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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)

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

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.

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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

Resource links provided by the National Library of Medicine


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.




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05459532


Contacts
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Contact: Bukani X Dyariwe 0110844961 bdyariwe@ezintsha.org
Contact: Simiso M Sokhela 0110844933 ssokhela@ezintsha.org

Locations
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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
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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

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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    Key Record Dates
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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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