Placebo-controlled randomised trial of tecovirimat in non-hospitalised Monkeypox patients (PLATINUM)

This protocol describes a scalable, double-blind, placebo-controlled, randomised trial among non-hospitalised adults and children with laboratory-confirmed monkeypox virus disease in the United Kingdom. Eligibility and randomisation: Patients will be identified following clinical assessment and laboratory confirmation of monkeypox infection as part of usual NHS clinical care. All eligible and consenting patients will be randomly allocated (1:1) to receive tecovirimat or matching placebo for 14 days, each to be given in addition to the usual NHS care. Efficacy outcomes: The primary clinical efficacy endpoint is the time to resolution of active lesions. Secondary efficacy endpoints are time to complete lesion resolution, and the time to negative cultures for monkeypox virus in throat and lesion swabs. For the main analyses, follow-up will be censored at 28 days after randomisation. Additional information on longer term outcomes may be collected through review of medical records or linkage to medical databases such as those managed by NHS Digital and other health care organisations across the UK. Additional assessments may be conducted following the end of the main assessment period of the study (28 days) to assess complete resolution of monkeypox symptoms and other relevant adverse events. Safety: Serious adverse events, non-serious adverse events of special interest, and reasons for stopping study treatment will be recorded and will be reviewed by medical staff at the Central Coordinating Office. Suspected Unexpected Serious Adverse Reactions (SUSARs) to study medication (e.g., Stevens-Johnson syndrome, anaphylaxis, aplastic anaemia, etc.) will be reported in an expedited fashion. Data collection: To facilitate patient isolation and infection control, and participation by clinicians and patients, data collection and all other trial procedures are streamlined and focused on those aspects critical to participant safety and the reliability of the study results. Informed consent, randomisation and follow up will be conducted remotely by telephone or video and data will be recorded by electronic methods by participants and trial staff. Numbers to be randomised: The rates of clinical and microbiological resolution are uncertain for monkeypox in general, and in particular for the current epidemiological context. Sample size estimates using data on the natural history of Congo Basin clade monkeypox indicate that randomisation of 500 individuals would provide at least 85% power and a two-sided a of 0.05 to detect a 40% improvement in the rate of lesion resolution at day 28 (account for one interim analysis and approximately 10% losses to follow-up). Monitoring of blinded event rates will be used to re-estimate sample size requirements as data from the trial accrue.