Non-effectiveness of Ivermectin on Inpatients and Outpatients With COVID-19; Results of Two Randomized, Double-Blinded, Placebo-Controlled Clinical Trials

Rezai et al., Frontiers in Medicine, doi:10.3389/fmed.2022.919708, IRCT20111224008507N5

Jun 2022

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RCT 609 inpatients in Iran. Reported outcomes are very different from the pre-specified outcomes irct.ir. The outpatient trial is listed separately.

From the pre-specified outcomes, all are either positive or not reported. Pre-specified outcomes:

- Reduction in persistent cough - RR 0.36 p = 0.06
- Negative RT-PCR - not reported
- Main complaints recovery time - not reported
- Mortality - RR 0.69 p = 0.36
- Side effects - reported as none (anomalous)
- Reduction in tachypnea - RR 0.24 p = 0.38
- Oxygen saturation >94% - not reported

All negative outcomes are protocol violations and are not listed in the protocol, including the novel "relative recovery" outcome.

Authors include a researcher caught on video admitting that conclusions on ivermectin research were influenced by a funder c19ivm.org.

Severe cases were more frequent in the ivermectin group, 49% vs. 43%.

Dose was limited at a maximum of 30mg for 75+kg, resulting in underdosing for patients at higher risk.

Almost all patients received remdesivir, most patients received famotidine and vitamin C, and many patients received vitamin D, metformin, and zinc, limiting room for improvement.

32% of patients were lost to followup. Authors indicate bottles were identical, but tablets were only similar. Ivermectin was obtained from Alborz Daru Co.

This is the 37th of 46 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000014.

This is the 86th 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: multiple critical issues, see study page.

1. c19ivm.org, c19ivm.org/lawrieletter.html.c19ivm.org/lawrieletter.html.

2. irct.ir, www.irct.ir/trial/54402.www.irct.ir/trial/54402.

Important missing comments or errors? Let us know.

risk of death, 30.8% lower, RR 0.69, p = 0.36, treatment 13 of 311 (4.2%), control 18 of 298 (6.0%), NNT 54.

risk of mechanical ventilation, 50.0% lower, RR 0.50, p = 0.07, treatment 311, control 298.

risk of ICU admission, 16.0% lower, RR 0.84, p = 0.47, treatment 311, control 298.

hospitalization time, 11.5% higher, relative time 1.11, p = 0.009, treatment mean 7.98 (±4.4) n=311, control mean 7.16 (±3.2) n=298.

deterioration, 12.7% higher, RR 1.13, p = 0.74, treatment 20 of 311 (6.4%), control 17 of 298 (5.7%).

risk of no recovery, 24.2% lower, RR 0.76, p = 0.02, treatment 311, control 298, inverted to make RR<1 favor treatment, post-hoc primary outcome.

risk of no recovery, 64.0% lower, RR 0.36, p = 0.06, treatment 5 of 145 (3.4%), control 10 of 105 (9.5%), NNT 16, day 7, cough.

risk of no recovery, 76.0% lower, RR 0.24, p = 0.38, day 7, tachypnea.

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

Rezai et al., 16 Jun 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Iran, peer-reviewed, mean age 53.8, 29 authors, study period 19 February, 2021 - 14 August, 2021, average treatment delay 7.18 days, dosage 400μg/kg days 1-3, trial IRCT20111224008507N5.

Contact: drmsrezaii@yahoo.com.

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This Paper Ivermectin All

Non-effectiveness of Ivermectin on Inpatients and Outpatients With COVID-19; Results of Two Randomized, Double-Blinded, Placebo-Controlled Clinical Trials

Mohammad Sadegh Rezai, Fatemeh Ahangarkani, Andrew Hill, Leah Ellis, Manya Mirchandani, Alireza Davoudi, Gohar Eslami, Fatemeh Roozbeh, Farhang Babamahmoodi, Nima Rouhani, Ahmad Alikhani, Narges Najafi, Roya Ghasemian, Hossein Mehravaran, Azin Hajialibeig, Mohammad Reza Navaeifar, Leila Shahbaznejad, Golnar Rahimzadeh, Majid Saeedi, Reza Alizadeh-Navai, Mahmood Moosazadeh, Shahab Saeedi, Seyedeh-Kiana Razavi-Amoli, Shaghayegh Rezai, Fereshteh Rostami-Maskopaee, Fatemeh Hosseinzadeh, Faezeh Sadat Movahedi, John S Markowitz, Reza Valadan

Frontiers in Medicine, doi:10.3389/fmed.2022.919708

Background: Ivermectin which was widely considered as a potential treatment for COVID-19, showed uncertain clinical benefit in many clinical trials. Performing largescale clinical trials to evaluate the effectiveness of this drug in the midst of the pandemic, while difficult, has been urgently needed. Methods: We performed two large multicenter randomized, double-blind, placebocontrolled clinical trials evaluating the effectiveness of ivermectin in treating inpatients and outpatients with COVID-19 infection. The intervention group received ivermectin, 0.4mg/kg of body weight per day for 3 days. In the control group, placebo tablets were used for 3 days. Results: Data for 609 inpatients and 549 outpatients were analyzed. In hospitalized patients, complete recovery was significantly higher in the ivermectin group (37%) compared to placebo group (28%; RR, 1.32 [95% CI, 1.04-1.66]; p-value = 0.02). On the other hand, the length of hospital stay was significantly longer in the ivermectin group with a mean of 7.98 ± 4.4 days compared to the placebo receiving group with a mean of 7.16 ± 3.2 days (RR, 0.80 [95% CI, 0.15-1.45]; p-value = 0.02). In outpatients, the

ETHICS STATEMENT The studies involving human participants were reviewed and approved by the Ethics Committee of Mazandaran University of Medical Sciences (IR.MAZUMS.REC.1399.915 and IR.MAZUMS.REC.1399.869) and by the Iranian Registry of Clinical Trials identifier (IRCT20111224008507N5 and IRCT20111224008507N4). Written informed consent to participate in this study was provided by the participants or their legal guardian/next of kin. AUTHOR CONTRIBUTIONS MR contributed to the conception or design of the work. MR, FA, AHi, LE, and MMi contributed to the drafting and statistical analysis of the manuscript. All authors contributed toward the acquisition, analysis, or interpretation of data, critical revision of the manuscript, review and approval of the final version of the manuscript. SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed. 2022.919708/full#supplementary-material Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not..

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Late treatment
is less effective

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