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

NCT05459532 | Completed Phase 2 DMC

• 1 other identifier: EZ-SS-029
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 4

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.

Conditions

COVID-19

Outcome Measures

Primary Outcomes (3)

• To evaluate the effectiveness of molnupiravir compared to placebo in preventing severe disease progression in adults with mild COVID-19

  Combination of incidence of COVID-19-related hospitalisation (24 hours of care in a hospital or similar acute care facility) and COVID-19-related mortality to Day 29

  29 Days

• To evaluate the safety of molnupiravir in adults with mild COVID-19

  Adverse events (including serious adverse events and adverse drug reactions)

  29 Days

• To evaluate the safety of molnupiravir in adults with mild COVID-19

  Self-assessed vital signs to Day 10

  29 Days

Secondary Outcomes (16)

• To facilitate same-day COVID-19 diagnosis and treatment initiation in adults with mild COVID-19 and comorbid conditions

  29 Days

• To assess the tolerability of molnupiravir in adults with mild COVID-19

  29 Days

• To assess the tolerability of molnupiravir in adults with mild COVID-19

  29 Days

• To describe time to symptom resolution in adults with mild COVID-19 treated with molnupiravir compared to placebo

  29 Days

• To evaluate maximum COVID-19 disease severity in adults treated with molnupiravir compared to placebo

  29 Days

Study Arms (2)

Monulpiravir

EXPERIMENTAL

Eligible participants will be randomised in a 1:1 manner to receive either molnupiravir 800 mg orally approximately 12-hourly for five days or a placebo for the equivalent amount of time.

Drug: Molnupiravir 200 mg

Placebo

PLACEBO COMPARATOR

Eligible participants will be randomised in a 1:1 manner to receive either molnupiravir 800 mg orally approximately 12-hourly for five days or a placebo for the equivalent amount of time.

Drug: Molnupiravir 200 mg

Interventions

Molnupiravir 200 mg DRUG

The drug is orally bioavailable (and is indicated for treatment of mild to moderate COVID-19 in adults with a positive SARS-COV-2 diagnostic test and who have at least one risk factor for developing severe illness. The recommended dose is 800 mg (four 200 mg capsules) taken orally 12-hourly for five days, and should be administered as soon as possible after diagnosis of COVID-19 has been made and within five days of symptom onset.

Monulpiravir; Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able and willing to provide written or electronic informed consent prior to any study-specific procedure.
• Age ≥50 at the time of signing the informed consent form.
• 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
• 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.
• 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.
• 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.
• Participant is at high risk for progression to severe COVID-19, this defined as either:
• 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.
• Age ≥65
• 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.

You may not qualify if:

• Pregnant or breastfeeding women, or women planning/desiring to become pregnant during the 28 days following enrolment into the study.
• Duration of self-reported symptoms of COVID-19 for more than five days prior to screening.
• Signs of respiratory distress or severe disease prior to enrolment, including:
• Inability/unlikely to be in the study area for the duration of the 28-day follow-up period.
• Inability to tolerate oral medications.
• 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.
• The volunteer is assessed to be clinically unstable in the Investigator's opinion.
• Participation in another investigational study involving an investigational product within 30 days, or 5 half-lives, whichever is longer, prior to screening.
• 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.
• 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.

Sponsors & Collaborators

• University of Witwatersrand, South Africa: lead
• Bill and Melinda Gates Foundation: collaborator

Study Sites (4)

Nelson Mandela Academic Clinical Research Unit (NeMACRU)

Umtata, Eastern Cape, 5099, South Africa

Location

Sunnyside Office Park

Johannesburg, Gauteng, 2193, South Africa

Location

Nelson R. Mandela School of Medicine 3rd Floor, K-RITH Tower Building

Durban, KwaZulu-Natal, 3935, South Africa

Location

The Aurum Institute: Gavin J Churchyard Legacy Centre Klerksdorp Clinical Research Centre

Klerksdorp, North West, 2571, South Africa

Location

MeSH Terms

Conditions

COVID-19

Interventions

molnupiravir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Francois WD Venter

  Ezintsha, Faculty of Health Sciences University of the Witwatersrand

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Open Label
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head: Clinical Research

Model Details: 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.

Study Record Dates

• First Submitted: July 13, 2022
• First Posted: July 15, 2022
• Study Start: August 12, 2022
• Primary Completion: July 7, 2023
• Study Completion: September 30, 2023
• Last Updated: July 1, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Immediately following publication
• Access Criteria: Anyone who wishes to access the data

Locations

ZA (4)