Ivermectin: Studies come thick and fast; Regulators remain unmoved

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Three significant studies of Ivermectin in COVID-19  have been released in the past week, with two sets of meta-analyses delivering contradictory results and the third  — a randomised, double-blind placebo trial —  finding no significant effect on hospitalisation, writes MedicalBrief. In South Africa, the national Department of Health’s most recent evidence review (18 June) remains firm that Ivermectin “does not suggest any clear benefits with respect to mortality, clinical improvement, or viral clearance” in COVID-19.

As reported in MedicalBrief last week, a meta-analysis in the American Journal of Therapeutics of 18 randomised controlled treatment trials was conducted by scientists in the Front Line COVID-19 Critical Care Alliance (FLCCC), which has been campaigning for the legalisation of the anti-parasitic drug for the treatment of COVID-19. It found that it reduced mortality risk in mild-to-moderate COVID-19 patients by an average of 62%.

The authors concluded that Ivermectin in COVID-19 was linked to large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance and that “an oral agent effective in all phases of COVID-19 has been identified”.

In a statement, FLCCC said that the meta-analysis, “peer reviewed by medical experts that included three US government senior scientists … the research is the most comprehensive review of the available data taken from clinical, in vitro, animal, and real-world studies”.

“We did the work that the medical authorities failed to do, we conducted the most comprehensive review of the available data on Ivermectin,” said Dr Pierre Kory, president and chief medical officer of the FLCCC. “We applied the gold standard to qualify the data reviewed before concluding that Ivermectin can end this pandemic.”

Also, late-breaking in MedicalBrief last week, another meta-analysis, published in Clinical Infectious Diseases found that in comparison to standard of care or placebo, Ivermectin “did not reduce all-cause mortality”. It concluded that the drug “is not a viable option to treat COVID-19 patients”.

The study’s authors  — who do not specifically address the most recent FLCC study — write: “Several websites published systematic reviews and meta-analyses about Ivermectin in COVID-19 patients with unclear or absent methodology and reporting guidelines. These websites did not include protocol registration and have relevant omissions such as inclusion criteria, searched databases, study quality assessment, meta-analysis methods, and heterogeneity definition …

"In a context of a misinformation infodemic, the dissemination of these results caused confusion for patients, clinicians (in particular those without training in critical reading of scientific literature), and decision-makers, who may manipulate the information with political interests.”

 

IVERCOR-COVID-19 trial

The most recent study, published in BMC Clinical Diseases this week, was a randomised, double-blind, placebo-controlled study conducted in non-hospitalised individuals with COVID-19 in Corrientes, Argentina. The aim was assess whether Ivermectin prevented hospitalisation in those with early COVID-19 and the study concluded that Ivermectin had no significant effect on preventing hospitalisation.

Patients who received Ivermectin required invasive mechanical ventilatory support earlier in their treatment. No significant differences were observed in any of the other secondary outcomes.

Commenting on the IVERCOR-COVID-19 trial, Nathan Geffen and Elsabé Brits write in GroundUp: “Fourteen people on the Ivermectin arm were hospitalised versus 21 on the placebo arm. Besides this not being a statistically significant difference, there were more people with diabetes, perhaps the most serious risk factor for serious COVID, in the placebo arm; there were also more people with hypertension in the placebo arm (weight and age were well matched between the arms). Quite clearly Ivermectin was not shown to be beneficial in this trial.

“There was one statistically significant difference in outcomes. Four people on the ivermectin arm needed to be put on ventilators versus three in the placebo arm, but the ivermectin patients needed to be ventilated five days after they joined the study versus ten days for the placebo arm. This doesn’t mean ivermectin is unsafe, but it definitely doesn’t bode well for a drug that some have promoted so hard.

“This study confirms the results of a Columbian one published in March in the Journal of the American Medical Association, which also found no statistically significant benefit from Ivermectin versus placebo. That study had 476 participants.

“The problem with all the trials reported here is that they are still too small to reach definitive conclusions,” write Geffen and Brits.

 

Initial response to FLCC study

Writing on his Health Nerd blog, Australian epidemiologist Gideon Meyerowitz-Katz assesses the FLCC study as “a reasonably good meta-analysis” and that “in general the methodology was decent, although it has received some criticism from methodological experts online — the authors followed reporting guidelines and the study itself looks reasonably good.” However, after a detailed statistical analysis, Meyerowitz-Katz concludes: “What this means is that, if you exclude some of the low-quality research on Ivermectin, the study goes from showing a massive benefit to no benefit at all.

“On top of this, there’s an interesting point — even if you don’t agree with these assessments — taking the only three studies that the authors of the meta-analysis considered to be at a “low risk of bias” (i.e. high-quality), you find that these high-quality studies have failed to find any benefit for Ivermectin. In other words, while the conclusions the authors came to are very positive, the results section of the paper seems to show that the evidence might not be strong after all.

“That isn’t to say that the drug doesn’t work. What these guidelines are pointing out is that the evidence about Ivermectin generally is of extremely low quality … While the best evidence currently seems to show no benefit from the drug, even the best evidence isn’t very good.

“Ultimately, we’re left in a similar situation as we have been with so many things during this pandemic — uncertainty. That we are still so uncertain even after millions of people have been given the drug to treat Covid-19 worldwide is an incredibly depressing fact, but it is still absolutely true…”

 

BIRD response to Clinical Infectious Diseases study

The British Ivermectin Recommendation Group (BIRD) has responded with an “official rebuttal” to Roman et al’s meta-analysis “ with its embarrassing history” in Clinical Infectious Diseases.

They write:

“As authors of a recently published peer-reviewed meta-analysis with a very similar title we note a number of problems which need to be urgently addressed to avoid misleading the public:

Selectively small sample size: We note this recent meta-analysis covering n=1173 patients over 10 studies, asserting a conclusion the opposite of our own covering 3406 patients over 24 studies. This work ignores many of the larger trials, particularly those with mortality as an important endpoint.

Missing studies: Overall, we would recommend that other eligible trials are added in line with other reviews with the same inclusion criteria and data are re-analysed and interpreted correctly to avoid misleading conclusions. Otherwise, this review is of no value as we know the conclusions are incorrect and the results are different when eligible trials are added to the analyses. At present, they are simply underpowered and the assertion that ‘Ivermectin is not a viable option to treat COVID-19 patients’ is incorrect.

“Even if there were no missing studies from the Roman et al review, the results would show no statistically significant difference between the two treatment arms, but with the point estimates all favouring Ivermectin, suggesting if there was power to detect any difference then further trials may change the conclusions. In reality, knowing what the results for these trials are, then this is indeed the case.

Corrections made to article but ignored in the conclusions: This article has an embarrassing history whereby treatment arms in the study of Niaee1 were reversed, attracting protest from Dr Niaee himself. This egregious error has been corrected in the revised version, but with no change to the conclusions in spite of dramatic change in the evidence.

Absurd Confidence Levels, errors not corrected: Among other technical errors the study of Chaccour2 is assigned a RR of unity with absurd Confidence Intervals [0.02 46.56] when the correct assignment for a study with zero deaths in both arms (mortality outcome) is “not estimable”. Our own paper is particularly careful with analysis of “double-zero” studies. Several further errors are identified by contributors in the Comments section of medRxiv3 , apparently uncorrected.

“The point mortality reduction estimate of RR=0.37 in fact remarkably close to our own findings of RR=0.38 though the CIs ( [0.12, 1.13] vs [0.19, 0.73] ) are not, being based on fewer studies and in part by the absurd values assigned to Chaccour.

“The conclusion ‘Ivermectin did not reduce all-cause mortality’ does not follow from the evidence, with such selective study inclusion, and mishandling of data. Bias, statistical questions and ignoring existing evidence The authors of Roman et al erroneously interpret an absence of evidence of a difference as evidence of no difference. The authors may want to consider approaching a statistician to assist with the data analysis and interpretation of the results when updating their review. The authors could also consider reporting the optimal information size. The authors may want to use the updated review by Bryant and Lawrie et al as a point of reference. It is also unclear whether the review was guided by a written protocol a priori, this may be something to consider documenting going forward. The ROB-2 tool for assessing risk of bias was used, but the reviewers provide no justification for the judgements made.

“Bird Group strongly requests that that the article is withdrawn whilst the mistakes are reviewed, or a warning placed on the journal page to warn others of the incorrect information within.”


SA Department of Health’s Rapid Review Report update 

The DoH writes that its most recent report (18 June 2021)  updating the rapid evidence review of 21 January, found: “The current evidence for the use of Ivermectin in COVID-19 does not suggest any clear benefits with respect to mortality, clinical improvement, or viral clearance. The NEMLC COVID-19 sub-committee suggests that Ivermectin not be used routinely in the management of COVID-19, except in the context of a clinical trial.”

The reviewers, Trudy Leong, Jeremy Nel, Halima Dawood and Andy Parrish, conclude:

“The current evidence for the use of Ivermectin in COVID-19 does not suggest any clear benefits with respect to mortality, clinical improvement, or viral clearance. Many of the trials included have not yet been peer-reviewed. The available RCTs for the most part have very small sample sizes and suffer from considerable heterogeneity with respect to ivermectin dosing strategy and outcome measures. They also have several methodological limitations.

“These include a lack of allocation concealment, subjective and poorly defined endpoints and patient severity allocations, and baseline imbalances between the various trial arms in co-administered medications and in patients with risk factors for poor outcomes. In addition, trial designs combining ivermectin with doxycycline, or comparing Ivermectin to active controls such as azithromycin, hydroxychloroquine and lopinavir/ritonavir, do not allow for Ivermectin’s effects to be isolated from those of the other drugs (some of which may possibly worsen outcomes and thereby inflate the apparent beneficial effect in the Ivermectin arms).

“The large number of co-administered medications given as background “standard of care” further clouds this issue. Lastly, the potential for publication bias cannot be excluded; several trials were only added to trial registries after their completion.

“Together, these significant limitations limit the confidence in any conclusions with respect to Ivermectin. Further data from large, well-designed RCTs is needed.”

 

IVERCOR-COVID-19 details (Argentina study)

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID-19) a randomized, double-blind, placebo-controlled trial

Authors: Julio Vallejos, Rodrigo Zoni, María Bangher, Silvina Villamandos, Angelina Bobadilla, Fabian Plano, Claudia Campias, Evangelina Chaparro Campias, Maria Fernanda Medina, Fernando Achinelli, Hector Andres Guglielmone, Jorge Ojeda, Diego Farizano Salazar, Gerardo Andino, Pablo Kawerin, Silvana Dellamea, Antonia Cristina Aquino, Victor Flores, Carolina N. Martemucci, Silvina Maria Martinez, Juan Emanuel Segovia, Paola Itati Reynoso, Noelia Carolina Sosa, Mariana Elizabeth Robledo, Joaquina Maria Guarrochena, Maria Mercedes Vernengo, Natalia Ruiz Diaz, Elba Meza & María Gabriela Aguirre -Show fewer authors

Published in BMC Infectious Diseases 2 July 2021

Abstract

Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has changed our lives. The scientific community has been investigating re-purposed treatments to prevent disease progression in coronavirus disease (COVID-19) patients.

Objective
To determine whether ivermectin treatment can prevent hospitalization in individuals with early COVID-19.

Design, setting and participants: A randomized, double-blind, placebo-controlled study was conducted in non-hospitalized individuals with COVID-19 in Corrientes, Argentina. Patients with SARS-CoV-2 positive nasal swabs were contacted within 48 h by telephone to invite them to participate. The trial randomized 501 patients between August 19th 2020 and February 22nd 2021.

Intervention
Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient’s weight, for 2 days.

Main outcomes and measures
The efficacy of ivermectin to prevent hospitalizations was evaluated as primary outcome. We evaluated secondary outcomes in relationship to safety and other efficacy end points.

Results
The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3–6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32–1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes.

Limitations
Low percentage of hospitalization events, dose of ivermectin and not including only high-risk population.

Conclusion
Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes.

 

First meta-analysis details (FLCC)

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

Authors: Pierre Kory, Gianfranco Umberto Meduri, Joseph Varon, Jose Iglesias, Paul Marik

Published in American Journal of Therapeutics  29 June 2021

Abstract

Background

After COVID-19 emerged in the US, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials.

Areas of uncertainty

The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms, with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses.

Data sources

Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns.

Therapeutic advances

A large majority of randomised and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large “natural experiments” occurred in regions that initiated “ivermectin distribution” campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns.

Conclusions

Meta-analyses based on 18 randomised controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

 

Second meta-analysis details

Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials

Authors: Yuani M Roman, MD, MPH, Paula Alejandra Burela, BSc, Vinay Pasupuleti, MD, PhD, Alejandro Piscoya, MD, Jose E Vidal, MD, PhD, Adrian V Hernandez, MD, PhD

Published in Clinical Infectious Diseases on 30 June 2021

Abstract

Background

We systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients.

Methods

Published and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 22, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. Risk of bias (RoB) was evaluated using Cochrane RoB 2·0 tool. Inverse variance random effect meta-analyses were performed. with quality of evidence (QoE) evaluated using GRADE methodology.

Results

Ten RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. COVID-19 disease severity was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 0.37, 95%CI 0.12 to 1.13, very low QoE) or LOS vs. controls (MD 0.72 days, 95%CI −0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (all outcomes: low QoE). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality in three RCTs at high RoB was reduced with IVM.

Conclusions

In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have an effect on AEs or severe AEs. IVM is not a viable option to treat COVID-19 patients.

 

Full Health Nerd blog (Open access)

 

Full GroundUp story (Open access)

 

Full DoH Rapid Review of Ivermectin (June 2021) (Open access)

 

Full IVERCOR-COVID-19 details (Argentina study) (Open access)

 

Full FLCC study in American Journal of Therapeutics (Open access)

 

Full study in Clinical Infectious Diseases

 

See also from MedicalBrief’s archives:

 

Ivermectin significantly reduces COVID-19 mortality risk — FLCC meta-analysis

 

MedicalBrief Fact File: Making sense of the Ivermectin controversy

 

Ivermectin added to PRINCIPLE, world’s largest clinical trial of possible COVID-19 treatments

 


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