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

doi:10.3389/fmed.2022.919708

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

Front Med (Lausanne). 2022 Jun 16:9:919708. doi: 10.3389/fmed.2022.919708. eCollection 2022.

Authors

Mohammad Sadegh Rezai¹, Fatemeh Ahangarkani², Andrew Hill³, Leah Ellis⁴, Manya Mirchandani⁴, Alireza Davoudi², Gohar Eslami⁵, Fatemeh Roozbeh⁶, Farhang Babamahmoodi², Nima Rouhani², Ahmad Alikhani², Narges Najafi², Roya Ghasemian², Hossein Mehravaran⁷, Azin Hajialibeig¹, Mohammad Reza Navaeifar¹, Leila Shahbaznejad¹, Golnar Rahimzadeh¹, Majid Saeedi⁸, Reza Alizadeh-Navai⁶, Mahmood Moosazadeh⁶, Shahab Saeedi¹, Seyedeh-Kiana Razavi-Amoli⁹, Shaghayegh Rezai¹⁰, Fereshteh Rostami-Maskopaee¹, Fatemeh Hosseinzadeh¹, Faezeh Sadat Movahedi⁹, John S Markowitz¹¹, Reza Valadan¹²

Affiliations

¹ Pediatric Infectious Diseases Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.
² Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.
³ Department of Pharmacology and Therapeutics, Liverpool University, Liverpool, United Kingdom.
⁴ Faculty of Medicine, School of Public Health, Imperial College London, London, United Kingdom.
⁵ Department of Clinical Pharmacy, Faculty of Pharmacy, Cardiovascular Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
⁶ Gastrointestinal Cancer Research Center, Non-communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.
⁷ Department of Internal Medicine, Pulmonary and Critical Care Division, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
⁸ Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
⁹ Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran.
¹⁰ Department of Microbiology and Virology, Mashhad University of Medical Sciences, Mashhad, Iran.
¹¹ Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL, United States.
¹² Department of Immunology and Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Abstract

Background: Ivermectin which was widely considered as a potential treatment for COVID-19, showed uncertain clinical benefit in many clinical trials. Performing large-scale 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, placebo-controlled 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 mean duration of fever was significantly shorter (2.02 ± 0.11 days) in the ivermectin group versus (2.41 ± 0.13 days) placebo group with p value = 0.020. On the day seventh of treatment, fever (p-value = 0.040), cough (p-value = 0.019), and weakness (p-value = 0.002) were significantly higher in the placebo group compared to the ivermectin group. Among all outpatients, 7% in ivermectin group and 5% in placebo group needed to be hospitalized (RR, 1.36 [95% CI, 0.65-2.84]; p-value = 0.41). Also, the result of RT-PCR on day five after treatment was negative for 26% of patients in the ivermectin group versus 32% in the placebo group (RR, 0.81 [95% CI, 0.60-1.09]; p-value = 0.16).

Conclusion: Our data showed, ivermectin, compared with placebo, did not have a significant potential effect on clinical improvement, reduced admission in ICU, need for invasive ventilation, and death in hospitalized patients; likewise, no evidence was found to support the prescription of ivermectin on recovery, reduced hospitalization and increased negative RT-PCR assay for SARS-CoV-2 5 days after treatment in outpatients. Our findings do not support the use of ivermectin to treat mild to severe forms of COVID-19.

Clinical trial registration: www.irct.ir IRCT20111224008507N5 and IRCT20111224008507N4.

Keywords: COVID-19; effectiveness; inpatients; ivermectin; outpatients.

Copyright © 2022 Rezai, Ahangarkani, Hill, Ellis, Mirchandani, Davoudi, Eslami, Roozbeh, Babamahmoodi, Rouhani, Alikhani, Najafi, Ghasemian, Mehravaran, Hajialibeig, Navaeifar, Shahbaznejad, Rahimzadeh, Saeedi, Alizadeh-Navai, Moosazadeh, Saeedi, Razavi-Amoli, Rezai, Rostami-Maskopaee, Hosseinzadeh, Movahedi, Markowitz and Valadan.