Original article here.
A much-awaited ivermectin study in Argentina disappointed those looking for positive results as the IVERCOVID19 trial, sponsored by the Corrientes Institute of Cardiology “Juana F. Cabral” with funding from the Ministry of Public Health, Province of Corrientes, Argentina, came out with subpar results. The single-center, prospective, randomized, double-blind, placebo-controlled study centered on the primary endpoint as the need for hospitalization in patients with COVID-19 while secondary endpoints involved time to hospitalization in days, use of invasive mechanical ventilation, time to invasive mechanical ventilation in days, use of dialysis, and all-cause mortality. The study team acknowledged material limitations, including first that the study was underpowered but secondly and importantly the acknowledgment that the dosage was “below the doses proposed as probably effective.” Consequently, the study authors reported in the peer review journal BMC Infectious Diseases that at least in this study group, the drug had no significant effect on preventing the hospitalization of patients with COVID-19. As it turned out, those that did require invasive mechanical ventilation frequented the ivermectin group more while there were no discernible differences in any of the secondary endpoints. While this is overall a disappointment for ivermectin proponents, the balance of studies, as recorded in three primary meta-analyses, indicate the potential of this drug as a possible early-onset treatment. Remdesivir completely bombed in major studies to the point that the World Health Organization (WHO) recommended against any use, yet the National Institutes of Health (NIH) and U.S. Food and Drug Administration (FDA) still loyally back the drug, which has led to $3 billion of sales in the first nine months of the drug’s release. But nonetheless, the ivermectin proponents will have a more challenging time now with major economic regulatory bodies, including the one in this South American nation. The co-investigator exchanged emails with TrialSite and explained that the low dosages used in the study were primarily a function of timing and regulatory constraints. The critical point of view of another Argentinian principal investigator, Dr. Héctor Carvello, is included herein as well for what will hopefully become a dynamic dialogue worldwide.
The IVERCOVID19 study (NCT04529525) authors acknowledged considerable limitations, which included the following:
“The fact that no significant differences were found in the primary end point of hospitalizations in this study may be due to different factors. The first is that ivermectin is not effective in this group of patients to prevent hospitalizations. The second is that the IVERCORCOVID19 trial is underpowered because the hospitalization rate was lower than expected when performed in the sample size calculation, as well as the fact that an ambitious reduction of 50–70% was estimated of primary endpoint. Thirdly, the dose of ivermectin adjusted to the weight of the patients was low, which on the one hand could corroborate that these doses are not effective, but alternatively could provide the opportunity to study the efficacy of higher doses of ivermectin.”
With a mean age of study participants at 42 with a standard deviation of 15.5 years, the authors report that the median time since symptom onset to the inclusion was 4 days with an interquartile range of 3-6. When discussing the primary outcome of hospitalization while more in the placebo group (21/251) 8.4% that number was 14 out of 250 for 5.6% in the ivermectin group. According to the study odds ratio, however, 0.65; 95%, confidence interval, 0.32-1.31; p=0.227.
The time to hospitalization wasn’t statistically different while of note, the mean time from study enrollment to invasive mechanical ventilatory support was 5.25 days with a standard deviation of plus or minus 1.71 days in the ivermectin group and 10 days, with a standard deviation of plus or minus 2 in placebo group with a p value of 0.019. Other secondary endpoints are nothing of interest.
Discussion of Study Limitations
According to sources, the principal investigators are most certainly pro-ivermectin. This study doesn’t have any sort of potential conflict challenges like two other studies out of Latin America concerning questionable results. But according to another Argentinian investigator included below, that could not be the case.
Starting back in August 2020, the study investigator, according to one source, opted for a conservative and safe dose option, as the study authors would observe in the final results—it may have been too low a dose. But as will be discussed by one of the lead investigators himself, Dr. Rodrigo Zoni, regulatory matters would influence dosage but more on that later.
Interestingly, a study out of Argentina produced evidence of the safety and efficacy of ivermectin as an antiviral regimen, but with higher doses—that study can be reviewed here. However, this Argentinian study had already commenced and the sponsor-investigators couldn’t change their protocol. Perhaps it was these elements, in addition to a flaw in the design involving the acceptance of young patients, that generated little to no events.
Some colleagues point out that co-principal investigator Dr. Julio Vallejos still thinks that Ivermectin can work, and he keeps working for the drug’s acceptance. This trial was, of course, mission-critical for that cause as compelling results would have probably led to an approval in Argentina for ambulatory patients.
PI: Still Bullish on the Potential of Ivermectin
TrialSite was able to correspond with Dr. Rodrigo Zoni, co-investigator in the IVERCOVID19 study. Commenting on why the lower dose was used, he noted:
“When we designed the IVERCORE trial (June 2020) and started the recruitment (August 2020), we knew no more about the possible dose of ivermectin. So we decided to use the dose that is allowed in our country for some parasitic diseases because if we would use a higher dose, we needed regulatory agencies authorizations and this is not easy in our country.”
The cardiologist who serves as Secretary of the Board of Directors of the Argentine Federation of Cardiology and earned a degree from Harvard Medical School GCSRT Program went on, saying, “Now a day, there is some initial evidence that maybe, higher doses of ivermectin could work. We need to wait for the results of these ongoing trials.”
Some Critical Vantage Points
TrialSite exchanged emails with Dr. Pierre Kory, co-founder of the Front Line COVID-19 Critical Care Alliance (FLCCC) and well-known ivermectin proponent, as well as co-author of a published meta-analysis that pointed to significant safety and efficacy. Dr. Kory elaborated:
“The Vallejos study appears to be nearly identical to the Lopez-Medina study in that they included young patients with mild disease, started treatment late and at a low dose in an area with rampant ivermectin use – note that 12,356 patients of the 22,533 patents screened were excluded for having taken ivermectin within 7 days. Despite these very strong limitations, they still found a large reduction in the need for hospitalization although it did not meet statistical significance due to so few events being observed. “
Dr. Héctor Carvallo Point of View
TrialSite exchanged communications with Dr. Héctor Carvallo, also from Argentina, who pioneered ivermectin-based research covered by this media during the pandemic. Working out of Eurnekian Public Hospital, he raised some constructively critical elements about this study. They can be segmented into 1) the population dynamics and demographics in the Province of Corrientes; 2) Ethical issues; 3) Technical issues; and 4) Methodical issues. TrialSite has shared the core arguments with doctors Vallejos and Zoni and invited them to respond via comments, their own brief, or even in a live debate between the two research groups. What follows are Dr. Carvallos’s challenges with the IVERCOVID19 study.
Population Dynamics in Corrientes
As far as the population in this province, Dr. Carvallo shared that of the total 1,070,283, 26% are under the age of 12. Thus a population of 803,000 inhabitants live here from teenage years and up. Based on drug sales data, Carvallo reported that 668,321 packages of 6-mg pills were purchased at drugstores during the time of the IVERCOVID19 study. As infants, of course, were obviously excluded, Carvallo suggests that much like the study in Cali, Colombia, approximately 80% of the Corrientes population was already receiving ivermectin, either prescribed or self-medicated.
Moreover, argues the Argentinian investigator, this wouldn’t factor in the medication offered to the subjects recruited in the study but raises the issue that there was a high probability of likelihood that any recruited subject in both arms would have received ivermectin.
Thus, argues this ivermectin expert, it would most certainly be difficult to find “subjects of virgin ivermectin” suggested by the principal investigator to Carvallo a year ago.
According to Dr. Carvallo, the IVERCOVID19 team had to modify trial conditions midstream of the study, in that quest to reach the proposed number of persons included—and to consider those who hadn’t received ivermectin in the last week. Carvallo emphasizes that this ignores the fact that ivermectin accumulates in the fat tissue—a fact, he points out, African physicians have taken advantage of for decades, in order to maintain an administration twice per annum in a bid to prevent river blindness.
Dr. Carvallo does raise some questions about IVERCOVID19 as there was a declaration at the beginning of the peer-reviewed article that “…it would be the first one in Argentina.” Carvallo and team thus shared with TrialSite that their investigational unit had already accomplished an ivermectin study, completed them, submitted them to the National Library of Medicine (USA), and published the results.
Moreover, Carvallo argues that there was actually a dispute about the ethical inconvenience of the use of a placebo arm (29th Amendment of Helsinki protocol) in a potentially lethal disease. While the Carvallo et al. outcomes were solid, the question remains: why another study? Of course, this argument is refuted as health systems around the world continue to demand randomized controlled trials. A moral quandary, undoubtedly.
Not included in the limitations was the fact, according to Carvallo, that the ivermectin produced for this study was compounded in a local lab facility, hence raising the question as to the quality of the compound used for the study drug. Carvallo informed the TrialSite that the dose administered to subjects was in fact standardized at 12 mg per person, regardless of weight, the moment of recruitment, or the severity of the case, etc.
While Zoni et al. disclosed to the TrialSite that the regulatory overhead was too great to modify the dosage beyond what was acceptable by authorities for current indications at the time, Carvallo wonders about how this study could be designed with a high probability that it wouldn’t succeed.
Carvallo shared with the TrialSite that security forces located at Corrientes (known as Gendarmería Nacional ), asked both Professor Hirsch and Carvallo to provide them ivermectin of “known origin,” which the investigator reports they obliged at no cost—and since then, there has been no outbursts of the pandemic there.
According to Carvallo, the concerns raised above by this investigational group also raise the issue of the modification to outcomes during the middle of the study. The investigator suggests that IVERCOVID19 commenced the study on the original Wuhan variant but with such a lengthy stretch of time to conclude—that is over a year for 500 subjects—that new variants circulate through South America, including UK, Brazilian, and the South African variants yet the study protocol went back to a far earlier time in the pandemic.
Carvallo shared his concern about not only IVERCOVID19 but also the current University of Oxford PRINCIPLE study in that subjects are recruited even though they were diagnosed 14 days prior, thus that particular subject could be in either convalescence period or in worsening severity, thus the outcomes were not properly adjusted to the real-time in which ivermectin is recommended to be administered based on the dozens of studies around the world, including their own in Argentina—at the very beginning.
There are varying points of view, and again, TrialSite has invited Dr. Zoni and Vallejos to respond and provide their counterarguments either in comments or in dedicated responses. Moreover, both the parties are invited to a TrialSite podcast for a live debate, should they be interested.
Rodrigo Zoni, Instituto de Cardiología de Corrientes, Bolivar 1334, Zip code, 3400, Corrientes, Argentina
Julio Vallejos, Dr., Instituto de Cardiología de Corrientes, Bolivar 1334, Zip code, 3400, Corrientes, Argentina
Call to Action: Check out the study results here. TrialSite suggests both groups sought a good outcome but one study’s conditions weren’t conducive to a compelling outcome.