Phase 3, randomized, placebo-controlled, double-blind trial of tecovirimat for the treatment of human monkeypox virus (HMPXV) disease (Arm A and B). The study will also include a cohort of people (Arm C) who will receive open-label tecovirimat. Duration is 57 days, sample size 530 Arms A+B ; Arm C sample size not specified.

Laboratory-confirmed or presumptive HMPXV infection:
Laboratory-confirmed HMPXV infection is defined as determined by PCR, culture, or antigen test obtained from a sample collected from a skin lesion, oropharynx, or rectal swab obtained within 7 days prior to study entry
OR
Presumptive diagnosis:
• Skin lesion(s), mucosal lesion(s) or proctitis consistent with a high probability of HMPXV in the opinion of the site investigator
AND
• Sexual contact with 1 or more persons in the 21 days prior to symptom onset or close exposure to another person known to be infected with HMPXV.
OR
• Neonates (<4 weeks of age) born to mothers with monkeypox infection. These neonates are assumed to have monkeypox and no confirmatory testing is required.
4.1.2 HMPXV illness of <14 days duration immediately prior to study entry.
4.1.3 At least one active (not yet scabbed) skin lesion, mouth lesion, or proctitis with or without visible ulcers.
4.1.4 Non-pregnant people of reproductive potential must agree to use at least one effective means of contraception when engaging in sexual activities that can result in pregnancy, from the time of enrollment through the end of study participation. Acceptable methods of contraception include the following:
• Abstinence
• Hormonal contraception
• Male or female condom
• Diaphragm or cervical cap with a spermicide
• Intrauterine device

Reproductive potential is defined as:
• Participants who have reached menarche
• Participants who have not been post-menopausal for at least 12 consecutive months with follicle-stimulating hormone (FSH) ≥40 IU/mL or 24 consecutive months if an FSH is not available
• Participants who have not undergone surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or bilateral salpingectomy)
• For individuals with permanent infertility due to an alternate medical cause (e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be applied to determining study entry.
4.1.5 Ability to provide informed consent (for those above the legal age of consent and those providing consent for minors) and assent (for those who have reached the age of assent, but not the legal age of consent), as allowed by local ethics committees.
4.1.6 For participants to be enrolled/followed remotely, ability and willingness to participate in remote telehealth assessments (i.e., video visits).
4.2 Additional Inclusion Criteria for Arms A and B
4.2.1 Age ≥18 years at the time of study entry.
4.3 Additional Inclusion Criteria for Arm C
Participants who meet the above entry criteria (section 4.1) who also meet any of the following criteria will be registered to Arm C.
4.3.1 Participants age <18 years at the time of study entry

Those with severe HMPXV disease defined as having one or more of the following conditions:
• Suspected or confirmed ocular involvement
• Facial lesions on the malar, nose, or eyelid region
• Confluent facial lesions
• Hospitalization due to HMPXV infection or its complications
• Lesions that require surgical intervention including debridement, urinary catheterization or sigmoidoscopy, or lesions extending below the dermis
Those with or without severe disease and with one or more of the following will also be enrolled into Arm C:
• Severe immunosuppression defined as:
o HIV with CD4 <200 cells/mm3 or plasma HIV-1 RNA >1000 copies/mL
o Leukemia
o LymphomaGeneralized malignancy
o Solid organ transplantation
o Therapy with alkylating agents within 180 days prior to study entry
o Antimetabolites within 180 days prior to study entry
o Radiation therapy within 180 days prior to study entry
o Tumor necrosis factor inhibitors within 180 days prior to study entry
o High-dose corticosteroids (equivalent of 20 mg or greater of prednisone for at least 14 days) within 90 days prior to study entry
o Being a recipient with hematopoietic stem cell transplant <24 months post-transplant or ≥24 months but with graft-versus-host disease or disease relapse, or having autoimmune disease with immunodeficiency as a clinical component)
o Other severe immunosuppression in the opinion of the site investigator
• Active skin conditions placing the person at higher risk for disseminated infection as defined as:
o Atopic dermatitis
o Active exfoliative skin condition(s) such as eczema, burns, impetigo, active varicella zoster virus infection, psoriasis, or Darier disease (keratosis follicularis)
• Breastfeeding
• Pregnancy
• Receipt of potent inducers, including rifampin, rifapentine, rifabutin, St. John’s Wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir
• Current or planned use of another investigational drug at any point during tecovirimat/placebo dosing that would be predicted to have a significant drug-drug interaction with tecovirimat therapeutics.

Exclusion Criteria (All participants; Arms A, B, and C)
4.4.1 Prior or concomitant receipt of tecovirimat (e.g., under an alternative access mechanism).
NOTE: Participants <18 years of age, pregnant, and/or breastfeeding in Arm C are allowed up to 3 days of tecovirimat immediately prior to entry.
4.4.2 Planned initiation of intramuscular cabotegravir/rilpivirine during study drug administration or for two weeks following completion of study drug administration. Participants who are stable on long-acting intramuscular cabotegravir/rilpivirine may enroll.
4.4.3 Participants who, in the judgement of the investigator, will be at significantly increased risk as a result of participation in the study.
4.4.4 Participants who require intravenous dosing of tecovirimat.