European Randomised Clinical Trial on mPOX Infection (EPOXI)

The primary objective of the European Randomised Clinical Trial on **Monkeypox** Infection (EPOXI) is to provide evidence regarding the clinical efficacy of a treatment compared to a control group in patients with confirmed monkeypox. This is assessed by the time to resolution of cutaneous and mucosal lesions. The clinical relevance of this objective lies in its potential to inform treatment protocols and improve patient outcomes by reducing the duration of visible symptoms associated with monkeypox.

Secondary objectives include:

• Providing evidence about the clinical efficacy of the treatment versus control in terms of duration of symptoms, complications of infection, clinical severity, and mortality in patients with proven monkeypox.
• Evaluating the safety of the treatment relative to the control in patients with confirmed monkeypox.

The clinical trial involves participants diagnosed with **Monkeypox**, focusing on both male and female subjects. The study population includes individuals from two age categories, specifically adults and adolescents. Participants are required to have a PCR/NAAT-confirmed infection and exhibit active skin or mucosal lesions. The trial does not target a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified as part of the selection criteria. Key inclusion criteria include the confirmation of infection and the presence of lesions, with informed consent being mandatory for participation.

The clinical trial is designed to evaluate the **clinical efficacy** of Tecovirimat SIGA 200 mg hard capsules in patients with confirmed **monkeypox** infection. This is a randomized, double-blind, controlled trial, where participants will be randomly assigned to receive either the active treatment or a placebo. The trial aims to assess the time to resolution of cutaneous and mucosal lesions, with the primary endpoint being the time to complete lesion resolution, evaluated at day 28 post-randomization. Secondary endpoints include the time to active lesion resolution, status of lesions at various intervals, and changes in quality of life, among others.

The trial is expected to commence recruitment on June 15, 2024, and conclude by January 30, 2027. Participants will be involved in the study for a maximum of 90 days, with the treatment period lasting up to 2 weeks. The study will include several visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits on days 7, 14, 21, and 28 to monitor lesion status and other health parameters. An end-of-study visit will occur on day 90 to assess long-term outcomes such as scar persistence and quality of life changes.

Inclusion criteria for the study require participants to have a PCR/NAAT-confirmed **monkeypox** infection, active skin or mucosal lesions, and to provide signed informed consent. Participants may be terminated early from the study if they experience severe adverse events, withdraw consent, or if the investigator deems it necessary for their safety. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Tecovirimat SIGA 200 mg hard capsules** as the experimental medication. Tecovirimat is a chemical substance, and the pharmaceutical form is a hard capsule. The medication is administered orally. The maximum daily dose is 1200 mg, and the treatment period is limited to a maximum of 2 days. The active substance, tecovirimat, is intended to provide evidence of clinical efficacy in the treatment of mPOX infection by assessing the time to resolution of cutaneous and mucosal lesions. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** treatment, which consists of capsules identical in appearance to the active Tecovirimat capsules. These placebo capsules are relabeled to match the study drug and contain the same excipients, excluding the active substance. The composition includes microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, hypromellose, sodium lauryl sulfate, magnesium stearate, and purified water, encapsulated in an opaque orange/black hard gelatin capsule shell size 0. The placebo serves as a comparator to evaluate the efficacy of the experimental treatment.

Efficacy in the clinical trial titled "European Randomised Clinical Trial on mPOX Infection (EPOXI)" will be assessed primarily by measuring the **time to complete lesion resolution**. This is defined as the number of days from the start of therapy to the first day on which all lesions are completely healed with a new fresh layer of skin. This primary endpoint will be evaluated at day 28 after randomization. Secondary endpoints include the time to active lesion resolution, status of lesions on days 7, 14, 21, and 28 using an ordinal scale, and time to resolution of symptoms such as fatigue, malaise, and fever, among others. Additionally, the occurrence of a negative monkeypox PCR from skin or mucosa swabs will be assessed at days 7, 14, and 28. Other secondary measures include the persistence of scars and skin discoloration assessed on day 90, changes in quality of life measured by the Dermatology Quality of Life Index (DQLI) on days 7, 14, 28, and 90, and all-cause mortality within 28 and 90 days. The trial will also monitor the time to complications, hospital admissions, or death within 28 and 90 days, and the frequency of adverse events (AEs), serious adverse events (SAEs), and suspected unexpected serious adverse reactions (SUSARs) within the first 28 days and up to day 90. In a subset of patients, the resolution of pain at the lesion site will be assessed using the Numeric Rating Scale (NRS) for pain and the Health Related Symptom Index on specified days up to 90 days post-randomization.