Recently, the results of a new ivermectin study out of Columbia were reported in the medical journal JAMA. Led by Eduardo Lopez Medina, MD, a physician and researcher at the Center for Pediatric infectious Diseases in Cali, Colombia, the double-blind, placebo controlled randomized clinical trial was organized to test the efficacy of ivermectin in preventing progression of disease in adult patients with early states of COVID-19. Interestingly, as the results were not compelling, the New York Times decided to swoop in on the news. The study (Lopez 2021) team found the patient participants taking the 5-day course of ivermectin failed to significantly improve the time to resolution of the symptoms. Although the investigative team concluded that the study results failed to support the use of ivermectin as a treatment of mild COVID-19, they acknowledge that perhaps larger trials may be needed to better understand the effects of the drug on other clinically relevant outcomes. TrialSite suggests that the results of this study do little to change the comprehensive meta analyses currently generated from researchers in America and the UK.
The study results indicated the time to resolution of symptoms was shorter (10 vs. 12 days) but not statistically significant. Very few participants in this trial got seriously ill, but there were “trends” in favor of ivermectin. For example, 2% vs. 3.5% clinically deteriorated—this is 2 points on the clinical scale but not significant. Additionally, a 2% vs. 5% required escalation of care, not statistically significant (although perhaps not a totally fair comparison as 4 of the recipients of placebo went to the hospital within 12 hours of randomization). Overall, the study drug was deemed safe with no increase in serious adverse events but again the statistically significant results were not there for ivermectin either.
In this study reported in JAMA, the team reported zero deaths associated with ivermectin and one control death. An interesting quirk in the study centered on the unusually high cumulative dosage of 1,500 μg/kg over five days. At that dose, 7.5x the normal, some non-life threatening and transient side effects can occur, notably blurring vision, and it was therefore appropriate for this study to track them, as shown from the study, supplementary file 2. Interestingly, the control group had exactly the same rate of these characteristics ivermectin-related adverse events as the ivermectin group; Diarrhea (30.2% v. 32.8%); Nausea (24.0% v. 23.7%); and blurred vision (16.0% v. 14.1%).
So, this study showed that both the ivermectin group and the control group had adverse events characteristic of ivermectin, at the same rate, within the limit of tolerability. Note that ivermectin is freely and inexpensively available over the counter without prescription in Colombia, the study locale.
These quirky results for IVM to treat mild cases of COVID-19 cases with no significant differences in deaths (0 for IVM, 1 for controls) stand in contrast to what happened in Peru as reported in a recent study when the army went in with mass IVM treatments through operation MOT, and state by state for those 10 states, excess deaths dropped 74% (mean reduction) over 30 days within 1-11 days after MOT start date. For the 25 states of Peru, the reduction in excess deaths correlated with the extent of IVM distribution and treatment with a p value of 0.002. These results are far more precise than the battlefield experience for penicillin in World War II, in which only general indications of good success were known, no RCTs at all, and then were followed with mass treatments of civilians.
While the results of this study cannot be denied, the measurement of time to symptom resolution as an outcome measure can also represent a challenge. Symptoms can be somewhat to quite heterogenous—that is they can fluctuate, and can tend to linger on for a while even after the individual has recovered. There was a hint of difference between groups on some other outcomes that were more closely related to clinical deterioration, but for those outcomes they did not have enough statistical power to show whether there is a true difference.
Interestingly, the primary outcome was changed 6 weeks into the trial but the concern of many TrialSite readers, as picked up by their comments, was that medical journals and press appear to not mind when the randomized controlled trial reveals negative or neutral results associated with a repurposed drug.
Of course, this particular trial was conducted among young people with mild COVID so one would not expect a lot of deaths and other poor outcomes. However, one death in the placebo group is one death too many.
Among other notable points was the New York Times‘ fascination with this particular ivermectin study results as none of the overwhelmingly positive study results, nor positive meta-analyses results, gained any attention from that nor other mainstream media.
Many in the TrialSite Network found it ironic that the prestigious paper swooped in on a neutral- to negative-leaning ivermectin study. After all, TrialSite has reported on one study after another that evidenced positive results. Yes, not all of these studies were designed the same but note there was no interest in major press for anything positive. But in this case, there was certainly considerable interest with bold declarations upfront. Interesting, no doubt.
The Importance of Meta Analyses
There are a few compelling meta-analysis studies circulating around North America and the United Kingdom, and these studies compare dozens of ivermectin-based trials. The net takeaway from these studies is an overwhelming positive outcome associated with the generic drug in the context of ivermectin and the coronavirus. Many challenge the underlying study quality of design, however, discounting the power of these broader analyses.
Whether one particular study is positive or negative, this hammers home the importance of meta-analysis studies. A relevant example is the remdesivir story. The U.S. FDA approved remdesivir on what Dr. Anthony Fauci himself declared as not the most compelling data (see TrialSite article) yet the World Health Organization in the Solidarity study revealed remdesivir wasn’t beneficial at all. The reality is that remdesivir is beneficial and just because one study shows it wasn’t doesn’t stop Gilead from generating nearly $3 billion in revenues. But TrialSite did ask the question whether power and politics was also at play with the drug. It takes many studies to make up a meta analysis, which provides a more accurate picture of a drug’s true efficacy.
Call to Action: TrialSite will continue to monitor the ivermectin study results as they are available and thereafter provide as much of an objective, non-commercially interested and unbiased perspective as possible. For example, despite this media platform’s favorable view of the current ivermectin meta analyses currently circulating, this particular Colombian study falls under our “TrialWatch Challenge” category, meaning the results were neutral to negative.