BACKGROUND: Tecovirimat is approved for smallpox treatment under the Food and Drug Administration Animal Rule on the basis of efficacy in nonhuman primate models of mpox (previously known as monkeypox). However, the clinical efficacy of tecovirimat against human clade II mpox is unclear.

METHODS: In a phase 3, international, double-blind, randomized, placebo-controlled trial, we evaluated the efficacy of oral tecovirimat in adults with laboratory-confirmed clade II mpox. Participants were randomly assigned in a 2:1 ratio to receive tecovirimat or placebo for 14 days. The primary outcome was clinical resolution, assessed in a time-to-event analysis in participants with active skin or mucosal lesions. Secondary outcomes included reduction in pain, assessed in all participants with laboratory-confirmed mpox and in those with severe pain at baseline (pain score, 7 to 10; scale, 0 [no pain] to 10 [worst pain imaginable]); complete lesion healing (assessed in a time-to-event analysis); viral DNA clearance; and safety.

RESULTS: Of 412 participants who underwent randomization (275 to tecovirimat and 137 to placebo), 344 had laboratory-confirmed mpox, and 336 had active skin or mucosal lesions and were included in the primary analysis. By day 29, the estimated cumulative incidence of clinical resolution was 83% with tecovirimat and 84% with placebo; the competing-risks hazard ratio for clinical resolution was 0.98 (95% confidence interval [CI], 0.74 to 1.31; P = 0.89). No substantial between-group differences were seen in pain reduction among participants with severe pain (difference, 0.1 point; 95% CI, -0.8 to 1.0), in complete lesion healing (competing-risks hazard ratio, 0.97; 95% CI, 0.75 to 1.26), or in viral DNA clearance. The incidence of adverse events of grade 3 or higher was similar in the two groups (4% with tecovirimat and 3% with placebo).

CONCLUSIONS: This trial showed no evidence that tecovirimat therapy shortened the time to clinical resolution, reduced pain, or increased viral clearance among adults with clade II mpox. (Funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; STOMP/A5418 ClinicalTrials.gov number, NCT05534984.).