Yupin Suputtamongkol1, Panisadee Avirutnan2,3,4, Dumrong Mairiang2,3,4, Nasikarn Angkasekwinai1, Kannika Niwattayakul5, Eakkawit Yamasmith1, Fadhil A-Hamad Saleh-Arong1, Adisak Songjaeng2,3, Tanapan Prommool4, Nattaya Tangthawornchaikul4, Chunya Puttikhunt2,3,4, Saowalak Hunnangkul6, Chulaluk Komoltri6, Suwich Thammapalo7, Prida Malasit2,3,4. 1. Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 2. Division of Dengue Hemorrhagic Fever Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 3. Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 4. Molecular Biology of Dengue and Flaviviruses Research Team, Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand. 5. Medical Department, Loei Hospital, Ministry of Public Health, Loei, Thailand. 6. Research Group and Research Network Division, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 7. Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
Abstract
BACKGROUND: Dengue is the most significant mosquito-borne viral disease; there are no specific therapeutics. The antiparasitic drug ivermectin efficiently inhibits the replication of all 4 dengue virus serotypes in vitro. METHODS: We conducted 2 consecutive randomized, double-blind, placebo-controlled trials in adult dengue patients to evaluate safety and virological and clinical efficacies of ivermectin. After a phase 2 trial with 2 or 3 days of 1 daily dose of 400 µg/kg ivermectin, we continued with a phase 3, placebo-controlled trial with 3 days of 400 µg/kg ivermectin. RESULTS: The phase 2 trial showed a trend in reduction of plasma nonstructural protein 1 (NS1) clearance time in the 3-day ivermectin group compared with placebo. Combining phase 2 and 3 trials, 203 patients were included in the intention to treat analysis (100 and 103 patients receivingivermectin and placebo, respectively). Dengue hemorrhagic fever occurred in 24 (24.0%) of ivermectin-treated patients and 32 (31.1%) patients receiving placebo (P = .260). The median (95% confidence interval [CI]) clearancetime of NS1 antigenemia was shorter in the ivermectin group (71.5 [95% CI 59.9-84.0] hours vs 95.8 [95% CI 83.9-120.0] hours, P = .014). At discharge, 72.0% and 47.6% of patients in the ivermectin and placebo groups, respectively had undetectable plasma NS1 (P = .001). There were no differences in the viremia clearance time and incidence of adverse events between the 2 groups. CONCLUSIONS: A 3-day 1 daily dose of 400 µg/kg oral ivermectin was safe and accelerated NS1 antigenemia clearance in dengue patients. However, clinical efficacy of ivermectin was not observed at this dosage regimen.
RCT Entities:
BACKGROUND: Dengue is the most significant mosquito-borne viral disease; there are no specific therapeutics. The antiparasitic drug ivermectin efficiently inhibits the replication of all 4 dengue virus serotypes in vitro. METHODS: We conducted 2 consecutive randomized, double-blind, placebo-controlled trials in adult dengue patients to evaluate safety and virological and clinical efficacies of ivermectin. After a phase 2 trial with 2 or 3 days of 1 daily dose of 400 µg/kg ivermectin, we continued with a phase 3, placebo-controlled trial with 3 days of 400 µg/kg ivermectin. RESULTS: The phase 2 trial showed a trend in reduction of plasma nonstructural protein 1 (NS1) clearance time in the 3-day ivermectin group compared with placebo. Combining phase 2 and 3 trials, 203 patients were included in the intention to treat analysis (100 and 103 patients receiving ivermectin and placebo, respectively). Dengue hemorrhagic fever occurred in 24 (24.0%) of ivermectin-treated patients and 32 (31.1%) patients receiving placebo (P = .260). The median (95% confidence interval [CI]) clearance time of NS1 antigenemia was shorter in the ivermectin group (71.5 [95% CI 59.9-84.0] hours vs 95.8 [95% CI 83.9-120.0] hours, P = .014). At discharge, 72.0% and 47.6% of patients in the ivermectin and placebo groups, respectively had undetectable plasma NS1 (P = .001). There were no differences in the viremia clearance time and incidence of adverse events between the 2 groups. CONCLUSIONS: A 3-day 1 daily dose of 400 µg/kg oral ivermectin was safe and accelerated NS1 antigenemia clearance in dengue patients. However, clinical efficacy of ivermectin was not observed at this dosage regimen.
Authors: Marcos Alejandro Mayer; Alejandro Krolewiecki; Alejandro Ferrero; Marcelo Bocchio; Juan Barbero; Marcos Miguel; Ariel Paladini; Carlos Delgado; Juan Ramón Ojeda; Claudia Elorza; Ana Bertone; Pedro Emanuel Fleitas; Gustavo Vera; Mario Rubén Kohan Journal: Front Public Health Date: 2022-02-22