Title: A randomized, placebo-controlled, double-blinded trial of the safety and efficacy of tecovirimat for the treatment of non-hospitalised patients with monkeypox virus disease
Funder: Department of Health and Social Care

Abstract: Monkeypox is a viral disease that causes a fever and a rash, and can be more severe in some people. Usually, it is more common in Africa, but this year there have been a growing number of cases in the United Kingdom, where it has continued to spread from person to person. _x000D_ _x000D_ At the moment, most patients with monkeypox are treated only for their symptoms, such as pain and itch, and not the root cause of their disease. However, there are several treatments that have been developed to specifically treat monkeypox and similar viruses. The most promising treatment is a drug called tecovirimat. This drug has been shown to be effective at treating monkeypox in animals, and to be safe in human after testing it in healthy individuals without the disease. However, there has never been a clinical trial to measure if tecovirimat treatment can help monkeypox patients recover from the disease. Clinical trials are the standard and regulated method of testing new drugs in humans and the most reliable way to measure if tecovirimat can help monkeypox patients recover from their disease. This drug is already approved by the US Food and Drug Administration (FDA) for the treatment of smallpox (a related virus) and by the European Medicines Agency (EMA) for the treatment of smallpox, cowpox and monkeypox. _x000D_ _x000D_ In this research proposal we describe a new clinical trial to enroll patients with mild monkeypox disease to determine if tecovirimat improves the time it takes for patients to recover from the infection. We plan to enroll adults and children who agree to being involved in the study after we have explained the benefits and potential risks, and who have tested positive for monkeypox, but who do not need to be in hospital as their disease is not severe. Half of the patients will receive tecovirimat, and half will receive an identical looking placebo drug so that we can compare how quickly each group recovers. All patients will still receive the standard care from the NHS. We will not know which patients receive tecovirimat and which receive placebo during the study so that we cannot bias the results. Patients will receive one of the drugs as a tablet for 14 days. Patients are free to stop taking the tablets and stop participating in the study if they wish._x000D_ _x000D_ To know whether tecovirimat works, we will compare how quickly patient symptoms (skin lesions specifically, which is a common monkeypox symptom) improve through an electronic form the patient fills in each day, and also how quickly patients clear the virus from their system (through throat and lesion swabs used to detect the virus) in patients who take tecovirimat compared to patients who take the placebo. We will also be monitoring for potential side effects and adverse reactions to the treatment. We will review patients when they are enrolled and once a week subsequently. We will continue to follow up each patient for a total of 28 days to check their progress. We expect to enroll around 500 patients to be confident that our findings are not due to chance. _x000D_ _x000D_ This trial is led by researchers from the University of Oxford and includes experts in infectious diseases and clinical trials. An independent committee will monitor the safety and findings of the study. When the trial is complete, we will publish the anonymous results in a scientific journal so the results can be used by others.

Lay abstract: 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. _x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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. _x000D_ _x000D_ 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._x000D_ _x000D_ 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.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION