Ivermectin and the TOGETHER Trial.

• Author: Hooper, Charles L.

In our recent Regulation article "Ivermectin and Statistical Significance" (Spring 2022), we looked at the empirical evidence and debate over whether the antiparasitic drug ivermectin helps prevent or treat COVID-19 infection. As indicated by the title, much of our article was devoted to the long-running issue of the use and misuse of a defined statistical threshold researchers employ to determine if results for the treatment group are genuinely different from results for the control group. We also discussed the incentives that both the pharmaceutical giant Merck (the developer of ivermectin, whose patent has now expired) and the Food and Drug Administration have to dismiss evidence that the drug is effective against COVID-19.

About the time our article appeared, the New England Journal of Medicine (NEJM) published a multi-author article on ivermectin's effects on COVID patients in Brazil. The authors conducted a large-scale trial known as TOGETHER that looked at both ivermectin and the antidepressant fluvoxamine as possible treatments, and they concluded that ivermectin is not useful against the disease. According to the article, "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." Reporting on the article, the New York Times quoted one infectious disease expert who had read the study, Dr. David Boulware of the University of Minnesota, stating, "There's really no sign of any benefit," while another, Dr. Paul Sax of Brigham and Women's Hospital in Boston, said, "At some point it will become a waste of resources to continue studying an unpromising approach."

Given this negative news, it appeared, ivermectin had reached the end of its COVID road.

However, a careful reading of the NEJM article finds it is not nearly as conclusive and persuasive as the two doctors' quotes and other media coverage would lead us to believe. In fact, because the results of the TOGETHER Trial suggest that ivermectin actually did benefit the Brazilians in the treatment group--results that are in agreement with 87% of the other clinical trials that have tested ivermectin--there is still good reason to continue studying the drug as a possible preventative or treatment for COVID-19.

Clinical trials and the truth / By the very nature of clinical trials, there is only an indirect linkage between their results and the truth. Ideally, a trial uses a relatively small sample to represent a population --say, a thousand people to represent all of humanity--some of whom receive the treatment under investigation while others do not. Investigators then try to determine if the treatment, or "active," group has a different outcome than the control group, with the hope that the only difference between the groups is the treatment under investigation and with the further hope that the sample truly is representative of the population.

Running clinical trials on medications is difficult and many things can go wrong. We must scrutinize each trial to see its strengths and weaknesses and then look at the whole body of evidence concerning the possible intervention that is under investigation. Here's a partial list of factors to consider when evaluating a drug study:

* Was the correct dose given? If not, was the dose too low or too high?

* Was the treatment given at the correct time? Was it given too late in the course of the illness to be effective?

* Was the drug correctly formulated? Was the active ingredient actually active?

* Were the study participants split...