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 (CoTeT)

• ClinicalTrials.gov Identifier: NCT05459532
• Recruitment Status: Recruiting
• First Posted: July 15, 2022
• Last Update Posted: August 16, 2022
• Sponsor: University of Witwatersrand, South Africa
• Collaborator: Bill and Melinda Gates Foundation
• Information provided by (Responsible Party): Professor Francois Venter, University of Witwatersrand, South Africa

Study Description

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.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Molnupiravir 200 mg	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 4000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Double-Blinded
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: August 12, 2022
• Estimated Primary Completion Date: July 2024
• Estimated Study Completion Date: July 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Monulpiravir; 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; 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.
Placebo Comparator: Placebo; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. To evaluate the effectiveness of molnupiravir compared to placebo in preventing severe disease progression in adults with mild COVID-19 [ Time Frame: 29 Days ]
   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
2. To evaluate the safety of molnupiravir in adults with mild COVID-19 [ Time Frame: 29 Days ]
   Adverse events (including serious adverse events and adverse drug reactions)
3. To evaluate the safety of molnupiravir in adults with mild COVID-19 [ Time Frame: 29 Days ]
   Self-assessed vital signs to Day 10

Secondary Outcome Measures :

1. To facilitate same-day COVID-19 diagnosis and treatment initiation in adults with mild COVID-19 and comorbid conditions [ Time Frame: 29 Days ]
   Proportion of enrolled patients for whom diagnosis and same day treatment initiation was facilitated through use of a LumiraDx™ rapid antigen test
2. To assess the tolerability of molnupiravir in adults with mild COVID-19 [ Time Frame: 29 Days ]
   Severity of adverse events
3. To assess the tolerability of molnupiravir in adults with mild COVID-19 [ Time Frame: 29 Days ]
   Adverse event-related study drug discontinuations
4. To describe time to symptom resolution in adults with mild COVID-19 treated with molnupiravir compared to placebo [ Time Frame: 29 Days ]
   Time to sustained resolution of symptoms as reported in the Flu-PRO© Plus
5. To evaluate maximum COVID-19 disease severity in adults treated with molnupiravir compared to placebo [ Time Frame: 29 Days ]
   Maximum score on the WHO Clinical Progression Scale from Day 1 to Day 29
6. To evaluate the relationship between effectiveness of molnupiravir and time between onset of symptoms and initiation of treatment [ Time Frame: 29 Days ]
   Number of days from symptom onset to initiation of treatment
7. To evaluate the relationship between effectiveness of molnupiravir and time between onset of symptoms and initiation of treatment [ Time Frame: 29 Days ]
   Incidence of hospitalisation (24 hours of care in a hospital or similar acute care facility) and/or death to Day 29 in patients with co-morbid conditions
8. To evaluate the relationship between effectiveness of molnupiravir and time between onset of symptoms and initiation of treatment [ Time Frame: Day 1 to Day 10 and Day 29 ]
   Time to sustained resolution of symptoms as reported in the Flu-PRO Plus
9. To evaluate the relationship between effectiveness of molnupiravir and time between onset of symptoms and initiation of treatment [ Time Frame: Day 0, 3, 6, 10, 29 ]
   Maximum score on the WHO Clinical Progression Scale from Day 1 to Day 29. On a scale of 0 to 10 (0 being uninfected and 10 being worse/death)
10. To describe adherence to a 5-day course of molnupiravir in adults with mild COVID-19 [ Time Frame: 29 Days ]
    Proportion of patients completing the course of molnupiravir as prescribed
11. To describe the utilisation of health care services by adults with mild COVID-19 treated with molnupiravir compared to placebo [ Time Frame: 29 Days ]
    Rate of hospital, emergency facility, clinic, health care practitioner or home visits to Day 29
12. To report the incidence and outcome of pregnancies in female participants who received molnupiravir [ Time Frame: 29 Days ]
    Incidence of pregnancy in female participants to Day 29
13. To report the incidence and outcome of pregnancies in female participants who received molnupiravir [ Time Frame: Once ]
    20-week gestational age ultrasound findings
14. To report the incidence and outcome of pregnancies in female participants who received molnupiravir [ Time Frame: Throughout the pregnancy ]
    Pregnancy complications
15. To report the incidence and outcome of pregnancies in female participants who received molnupiravir [ Time Frame: Once ]
    Pregnancy outcome
16. To report the incidence and outcome of pregnancies in female participants who received molnupiravir [ Time Frame: Once ]
    Infant wellbeing to three months of age

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Contacts

Contact: Bukani X Dyariwe; 0110844961; bdyariwe@ezintsha.org

Contact: Simiso M Sokhela; 0110844933; ssokhela@ezintsha.org

Locations

South Africa

Nelson Mandela Academic Clinical Research Unit (NeMACRU); Recruiting

Umtata, Eastern Cape, South Africa, 5099

Contact: Pamela Mda, M.Med 0471500012 pmda@witshealth.co.za

Contact: Bomikazi Tutshana 0471500012 btutshana@witshealth.co.za

Sub-Investigator: Thozama Dubula, M.Med

Sub-Investigator: Sinalo Toni, MBCHB

Sub-Investigator: Bulelwa Mabindla, MBCHB

Sunnyside Office Park; Recruiting

Johannesburg, Gauteng, South Africa, 2193

Contact: Nonkululeko Mashabane, BPharm 0110844953 nmashabane@ezintsha.org

Contact: Godspower Akpomiemie, MPH 0110844984 gakpomiemie@ezintsha.org

Principal Investigator: Simiso M Sokhela, MBBCh

Sub-Investigator: Nomathemba Chandiwana, MBBCh

Sub-Investigator: Joana Woods, MBBCh

Sub-Investigator: Esther S Bhasker, MBBCh

Sub-Investigator: Ncomeka Manentsa, MBBCh

Sub-Investigator: Bronwyn Bosch, MBBCh

Sub-Investigator: Karlien Moller, MBBCh

Principal Investigator: Francois WD Venter, MBBCh

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

Durban, Kwa-Zulu Natal, South Africa, 3935

Contact: Limakatso Lebina, MD 0312604112 limakatso.lebina@ahri.org

Contact: Willem Hanekom, MD 0312604112 willem.hanekom@ahri.org

Sub-Investigator: Mark Siedner, MD

Sub-Investigator: Ngundu Behuhuma, MD

Sub-Investigator: Ngcebo Mhlongo, MD

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

Klerksdorp, North West, South Africa, 2571

Contact: Tania Adonis, BPsych tadonis@auruminstitute.org

Contact: Olebogeng Jonkane, BA ojokane@auruminstitute.org

Principal Investigator: Oteng Letlape, MBBCH

Sub-Investigator: James C Innes, MBChB

Sub-Investigator: Raesibe AP Selepe, MBChB

Sub-Investigator: Mgcini Moyo, MBChB

Sub-Investigator: Tanya Nielson, MSc

Sponsors and Collaborators

University of Witwatersrand, South Africa

Bill and Melinda Gates Foundation

Investigators

• Study Director: Francois WD Venter; Ezintsha, Faculty of Health Sciences University of the Witwatersrand

  Study Documents (Full-Text)

Documents provided by Professor Francois Venter, University of Witwatersrand, South Africa:

Study Protocol  [PDF] April 22, 2022

Informed Consent Form  [PDF] May 30, 2022

More Information

• Responsible Party: Professor Francois Venter, Head: Clinical Research, University of Witwatersrand, South Africa
• ClinicalTrials.gov Identifier: NCT05459532
• Other Study ID Numbers: EZ-SS-029
• First Posted: July 15, 2022
• Last Update Posted: August 16, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The data that will be shared is all of the individual participant data collected during the trial, after deidentification.
• Supporting Materials: Study Protocol; Informed Consent Form (ICF)
• Time Frame: Immediately following publication
• Access Criteria: Anyone who wishes to access the data

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases