was defended by President Jair Bolsonaro and his supporters.

The conduction of the tests spread throughout the national territory was declared irregular by Conep (National Research Ethics Commission), the highest instance of ethical evaluation in research protocols involving human beings in the country.

The entity claims that the group disrespected the initial authorization, which would have been given to a single institution in Brasília, and carried out experiments with the drug in other parts of the country. The entity also makes references to other methodological and ethical issues.

Conep reported the case to the Attorney General’s Office, which is now investigating the study in Manaus, which recorded 200 deaths among volunteers.

The complaints made the collegiate board of Anvisa (National Health Surveillance Agency) unanimously decide, in September 2021, to suspend the importation and use of proxalutamide in scientific research in Brazil.

The matter was also addressed at the Covid CPI, which asked, in its final report, for the indictment of doctor Flávio Cadegiani.

With no marketing approval in Brazil or any other country in the world, proxalutamide is an experimental antiandrogenic drug – that is, it blocks male hormones, such as testosterone – and was tested against breast and prostate tumors.

At the beginning of the pandemic, faced with the hypothesis that men would be more subject to the serious effects of the new coronavirus, some research began to bet on male hormone blockers as a treatment.

According to intensive care physician Ana Carolina Peçanha, as knowledge about the virus increased, the use of male hormone inhibitors against Covid-19 was proving ineffective.

“I work on the front lines, taking care of patients with Covid-19. I would be the first to want a miracle treatment that would stop people from dying. But it’s absolutely irresponsible the way these antiandrogenic drugs have been promoted”, says the doctor, who, with the worsening of the pandemic in 2021, interrupted her maternity leave a month before the deadline to help strengthen the team at the hospital where she works.