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

Monkeypox Clinical Trial

— UNITY  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05597735
• Other study ID #: 2022-01579
• Status: Recruiting
• Phase: Phase 3
• Start date: March 3, 2023
• Est. completion date: January 1, 2025

Study information

• Verified date: October 2023
• Source: University Hospital, Geneva
• Contact: Alexandra CALMY, Pr.
• Phone: +41 (0) 22 372 98 12
• Email: alexandra.calmy[@]hcuge.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: January 1, 2025
• Est. primary completion date: January 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Monkeypox
• Virus Diseases

Intervention

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

Locations

Country	Name	City	State
Argentina	Fundación Huésped	Ciudad Autonoma de Buenos Aires
Brazil	Faculty of Medicine, Federal University of Minas Gerais	Belo Horizonte
Brazil	Evandro Chagas National Institute of Infectious Diseases-Oswaldo Cruz Foundation-FIOCRUZ	Rio de Janeiro
Brazil	Federal Hospital for State Employees	Rio De Janeiro
Brazil	Nova Iguaçu General Hospital	Rio De Janeiro
Brazil	University Hospital Prof. Edgard Santos	Salvador
Brazil	Emílio Ribas Institute of Infectious Diseases	São Paulo
Brazil	STD/AIDS Reference and Training Center	São Paulo
Switzerland	Hôpitaux Universitaires de Genève	Genève
Switzerland	CHUV	Lausanne	Vaud
Switzerland	Zürich checkpoint	Zürich

Sponsors (3)

Lead Sponsor	Collaborator
Calmy Alexandra	ANRS, Emerging Infectious Diseases, Oswaldo Cruz Foundation

Countries where clinical trial is conducted

Argentina,  Brazil,  Switzerland, 

References & Publications (9)

Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF, Osborne JC, Rampling T, Beadsworth MB, Duncan CJ, Dunning J, Fletcher TE, Hunter ER, Jacobs M, Khoo SH, Newsholme W, Porter D, Porter RJ, Ratcliffe L, Schmid ML, Semple MG, Tunbridge AJ, Wingfield T, Price NM; NHS England High Consequence Infectious Diseases (Airborne) Network. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect Dis. 2022 Aug;22(8):1153-1162. doi: 10.1016/S1473-3099(22)00228-6. Epub 2022 May 24. Erratum In: Lancet Infect Dis. 2022 Jul;22(7):e177. Lancet Infect Dis. 2022 Jul;22(7):e177. — View Citation

Carvalho T. The unknown efficacy of tecovirimat against monkeypox. Nat Med. 2022 Nov;28(11):2224-2225. doi: 10.1038/d41591-022-00094-0. No abstract available. — View Citation

Desai AN, Thompson GR 3rd, Neumeister SM, Arutyunova AM, Trigg K, Cohen SH. Compassionate Use of Tecovirimat for the Treatment of Monkeypox Infection. JAMA. 2022 Oct 4;328(13):1348-1350. doi: 10.1001/jama.2022.15336. — View Citation

Girometti N, Byrne R, Bracchi M, Heskin J, McOwan A, Tittle V, Gedela K, Scott C, Patel S, Gohil J, Nugent D, Suchak T, Dickinson M, Feeney M, Mora-Peris B, Stegmann K, Plaha K, Davies G, Moore LSP, Mughal N, Asboe D, Boffito M, Jones R, Whitlock G. Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis. Lancet Infect Dis. 2022 Sep;22(9):1321-1328. doi: 10.1016/S1473-3099(22)00411-X. Epub 2022 Jul 1. — View Citation

Merchlinsky M, Albright A, Olson V, Schiltz H, Merkeley T, Hughes C, Petersen B, Challberg M. The development and approval of tecoviromat (TPOXX(R)), the first antiviral against smallpox. Antiviral Res. 2019 Aug;168:168-174. doi: 10.1016/j.antiviral.2019.06.005. Epub 2019 Jun 7. — View Citation

O'Laughlin K, Tobolowsky FA, Elmor R, Overton R, O'Connor SM, Damon IK, Petersen BW, Rao AK, Chatham-Stephens K, Yu P, Yu Y; CDC Monkeypox Tecovirimat Data Abstraction Team. Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol - United States, May-August 2022. MMWR Morb Mortal Wkly Rep. 2022 Sep 16;71(37):1190-1195. doi: 10.15585/mmwr.mm7137e1. — View Citation

Siegrist EA, Sassine J. Antivirals With Activity Against Mpox: A Clinically Oriented Review. Clin Infect Dis. 2023 Jan 6;76(1):155-164. doi: 10.1093/cid/ciac622. — View Citation

Smith SK, Self J, Weiss S, Carroll D, Braden Z, Regnery RL, Davidson W, Jordan R, Hruby DE, Damon IK. Effective antiviral treatment of systemic orthopoxvirus disease: ST-246 treatment of prairie dogs infected with monkeypox virus. J Virol. 2011 Sep;85(17):9176-87. doi: 10.1128/JVI.02173-10. Epub 2011 Jun 22. — View Citation

Thornhill JP, Barkati S, Walmsley S, Rockstroh J, Antinori A, Harrison LB, Palich R, Nori A, Reeves I, Habibi MS, Apea V, Boesecke C, Vandekerckhove L, Yakubovsky M, Sendagorta E, Blanco JL, Florence E, Moschese D, Maltez FM, Goorhuis A, Pourcher V, Migaud P, Noe S, Pintado C, Maggi F, Hansen AE, Hoffmann C, Lezama JI, Mussini C, Cattelan A, Makofane K, Tan D, Nozza S, Nemeth J, Klein MB, Orkin CM; SHARE-net Clinical Group. Monkeypox Virus Infection in Humans across 16 Countries - April-June 2022. N Engl J Med. 2022 Aug 25;387(8):679-691. doi: 10.1056/NEJMoa2207323. Epub 2022 Jul 21. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to all visible lesion(s) resolution	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.	28 days
Secondary	All-cause mortality within the first 28 days (applied to all patients)	All-cause mortality is more reliably measured than monkeypox-specific mortality. It is easy to measure and is reliable.	28 days
Secondary	All-cause unplanned admission to hospital within first 28 days (applies to outpatients)	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.	28 days
Secondary	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.	28 days
Secondary	Time to resolution of symptoms and signs within first 28 days (applies to all patients)	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.	28 days
Secondary	Viral clearance up to 28 days after randomization	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.	28 days
Secondary	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.	60 days

External Links

•   CDC. Monkeypox in the U.S. Centers for Disease Control and Prevention
•   Commissioner, O. of the. FDA approves the first drug with an indication for treatment of smallpox. FDA
•   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
•   Second meeting of the International Health Regulations (2005) (IHR) Emergency Committee regarding the multi-country outbreak of monkeypox
•   WHO Director-General's statement at the press conference following IHR Emergency Committee regarding the multi-country outbreak of monkeypox - 23 July 2022