Ivermectin compared with placebo in the clinical course in Mexican patients with asymptomatic and mild COVID-19: a randomized clinical trial

de la Rocha et al., BMC Infectious Diseases, doi:10.1186/s12879-022-07890-6 (date from preprint), NCT04407507

May 2022

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Small low-risk patient RCT with 30 low-dose ivermectin and 26 control patients, with no primary outcome events in either arm. Viral load was significantly better with ivermectin on day 5, while there was no significant difference on day 1 or day 14. There was no significant difference in combined symptoms, however authors include cough which was the most frequent symptom and may persist long after infection has been cleared. Ivermectin patients were 4 years older with a higher standard deviation, had higher prevalence of obesity, diabetes, hypertension, and cardiovascular disease, and lower prevalence of hepatic and kidney disease.

SOC included acetaminophen, which has 26 studies showing 29% [17‑42%] higher risk. The slow viral clearance seen may be in part due to acetaminophen use.

Authors conclude that "ivermectin is not effective to prevent progression to a severe state", however there was no progression to severe in either group.

Authors report 92.9% of ivermectin patients compliant with the symptom diary, however there is no number of 30 patients that is 92.9%.

Authors report 45.8% asymptomatic placebo patients on day 14, howevere there is no number of 25 (exc. diary non-compliance) or 26 patients that is 45.8%.

Authors report 37% asymptomatic ivermectin patients on day 14, howevere there is no number of 28 (exc. diary non-compliance) patients that is 37%.

Authors report 28% viral- for ivermectin on day 14, however there is no number of 30 patients that is 28%.

Authors have not yet responded to a data query.

The pre-registered outcome had no events. All other outcomes reported are post-hoc, added after completion of the study: clinicaltrials.gov

External influences may have altered the paper. For example, in the preprint authors state: "Taken together, these data do not show that ivermectin is effective in the treatment of COVID-19 by "accelerating" viral clearance in the first week, which may translate into a lower rate of complications." Elsewhere, authors note faster viral clearance at day 5, which is a positive result. This sentence may have been modified to be negative, while not fully updating the new sentence to be logical.

This is the 34th of 46 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000014.

This is the 83rd of 99 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 2 sextillion).

This study is excluded in the after exclusion results of meta analysis: data mismatch, no response from authors.

1. clinicaltrials.gov, clinicaltrials.gov/ct2/history/NCT04407507?A=1&B=2&C=merged#StudyPageTop.clinicaltrials.gov/ct2/history/NCT04407507?A=1&B=2&C=merged#StudyPageTop.

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risk of progression to serious adverse events, 186.7% higher, RR 2.87, p = 1.00, treatment 1 of 30 (3.3%), control 0 of 26 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).

risk of no recovery, 14.8% higher, RR 1.15, p = 0.58, treatment 18 of 28 (64.3%), control 14 of 25 (56.0%), day 14.

risk of no recovery, 6.7% lower, RR 0.93, p = 0.71, treatment 23 of 28 (82.1%), control 22 of 25 (88.0%), NNT 17, day 5.

viral load, 2.4% lower, relative load 0.98, p = 0.64, treatment mean 33.74 (±4.77) n=30, control mean 32.94 (±7.74) n=26, day 14.

viral load, 7.8% lower, relative load 0.92, p = 0.04, treatment mean 30.64 (±3.74) n=30, control mean 28.25 (±4.21) n=26, mid-recovery, day 5.

risk of no viral clearance, 4.7% lower, RR 0.95, p = 1.00, treatment 22 of 30 (73.3%), control 20 of 26 (76.9%), NNT 28, day 14.

risk of no viral clearance, 6.1% lower, RR 0.94, p = 0.67, treatment 26 of 30 (86.7%), control 24 of 26 (92.3%), NNT 18, mid-recovery, day 5.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

de la Rocha et al., 23 May 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Mexico, peer-reviewed, 21 authors, study period 1 July, 2020 - 29 January, 2021, dosage 12mg days 1-3, trial NCT04407507 (history).

Contact: arieh.mercado@academicos.udg.mx (corresponding author).

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Ivermectin compared with placebo in the clinical course in Mexican patients with asymptomatic and mild COVID-19: a randomized clinical trial

Carmen De La Rocha, Marco A Cid-López, Blanca I Venegas-López, Sandra C Gómez-Méndez, Adriana Sánchez-Ortiz, Alma M Pérez-Ríos, Ricardo A Llamas-Velázquez, Aidé I Meza-Acuña, Bárbara Vargas-Íñiguez, Daniela Rosales-Galván, Alejandra Tavares-Váldez, Nizdali Luna-Gudiño, Cinthia V Hernández-Puente, Jovana Milenkovic, Cecilia Iglesias-Palomares, Miriam Méndez-Del Villar, Gerardo A Gutiérrez-Dieck, Carlos G Valderrábano-Roldán, Jennefer Mercado-Cerda, Jocelyn G Robles-Bojórquez, Arieh R Mercado-Sesma

BMC Infectious Diseases, doi:10.1186/s12879-022-07890-6

Background: Despite the development and application of vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) around the world, the scientific community is still trying to find some therapies to avoid or ameliorate the fatal evolution of the Coronavirus disease 2019 . Since the publication of the potential use of ivermectin as a treatment against the disease, a pleiad of information about it has been published. However, the evidence is not strong or weak enough to conclude its usefulness in the clinical evolution of patients infected with SARS-CoV-2. We evaluate the efficacy and safety of ivermectin in the treatment of Mexican patients with asymptomatic and mild COVID-19 in a three-day administration in comparison to placebo. Methods: A randomized, double-blind, placebo-controlled trial was carried out in 66 adults with asymptomatic and mild COVID-19. Patients were randomly assigned 1:1 ratio to ivermectin plus acetaminophen or placebo plus acetaminophen. The primary endpoint was the proportion of subjects without a disease progression to severity according to COVID-19 guidelines by the National Institutes of Health (NIH) since randomization to 14 days. Results: None of the participants presented progression to a severe state in either group. Viral load was measured on Days 1, 5, and 14. No significant differences were observed in baseline or 14-day between groups (p = 0.720 and 0.362, respectively). However, on Day 5, a significant difference in viral load was observed between groups (p = 0.039). The frequency of symptoms was similar between groups, and no significant differences were observed. The most frequent symptom was cough. One severe adverse event associated with SARS-CoV-2 infection was observed in the ivermectin group.

Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12879-022-07890-6. Additional file 1. CONSORT checklist. Additional file 2. Supplementary tables. Author contributions dlRC, MSAR and CLM: Conceptualization, methodology, formal analysis, investigation, writing original draft visualization, and validation. VLB and GMSC: writing review and editing. HPCV, MJ, SOA, PRAM, LVRA, MAAI, VIB, IPC, and RGD: resources, formal analysis, software and methodology. TVA, LGN, MVM GDGA, VRCG, MCJ and RBJG: writing review, conceptualization, funding acquisition and supervision. All authors contributed to the interpretation of the results, provided critical revisions. All authors read and approved the final manuscript. Funding Investigación Biomédica para el Desarrollo de Fármacos S.A. de C.V. covered all the expenses generated during the study. This trial was supported Investigación Biomédica para el Desarrollo de Fármacos S.A. de C.V. The funding source participated in study design, data collection, data analysis, data interpretation, or writing of the report, since most of the team are affiliated, but no commercial purposes are intended with this trial results. Declarations Ethics approval and consent to participate The protocol was approved by the local ethics, biosafety and investigation committees and the Mexican health ministry COFEPRIS: 203301410A0055. The study is registered on ClinicalTrials.gov: NCT04407507...

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