Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial

Vallejos et al., BMC Infectious Diseases, doi:10.1186/s12879-021-06348-5

Jul 2021

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RCT with 501 relatively low-risk outpatients in Argentina showing hospitalization OR 0.65 [0.32-1.31]. With only 7% hospitalization, this trial is underpowered. The trial primarily includes low-risk patients that recover quickly without treatment, leaving minimal room for improvement with treatment. 74 patients had symptoms for >= 7 days. Among the 7 patients requiring ventilation, authors note that the earlier requirement in the ivermectin group may be due to those patients having higher severity at baseline. However, authors know the answer to this - it is unclear why it is not reported. There were more adverse events in the placebo group than the ivermectin group, suggesting a possible issue with dispensing or non-trial medication usage. 25+% of patients were hospitalized within 2/3 days for the placebo/treatment groups (Figure S2).

The companion prophylaxis study IVERCOR PREP has reported results in the press and an online presentation lanacion.com.ar, twitter.com, however these results have not yet been formally published. The prophylaxis study results are very positive and statistically significant, and would be expected to receive priority publication due to the predicted impact on the pandemic and confirmation of previous prophylaxis studies. The lack of formal publication suggests a negative publication bias that may be due to politicization in the authors' location.

Authors pre-specify multivariate analysis but do not present it, however multivariate analysis could significantly change the results. Consider for example if just a few extra patients in the ivermectin group were in severe condition based on baseline SpO₂. The lower mean SpO₂ in the ivermectin group, and the shorter time to ventilation, are consistent with this being the case. Additionally, there are 14% more male patients in the ivermectin group.

An extremely large percentage of patients (55%) were excluded based on ivermectin use in the last 7 days. However, ivermectin may retain efficacy much longer (for example antiparasitic activity may persist for months Canga). A significant number of patients may also misrepresent their prior and future usage — the population is clearly aware of ivermectin, and patients with progressing disease may be motivated to take it, knowing that they may be in the control group. Another report states that 12,000 patients were excluded for recent use of ivermectin scidev.net).

RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that believe they need treatment are more likely to decline participation and take the intervention Yeh, i.e., RCTs are more likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin was very widely known and used.

For other issues see trialsitenews.com.

There were no serious adverse events. NCT04529525 (history).

This is the 28th of 46 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000014. This is the 58th of 99 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 2 sextillion).

1. Canga et al., The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review, AAPS J., doi:10.1208/s12248-007-9000-9.nih.gov, doi.org.

2. IVERCOR PREP, Ivermectina en agentes de salud e IVERCOR COVID19, Preliminary Results, web.archive.org/web/20210226215453/https://twitter.com/Covid19Crusher/status/1365420061859717124.archive.org.

3. lanacion.com.ar, www.lanacion.com.ar/sociedad/coronavirus-argentina-advertencias-evidencias-consumo-ivermectina-covid-19-nid2528989/.www.lanacion.com.ar/sociedad/coronavirus-argentina-advertencias-evidencias-consumo-ivermectina-covid-19-nid2528989/.

4. scidev.net, www.scidev.net/america-latina/news/uso-excesivo-de-ivermectina-dificulta-saber-si-sirve-contra-covid-19/.www.scidev.net/america-latina/news/uso-excesivo-de-ivermectina-dificulta-saber-si-sirve-contra-covid-19/.

5. trialsitenews.com, trialsitenews.com/ivercovid19-study-in-argentina-disappoints-study-underdoses-ivermectin-comes-up-short/.trialsitenews.com/ivercovid19-study-in-argentina-disappoints-study-underdoses-ivermectin-comes-up-short/.

6. twitter.com, twitter.com/Covid19Crusher/status/1365420061859717124.twitter.com/Covid19Crusher/status/1365420061859717124.

7. Yeh et al., Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial, BMJ, doi:10.1136/bmj.k5094.bmj.com, doi.org.

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risk of death, 33.5% higher, RR 1.33, p = 0.70, treatment 4 of 250 (1.6%), control 3 of 251 (1.2%), odds ratio converted to relative risk.

risk of mechanical ventilation, 33.5% higher, RR 1.33, p = 0.70, treatment 4 of 250 (1.6%), control 3 of 251 (1.2%), odds ratio converted to relative risk.

risk of hospitalization, 33.0% lower, RR 0.67, p = 0.23, treatment 14 of 250 (5.6%), control 21 of 251 (8.4%), NNT 36, odds ratio converted to relative risk, primary outcome.

risk of no viral clearance, 5.0% higher, RR 1.05, p = 0.55, treatment 137 of 250 (54.8%), control 131 of 251 (52.2%), inverted to make RR<1 favor treatment, odds ratio converted to relative risk, day 3.

risk of no viral clearance, 26.8% higher, RR 1.27, p = 0.29, treatment 38 of 250 (15.2%), control 30 of 251 (12.0%), inverted to make RR<1 favor treatment, odds ratio converted to relative risk, day 12.

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Vallejos et al., 2 Jul 2021, Double Blind Randomized Controlled Trial, Argentina, peer-reviewed, 29 authors, study period 19 August, 2020 - 22 February, 2021, average treatment delay 4.0 days, dosage 12mg days 1-2, <80kg 12mg, 80-110kg 18mg, >110kg 24mg.

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Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial

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

BMC Infectious Diseases, doi:10.1186/s12879-021-06348-5

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 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 nonhospitalized 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.

Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s12879-021-06348-5. Additional file 1. Authors' contributions Declarations Ethics approval and consent to participate study authorized by Health Sciences Research Bioethics Committee (HSRBC) of the National University of the Northeast (UNNE) Faculty of Medicine, Argentina (Resolution 21/20 on August 17th, 2020). The consent to participate in the trial was approved by HSRBC of the UNNE. The study was performance in accordance with the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all participants prior to the study. The study has been supervised by a Steering Committee and Safety Committee. Consent for publication Not Applicable. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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