Safety and Preliminary Efficacy of Dengue Monoclonal Antibody in Adult Patients: A Randomized Clinical Trial.

Abstract

Dengue outbreaks are increasing in frequency and intensity. In the absence of any specific treatment, a pan-serotype recombinant monoclonal antibody (Dengue-mAb) was tested in adult patients with dengue as a therapeutic option. To assess the safety and effect of a single dose of Dengue-mAb on dengue viremia at different dose levels among patients with dengue. A phase 2, single-blind, randomized, placebo-controlled clinical trial was conducted from September 19, 2021, to May 13, 2023, at 12 hospitals in India. Study participants were aged 18 to 60 years with dengue and a history of fever onset within 48 hours. Key exclusion criteria were severe dengue, hemoglobin less than 10 g/dL, absolute neutrophil count less than 500/mm3, total leukocyte count less than 1500/mm3, platelet count less than 50 000/mm3, and any other clinically significant disorders. Data were analyzed from January 11, 2024, to March 26, 2024. Participants were randomly allocated 1:1:1:1:1 using an interactive web response system to receive 1 of 4 dose levels of Dengue-mAb (3, 5, 7, or 9 mg/kg) or placebo by slow intravenous infusion. Primary outcomes were reduction in viremia at 24 hours and causally related serious adverse events (SAEs). Secondary outcomes were RNAemia, fever, and hematologic and pharmacokinetic parameters. A total of 250 participants were randomized, with 50 participants in each group. The overall median age was 30 years (IQR, 24-37 years), and 180 participants (72.3%) were male. There were no causally related SAEs. The adjusted mean (SE) viral log reduction at 24 hours was significantly higher with Dengue-mAb-from 1.93 (0.23) with 3 mg/kg (P = .04) to 2.35 (0.27) with 9 mg/kg (P = .003)-compared with placebo (1.29 [0.22]), using a mixed model for repeated measures. Participants with detectable viremia (n = 32) at baseline were negative for dengue virus by 8 hours when treated with a 5- to 9-mg/kg dose of Dengue-mAb compared with 72 hours with placebo. Median time to fever clearance was 3.5 (95% CI, 1.0-24.0) hours (hazard ratio [HR], 2.6 [95% CI, 1.0-6.4]) with Dengue-mAb 5 mg/kg (n = 14) and 2.0 (95% CI, 0.5-6.0) hours (HR, 2.8 [95% CI, 1.2-6.8]) with Dengue-mAb 7 mg/kg (n = 14), compared with 26.8 (95% CI, 1.0-50.5) hours with placebo (n = 12). At 24 hours, between 13 of 14 participants (92.9%; 95% CI, 66.1%-99.8%) with Dengue-mAb (3 mg/kg), 14 of 14 participants (100.0%; 95% CI, 76.8%-100.0%) with Dengue-mAb (5 mg/kg and 7 mg/kg), and 16 of 17 participants (94.1%; 95% CI 71.3%-99.9%) with Dengue-mAb (9 mg/kg); and 7 of 12 participants (58.3%; 95% CI, 27.7%-84.8%) with placebo had fever clearance. In this randomized clinical trial, Dengue-mAb was safe and well tolerated. Dengue-mAb rapidly reduced dengue viremia and fever at doses of 5 mg/kg and 7 mg/kg, making this the first therapeutic against wild-type dengue virus to show preliminary efficacy in humans. Clinical Trial Registry-India Identifier: CTRI/2021/07/035290.