Efficacy of single‐dose and double‐dose ivermectin early treatment in preventing progression to hospitalization in mild COVID‐19: A multi‐arm, parallel‐group randomized, double‐blind, placebo‐controlled trial

Abstract

Background and objective Ivermectin is a known anti‐parasitic agent that has been investigated as an antiviral agent against coronavirus disease 2019 (COVID‐19). This study aimed to evaluate the efficacy of ivermectin in mild COVID‐19 patients. Methods In this multi‐arm randomized clinical trial conducted between 9 April 2021 and 20 May 2021, a total of 393 patients with reverse transcription‐PCR‐confirmed COVID‐19 infection and mild symptoms were enrolled. Subjects were randomized in a 1:1:1 ratio to receive single‐dose ivermectin (12 mg), double‐dose ivermectin (24 mg) or placebo. The primary outcome was need for hospitalization. Results There was no significant difference in the proportion of subjects who required hospitalization between the placebo and single‐dose ivermectin groups (absolute difference in the proportions: −2.3 [95% CI = −8.5, 4.1]) and between the placebo and double‐dose ivermectin groups (absolute difference in the proportions: −3.9 [95% CI = −9.8, 2.2]). The odds of differences in mean change in severity score between single‐dose ivermectin and placebo groups (ORdifference = 1.005 [95% CI: 0.972, 1.040]; p = 0.762) and double‐dose ivermectin and placebo groups (ORdifference = 1.010 [95% CI: 0.974, 1.046]; p = 0.598) were not statistically significant. None of the six adverse events (including mild dermatitis, tachycardia and hypertension) were serious and required extra action. Conclusion Single‐dose and double‐dose ivermectin early treatment were not superior to the placebo in preventing progression to hospitalization and improving clinical course in mild COVID‐19.

Ivermectin for treatment of COVID-19: A systematic review and meta-analysis

“…COVID-19 disease severity was asymptomatic/mild in 12 randomized controlled trials, moderate in 1, mild and moderate in 17, severe in 2, and moderate and severe in 1. Studies were done in 19 countries: Argentina (n = 3 studies) [ [58] , [59] , [60] ], Bangladesh (n = 2) [ 61 , 62 ], Brazil (n = 1) [ 10 ], China (n = 1) [ 63 ], Colombia (n = 1) [ 64 ], Egypt (n = 3) [ 23 , 65 , 66 ], India (n = 3) [ [67] , [68] , [69] ], Iran (n = 3) [ 26 , 70 , 71 ], Israel (n = 1) [ 72 ], Italy (n = 1) [ 22 ], Japan, (n = 1) [ 73 ], Malaysia (n = 1) [ 24 ], Mexico (n = 2) [ 74 , 75 ], Nigeria (n = 1) [ 76 ], Pakistan (n = 2) [ 77 , 78 ], Spain (n = 1) [ 79 ], Thailand (n = 2) [ 25 , 80 ], Turkey (n = 1) [ 81 ], and USA (n = 3) [ 21 , 82 , 83 ]. Of all 33 studies, 7 had an overall high risk of bias, 13 had some concerns of bias, and 13 had a low risk ( Supplementary Fig.…”

“…Med. Malaysia (n = 490) 0.4 mg/kg body weight daily for 5 days + SOC SOC Mild in 34.1%, moderate in 65.9% 62.5 (8.7) 100 0 54.5 11.6 53.5 75.3 All-cause mortality rate, LOS, Symptoms resolved, Admission to ICU, MV requirement, Progress to more severe disease 28 ND López-Medina et al (2021) [ 64 ] JAMA Colombia (n = 398) 300 μg/kg once daily for 5 d Placebo Mild in 100% 37 (29–48) 100 1 78 1.7 6 13 All-cause mortality rate, Time to complete resolution, AEs, SAEs, Escalation of care 21 Government Manomaipiboon et al (2022) [ 25 ] Trials Thailand (n = 72) 12 mg per day, for 5 days SOC Mild to moderate 48.57 (14.8) 100 100 62.5 2.8 23.6 40.3 PCR negative conversion, Symptoms resolved, Mean durations of symptoms 28 Government Mirahmadizadeh et al (2022) [ 26 ] Respirology Iran (n = 391) 3 mg for 2 days, cumulative dose of 24 mg Placebo Mild in 100% 39 (17) 100 0 …”

“…Twenty-nine of the thirty-three studies reported on all-cause mortality rate (n = 8738 participants) [ 10 , [21] , [22] , [23] , [24] , [25] , [26] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [79] , [80] , [81] , [82] , [83] ]. There was no significant difference in all-cause mortality rate between IVM and controls (RR 0.95, 95% CI 0.75–1.21, I 2 = 0%; Fig.…”

“…Multiple clinical trials have been conducted to evaluate clinical outcomes [ [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] ], with contradictory outcomes, and some of these studies have been withdrawn or retracted for fear of serious data inconsistencies or research fraud [ [27] , [28] , [29] ]. It is imperative to synthesize evidence for clinicians and communities.…”

Perspective: repurposed Drugs for COVID-19

“…This ivermectin should not be used for either prevention or treatment of COVID-19 in populations with a high rate of COVID-19 vaccination. In a multi-arm randomized clinical trial conducted in 393 patients with PCR-confirmed COVID-19 infection and mild symptoms, single-dose (12 mg) and double-dose (24 mg) ivermectin early treatment was not superior to the placebo in preventing progression to hospitalization and improving the clinical course in mild COVID-19 [ 29 ]. A phase II randomized trial was conducted in 112 patients with asymptomatic, mild, or moderate COVID-19 with predominantly hematological illnesses [ 30 ].…”