ACTG A5418: A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of Tecovirimat for the Treatment of Human Monkeypox Virus Disease, Study of Tecovirimat for Human Monkeypox Virus (STOMP) CLINICAL COORDINATION, MONITORING AND EVALUATION OF THE AIDS CLINICAL TRIALS GROUP PROTOCOL A5418 STUDY OF TECOVIRIMAT FOR HUMAN MONKEYPOX VIRUS (STOMP). A5418 (STOMP) is a study of tecovirimat (also known as TPOCC) for the treatment of human monkeypox virus (HMPXV) disease. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is sponsoring a Phase 3 clinical trial evaluating the antiviral tecovirimat, also known as TPOXX, for the treatment of human monkeypox infection. The NIAID-funded AIDS Clinical Trials Group (ACTG) is leading the study, which is now enrolling adults and children with monkeypox infection in the United States. Study investigators aim to enroll more than 500 people from up to 80 clinical research sites nationwide. Adults with severe monkeypox, severe immunodeficiency, or severe inflammatory skin conditions; individuals taking certain medications that could affect tecovirimat levels; and pregnant people, people who are breastfeeding and children all will be enrolled in an open-label arm in which all participants receive tecovirimat. Other adult participants—530 total—will be randomly assigned in a 2:1 ratio to receive tecovirimat or placebo pills, which participants will take for 14 days. This part of the trial is double-blind, meaning neither participants nor investigators will know who is receiving placebo or tecovirimat. Investigators will gather data to determine if participants receiving tecovirimat heal more quickly and have less pain compared with those taking placebo. Participants will be followed for at least 57 days and will be asked to fill out a symptom diary, do daily skin checks at home and attend virtual and in-person clinic appointments. They also will undergo physical exams and will be asked to provide blood and other bodily fluid samples, including swabbing fluid from their lesions. Data on the safety and efficacy of tecovirimat will be submitted to the FDA. An independent Data and Safety Monitoring Board (DSMB) will monitor participant safety throughout the duration of the study. In addition, any participant in the randomized cohort who progresses to severe disease will be unblinded and given tecovirimat if they were randomized to placebo.