Clinical trial NCT05597735: Assessment of the Efficacy and Safety of Tecovirimat in Patients With Monkeypox Virus Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Monkeypox
Mpox
Keywords: Tecovirimat
Antiviral agent
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: University Hospital, Geneva
name: Oswaldo Cruz Foundation
name: Fundacion Huesped, Buenos Aires, Argentina
First posted: 2022-10-28
Enrollment: 480
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Placebo-controlled, Double-blinded Trial
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to all visible lesion(s) resolution
timeFrame: 28 days
Secondary outcomes:
measure: All-cause mortality within the first 28 days (applied to all patients)
timeFrame: 28 days
measure: All-cause unplanned admission to hospital within first 28 days (applies to outpatients)
timeFrame: 28 days
measure: Occurrence of patients with a complication within first 28 days (applies to all patients who did not already have a complication at baseline)
timeFrame: 28 days
measure: Time to resolution of symptoms and signs within first 28 days (applies to all patients)
timeFrame: 28 days
measure: Viral clearance up to 28 days after randomization
timeFrame: 28 days
measure: Frequency of adverse events (AEs) and serious adverse events (SAEs) for specific therapeutics (applies to all patients)
timeFrame: 60 days
Other outcomes:
Locations:
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Fundación Huésped
city: Belo Horizonte
country: Brazil
facility: Faculty of Medicine, Federal University of Minas Gerais
city: Rio de Janeiro
country: Brazil
facility: Evandro Chagas National Institute of Infectious Diseases-Oswaldo Cruz Foundation-FIOCRUZ
city: Rio De Janeiro
country: Brazil
facility: Federal Hospital for State Employees
city: Rio De Janeiro
country: Brazil
facility: Nova Iguaçu General Hospital
city: Salvador
country: Brazil
facility: University Hospital Prof. Edgard Santos
city: São Paulo
country: Brazil
facility: Emílio Ribas Institute of Infectious Diseases
city: São Paulo
country: Brazil
facility: STD/AIDS Reference and Training Center
city: Lausanne
country: Switzerland
facility: CHUV
state: Vaud
city: Geneva
country: Switzerland
facility: Pr Alexandra Calmy
city: Genève
country: Switzerland
facility: Hôpitaux Universitaires de Genève
city: Zürich
country: Switzerland
facility: Zürich checkpoint
Study officials:
affiliation: ANRS, Emerging Infectious Diseases
name: Yazdan Yazdapanah, Pr.
role: STUDY_DIRECTOR
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