Clinical trial NCT05459532: A Randomised, Multi-centre, Double-blind, Phase 3 Study to Observe the Effectiveness, Safety and Tolerability of Molnupiravir Compared to Placebo Administered Orally to High-risk Adult Outpatients With Mild COVID-19 Receiving Local Standard of Care in South Africa
Official title: This is a Multi-centre, Double-blind, Phase 3 Study to Observe the Effectiveness, Safety, and Tolerability of Molnupiravir 800 mg Administered 12-hourly for Five Days to Adult Patients With Mild COVID-19 at the Time of Enrolment Who Are at Risk of Progression to Severe Disease, Compared to a Placebo. Patients With Recent Onset of COVID-19 Symptoms Will be Screened to Assess Eligibility for Enrolment. Confirmation of SARS-CoV-2 Infection Will be Performed Through Rapid Antigen Detection Using the LumiraDx Point of Care Diagnostic Platform.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: COVID-19
Lead sponsor: University of Witwatersrand, South Africa
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2022-07-15
Enrollment: 4000
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Molnupiravir is a broad-spectrum antiviral that is an orally bioavailable prodrug of the nucleoside analogue NHC. NHC distributes into cells where it is phosphorylated to form the pharmacologically active NHC-TP. NHC-TP acts by a mechanism known as viral error catastrophe. NHC-TP incorporation into viral RNA by the viral RNA polymerase, results in an accumulation of errors in the viral genome leading to inhibition of replication.
Primary purpose: TREATMENT

Brief summary: This is a multi-centre, double-blind, phase 3 study to observe the effectiveness, safety, and tolerability of molnupiravir 800 mg administered 12-hourly for five days in adult patients with mild COVID-19 at the time of enrolment, who are at risk of progression to severe disease, compared to a placebo.

Detailed description: This is a multi-centre, double-blind, phase 3 study to observe the effectiveness, safety, and tolerability of molnupiravir 800 mg administered 12-hourly for five days in adult patients with mild COVID-19 at the time of enrolment, who are at risk of progression to severe disease, compared to a placebo.

Patients with recent onset of COVID-19 symptoms will be screened to assess eligibility for enrolment. Confirmation of SARS-CoV-2 infection will be performed through rapid antigen detection using the LumiraDx point of care diagnostic platform. Approximately 4000 eligible patients will be enrolled and will be randomised in a 1:1 manner to start treatment with either molnupiravir or a placebo on the same day. Patients will record their symptoms (through a self-administered questionnaire) and self-observed vital signs daily for 10 days from the time of enrolment and will be contacted by study team personnel on Days 3, 6 and 10 to monitor their well-being. Adverse event and concomitant medication data will be collected. A final end-of-study follow-up visit will be conducted on Day 29.

An independent Data and Safety Monitoring Board (DSMB) will be convened for this study with expertise in COVID-19 or respiratory viruses, and emerging epidemics. The purpose of the DSMB is to monitor the study for safety and operational futility.

In addition to the usual, regular, required reporting to SAHPRA, the investigator anticipates that additional reporting will be required by the Clinical Trials Committee, noting the severity of the 3rd and 4th waves, the level of ''breakthrough'' infections in the context of high background comorbidities, and the urgent interest in this class of drugs.

Eligibility criteria: Inclusion Criteria:

1. Able and willing to provide written or electronic informed consent prior to any study-specific procedure.
2. Age ≥50 at the time of signing the informed consent form.
3. Women of reproductive potential must have a negative pregnancy test at screening and be using a highly effective method of contraception. Highly effective methods of contraception
4. A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another while taking the investigational product. Male participants should also be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak.
5. Self-reported symptoms of COVID-19 with onset no more than five days prior to screening informed consent including at least one of, fever or chills, cough, sore throat, rhinorrhoea or rhinitis or sinusitis, shortness of breath, headache, myalgia, new onset anosmia or ageusia, nausea, diarrhoea, or extreme fatigue, or other symptoms recognized in local and international guidelines as typical of mild COVID-19.
6. SARS-CoV-2 infection confirmed through a positive LumiraDx rapid antigen test on the day of screening or a positive RT-PCR within two days prior to screening.
7. Participant is at high risk for progression to severe COVID-19, this defined as either:

   1. Age ≥50 with at least one of the following background or medical conditions: diabetes mellitus, obesity (BMI 30 kg/m2), hypertension, HIV, active or previous TB.
   2. Age ≥65
8. Participant agrees to comply with study procedures, including the completion of a daily diary for 10 days from the time of enrolment, and to be available for study contacts and visits.

   -

Exclusion Criteria:

1. Pregnant or breastfeeding women, or women planning/desiring to become pregnant during the 28 days following enrolment into the study.
2. Duration of self-reported symptoms of COVID-19 for more than five days prior to screening.
3. Signs of respiratory distress or severe disease prior to enrolment, including:
4. Inability/unlikely to be in the study area for the duration of the 28-day follow-up period.
5. Inability to tolerate oral medications.
6. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the safety of the patient or the objectives of the study. The Investigator should make this determination in consideration of the volunteer's medical history.
7. The volunteer is assessed to be clinically unstable in the Investigator's opinion.
8. Participation in another investigational study involving an investigational product within 30 days, or 5 half-lives, whichever is longer, prior to screening.
9. Personnel (e.g., investigator, sub-investigator, research assistant, pharmacist, study coordinator or anyone mentioned in the delegation log) directly involved in the conduct of the study.
10. Any physical, mental, or social condition, drug/alcohol use, history of illness or laboratory abnormality that, in the Investigator's judgment, might jeopardise the safety of the patient in the context of this study, or might interfere with study procedures or the ability of the subject to adhere to and complete the study. The Investigator should make this determination in consideration of the volunteer's medical history.

Primary outcomes:
measure: To evaluate the effectiveness of molnupiravir compared to placebo in preventing severe disease progression in adults with mild COVID-19
timeFrame: 29 Days
measure: To evaluate the safety of molnupiravir in adults with mild COVID-19
timeFrame: 29 Days
measure: To evaluate the safety of molnupiravir in adults with mild COVID-19
timeFrame: 29 Days
Secondary outcomes:
measure: To facilitate same-day COVID-19 diagnosis and treatment initiation in adults with mild COVID-19 and comorbid conditions
timeFrame: 29 Days
measure: To assess the tolerability of molnupiravir in adults with mild COVID-19
timeFrame: 29 Days
measure: To assess the tolerability of molnupiravir in adults with mild COVID-19
timeFrame: 29 Days
measure: To describe time to symptom resolution in adults with mild COVID-19 treated with molnupiravir compared to placebo
timeFrame: 29 Days
measure: To evaluate maximum COVID-19 disease severity in adults treated with molnupiravir compared to placebo
timeFrame: 29 Days
measure: To evaluate the relationship between effectiveness of molnupiravir and time between onset of symptoms and initiation of treatment
timeFrame: 29 Days
measure: To evaluate the relationship between effectiveness of molnupiravir and time between onset of symptoms and initiation of treatment
timeFrame: 29 Days
measure: To evaluate the relationship between effectiveness of molnupiravir and time between onset of symptoms and initiation of treatment
timeFrame: Day 1 to Day 10 and Day 29
measure: To evaluate the relationship between effectiveness of molnupiravir and time between onset of symptoms and initiation of treatment
timeFrame: Day 0, 3, 6, 10, 29
measure: To describe adherence to a 5-day course of molnupiravir in adults with mild COVID-19
timeFrame: 29 Days
measure: To describe the utilisation of health care services by adults with mild COVID-19 treated with molnupiravir compared to placebo
timeFrame: 29 Days
measure: To report the incidence and outcome of pregnancies in female participants who received molnupiravir
timeFrame: 29 Days
measure: To report the incidence and outcome of pregnancies in female participants who received molnupiravir
timeFrame: Once
measure: To report the incidence and outcome of pregnancies in female participants who received molnupiravir
timeFrame: Throughout the pregnancy
measure: To report the incidence and outcome of pregnancies in female participants who received molnupiravir
timeFrame: Once
measure: To report the incidence and outcome of pregnancies in female participants who received molnupiravir
timeFrame: Once
Other outcomes:
Locations:
city: Umtata
country: South Africa
facility: Nelson Mandela Academic Clinical Research Unit (NeMACRU)
state: Eastern Cape
city: Johannesburg
country: South Africa
facility: Sunnyside Office Park
state: Gauteng
city: Durban
country: South Africa
facility: Nelson R. Mandela School of Medicine 3rd Floor, K-RITH Tower Building
state: Kwa-Zulu Natal
city: Klerksdorp
country: South Africa
facility: The Aurum Institute: Gavin J Churchyard Legacy Centre Klerksdorp Clinical Research Centre
state: North West
Study officials:
affiliation: Ezintsha, Faculty of Health Sciences University of the Witwatersrand
name: Francois WD Venter
role: STUDY_DIRECTOR
References: