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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'abstract': '<jats:sec><jats:title>Background</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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]; <jats:italic>p</jats:italic>-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]; <jats:italic>p</jats:italic>-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 <jats:italic>p</jats:italic> value = 0.020. On the day '
'seventh of treatment, fever (<jats:italic>p</jats:italic>-value = 0.040), cough '
'(<jats:italic>p</jats:italic>-value = 0.019), and weakness '
'(<jats:italic>p</jats:italic>-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]; '
'<jats:italic>p</jats:italic>-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]; <jats:italic>p</jats:italic>-value = '
'0.16).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Clinical Trial '
'Registration</jats:title><jats:p><jats:ext-link>www.irct.ir</jats:ext-link> '
'IRCT20111224008507N5 and IRCT20111224008507N4.</jats:p></jats:sec>',
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