Assessment of the Efficacy and Safety of Tecovirimat in Patients With Monkeypox Virus Disease (UNITY)

A Phase III, Multi-country, Randomized, Placebo-controlled, Double-blinded Trial to Assess the Efficacy and Safety of Tecovirimat Antiviral Treatment for Patients With Monkeypox Virus Disease

The overall purpose of this study is to evaluate whether tecovirimat is an efficient and safe antiviral in the treatment of monkeypox in adults and adolescents (14 years old and older). The primary objective is to evaluate the clinical efficacy, as assessed by time to all visible lesion(s) resolution, of tecovirimat treatment + Standard of Care (SOC) compared to placebo + SOC for patients with monkeypox. The secondary objective is to evaluate the clinical efficacy, as assessed by mortality, hospitalization, complications, duration of symptoms and virological shedding, and the safety of tecovirimat treatment + SOC compared to placebo + SOC in patients with monkeypox.

The study presented here is the Swiss-Brazil co-sponsored adaptation of the UNITY trial based on the WHO core protocol. It has an original governance to better respond to public health priorities, each country being its own sponsor, allowing for an easier scale-up of the trial and local adaptations of the protocol. Background and rationale: Monkeypox is an emerging viral zoonosis caused by a virus of the same name that is closely related to smallpox. It is usually endemic in central and West Africa but since May 2022, the virus has rapidly disseminated to Europe, North and South America, Africa and Australia, and has predominantly affected gay, bisexual and other men who have sex with men (MSM) with multiple partners. On 23 July 2022, the World Health Organization (WHO) declared that the monkeypox outbreak was an international public health emergency. In particular, the WHO called for the use of antivirals for the treatment of monkeypox cases. This declaration must therefore be translated not only into extraordinary public health measures but also as a call for greater investment in research. This study proposal is a national adaptation for Switzerland and Brazil based on the 'CORE protocol' developed by the WHO. The research team would like to emphasize that this randomized trial is international in scope. Thus, they are joining forces to achieve a more effective and rapid response to important questions, with a harmonized follow-up and in a time frame that can be useful to the patients the medical staff have been caring for since the very beginning of this epidemic. Candidate antivirals are already available for testing in monkeypox. The first studied treatment in this adaptative trial is the antiviral tecovirimat. Tecovirimat (TPOXX®, SIGA Technologies Inc.) is a treatment for smallpox, monkeypox and cowpox. Tecovirimat is approved by the European Medicine Agency (EMA) for this indication for adults and children weighing at least 13 kg, as well as by the United States Food and Drugs Administration (FDA) under expanded access investigational new drug protocol, but it is not yet approved in Switzerland and Brazil. Objectives: This study aims to evaluate whether tecovirimat is an efficient and safe antiviral in the treatment of monkeypox in adults and adolescents (14 years old and over). The primary objective is to evaluate the clinical efficacy of tecovirimat treatment + standard of care (SOC) compared to placebo + SOC for patients with monkeypox as assessed by time to visible lesion(s) resolution. The secondary objectives are to evaluate the clinical efficacy and safety of tecovirimat treatment + SOC compared to placebo + SOC in patients with monkeypox as assessed by mortality, hospitalization, complications, duration of symptoms and virological shedding. Methods: This study will include adult and adolescent patients aged ≥14 years with a confirmed or highly suspected monkeypox virus infection and with at least one visible active skin or mucosal lesion. Individuals with a known hypersensitivity to tecovirimat, who are taking medications which cannot be interrupted and for which a major interaction has been described or who, in the judgement of the investigator, will be at significantly increased risk as a result of participation in the study will not be included. Randomization will be in a ratio of 1:1 to either tecovirimat treatment combined with SOC or to placebo combined with SOC. All participants will be followed-up until day 29 and additionally at day 60 for those who accept this last optional follow-up visit. Outcome: The primary outcome is the time for all visible lesions (skin, mucosal) to heal with a new fresh layer of skin re-epithelialization (i.e. resurfacing of a wound with a new epithelium layer). Expected results: The hypothesis is that prompt oral treatment with tecovirimat will result in a reduction of the duration of illness in patients with monkeypox that may correlate with the duration of contagiousness. It is expected that tecovirimat will be well tolerated and acceptable for these patients.

The experimental intervention is tecovirimat, available as immediate-release capsules containing tecovirimat monohydrate, equivalent to 200 mg of tecovirimat. The route of administration of tecovirimat is oral. Tecovirimat treatment will be initiated as soon as possible after diagnosis. The international recommended doses will be followed: 25 kg to less than 40 kg: 400 mg (two tecovirimat 200 mg capsules) every 12 hours for 14 consecutive days. 40 kg and above: 600 mg (three tecovirimat 200 mg capsules) every 12 hours for 14 consecutive days.

The control intervention is a placebo and its route of administration will be identical to the experimental intervention administration to allow treatment arm blinding.

Time for all visible lesions (skin, mucosal) to heal with a new fresh layer of skin re-epithelialization (i.e resurfacing of a wound with a new epithelium layer). For skin lesions, typically this means the lesion has scabbed, desquamated and new layer of skin has been formed. For mucosal lesions, the phase of scabbing and desquamation is absent, and healing with new layer of skin ensues.

All-cause mortality is more reliably measured than monkeypox-specific mortality. It is easy to measure and is reliable.

Most patients will be managed at home or in community and this outcome is an important patient-centered and health system outcome. All-cause is easier to measure than monkeypox specific and will ease data burden.

Occurrence of patients with a complication within first 28 days (applies to all patients who did not already have a complication at baseline)

Complications include secondary bacterial skin infection (cellulitis, abscess, necrotizing fasciitis, need for antibiotics), severe pain, ocular impairment (e.g. keratitis), neurologic impairment (e.g. encephalitis) or mental health disturbance, confusion, cardiac impairment (e.g. cardiomyopathy, myocarditis), severe dehydration, and genitourinary complications as urinary retention. Progression to complications is an important patient-centered outcome and an important health system outcome to prepare and anticipate clinical services for monkeypox cases. It is easy to measure, as long as definitions are clear, and the relevant staff is trained. Complications will be differentiated based on drug-related complications and disease-related complications.

Symptoms include fatigue, malaise, nausea, vomiting, abdominal pain, anorexia, cough, dysphagia, odynophagia, fever, headache, oral pain, pain with urination, rectal/anal pain. Signs include lymphadenopathy, ocular lesions, pharyngitis, urethritis, and proctitis. Collection of symptoms and signs can be useful to understand the clinical characterization.

Occurrence of negative oropharyngeal , rectal swab, and skin swab PCR results, respectively, 7, 14, 21 days and 28 days after randomization. Viral clearance assessment is important to evaluate whether treatment is also a route for reducing transmission.

Frequency of adverse events (AEs) and serious adverse events (SAEs) for specific therapeutics (applies to all patients)

The collection of standardized data of adverse events is of importance in order to increase the understanding of safety and tolerability of the treatment.

Inclusion Criteria: Adults and adolescents (14 years old and older) with laboratory-confirmed (PCR if available) or highly suspected monkeypox virus infection of any duration At least one visible active skin or mucosal lesion Reachable via smartphone (for video calls) for outpatient participants Signed informed consent Exclusion Criteria: Current or planned use of another investigational drug at any point during study participation. Ongoing treatment which cannot be interrupted and for which a major interaction has been described with tecovirimat Patients who, in the judgement of the investigator, will be at significantly increased risk as a result of participation in the study (for example: if the investigator judges that an antiviral treatment is indicated in the framework of compassionate therapeutic access in Switzerland). Hypersensitivity to tecovirimat

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https://www.who.int/director-general/speeches/detail/who-director-general-s-statement-on-the-press-conference-following-IHR-emergency-committee-regarding-the-multi--country-outbreak-of-monkeypox--23-july-2022

WHO Director-General's statement at the press conference following IHR Emergency Committee regarding the multi-country outbreak of monkeypox - 23 July 2022

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Second meeting of the International Health Regulations (2005) (IHR) Emergency Committee regarding the multi-country outbreak of monkeypox

https://www.who.int/publications/m/item/core-protocol---an-international-adaptive-multi-country-randomized-placebo-controlled--double-blinded-trial-of-the-safety-and-efficacy-of-treatments-for-patients-with-monkeypox-virus-disease

CORE PROTOCOL - An international adaptive multi-country randomized,placebo-controlled, double-blinded trial of the safety and efficacy of treatments for patients with monkeypox virus disease

https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-indication-treatment-smallpox

Commissioner, O. of the. FDA approves the first drug with an indication for treatment of smallpox. FDA