COVID-19 Prophylaxis South Africa (COVER HCW) (COVER)

• ClinicalTrials.gov Identifier: NCT04561063
• Recruitment Status: Completed
• First Posted: September 23, 2020
• Last Update Posted: June 7, 2022
• Sponsor: University of Witwatersrand, South Africa
• Information provided by (Responsible Party): Professor Francois Venter, University of Witwatersrand, South Africa

Tracking Information

• First Submitted Date: September 21, 2020
• First Posted Date: September 23, 2020
• Last Update Posted Date: June 7, 2022
• Actual Study Start Date: December 8, 2020
• Actual Primary Completion Date: February 28, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 21, 2020)

Number of SARS-CoV-2 infections [ Time Frame: 6 months ]

Number of SARS-CoV-2 infection (COVID-19) confirmed by PCR and/or serology.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 24, 2020)

• Duration of symptoms [ Time Frame: 6 months ]
  Duration of symptoms for each symptomatic infection
• Maximum score on WHO Ordinal Scale [ Time Frame: 6 months ]
  Maximum score on WHO Ordinal Scale for Clinical Improvement for each symptomatic infection. Score of 0 being uninfected and a score of 8 being dead.
• Time to onset of SARS-CoV-2 infection [ Time Frame: 6 months ]
  Time to onset of SARS-CoV-2 infection (COVID-19) confirmed by PCR and/or serology
• Number of symptomatic SARS-CoV-2 infections [ Time Frame: 6 months ]
  Number of symptomatic SARS-CoV-2 infection (COVID-19) confirmed by PCR and/or serology
• Number of asymptomatic SARS-CoV-2 infections [ Time Frame: 6 months ]
  Number of asymptomatic • Asymptomatic SARS-CoV-2 infection suggested by serological outcome
• Peak score on modified Flu PRO [ Time Frame: 6 months ]
  Peak score on modified Flu-PRO during each symptomatic infection. 37-item questionairre assessing the severity of flu like symptoms one a scale of 0 - not at all to 5 - very much.

Original Secondary Outcome Measures (submitted: September 21, 2020)

• Duration of symptoms [ Time Frame: 6 months ]
  Duration of symptoms for each symptomatic infection
• Maximum score on WHO Ordinal Scale [ Time Frame: 6 months ]
  Maximum score on WHO Ordinal Scale for Clinical Improvement for each symptomatic infection
• Time to onset of SARS-CoV-2 infection [ Time Frame: 6 months ]
  Time to onset of SARS-CoV-2 infection (COVID-19) confirmed by PCR and/or serology
• Number of symptomatic SARS-CoV-2 infections [ Time Frame: 6 months ]
  Number of symptomatic SARS-CoV-2 infection (COVID-19) confirmed by PCR and/or serology
• Number of asymptomatic SARS-CoV-2 infections [ Time Frame: 6 months ]
  Number of asymptomatic • Asymptomatic SARS-CoV-2 infection suggested by serological outcome
• Peak score on modified Flu PRO [ Time Frame: 6 months ]
  Peak score on modified Flu-PRO during each symptomatic infection

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: COVID-19 Prophylaxis South Africa (COVER HCW)
• Official Title: A Multi-center, Randomised, Open Label Study of Nitazoxanide (NTZ), or Sofosbuvir and Daclatasvir (SOF/DCV), Compared to no Pharmacological Intervention for the Prevention of COVID-19 Disease in Healthcare Workers and Inner City Inhabitants at High Risk of Exposure to SARS-CoV-2
• Brief Summary: This is a randomised, multi-center, open label, adaptive, exploratory trial to assess the efficacy of two different drug regimens in terms of preventing symptomatic COVID-19 disease in healthcare workers at high risk of exposure to SARS-CoV-2. The trial will compare two different experimental medication arms to the control arm comprising the use of standard personal protective equipment (PPE) with no additional pharmacological intervention.

Detailed Description

This is a randomised, multi-center, open label, adaptive, exploratory trial to assess the efficacy of two different drug regimens in terms of preventing symptomatic COVID-19 disease in healthcare workers at high risk of exposure to SARS-CoV-2. The trial will compare two different experimental medication arms to the control arm comprising the use of standard personal protective equipment (PPE) with no additional pharmacological intervention.

Volunteers will be recruited from participating institutions and community healthcare workers (CHWs) that are responsible for collecting swabs for PCR detection of SARS-CoV-2. Up to 1950 (or 2130 pending funding) eligible participants will be randomised in a 1:1:1 ratio to one of the investigational arms.

Participants will be followed until 65 PCR and serology-confirmed, SARS-CoV-2 infections are identified in the control arm (or 165 in the entire study cohort). For each episode of PCR-confirmed COVID-19 disease, data on self-reported symptoms (modified Flu-PRO) and their duration, and an investigator-assessed severity score (WHO Ordinal Scale for Clinical Improvement) will be recorded. Data on self-reported symptoms and duration will also be collected for other all-cause acute respiratory illnesses. Safety and tolerability of each arm will be assessed through adverse event reporting. Participants who develop COVID-19 disease will have their IMP discontinued but will be followed up in the study until the completion of the trial, where possible. Multiple, discrete occurrences of COVID-19 disease could therefore be identified in a single participant.

Additional arms may be added, or existing ones substituted, should new potential agents be identified or other combinations for prophylaxis be proposed. A formal amendment will be documented should this be considered.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention

Condition

• Covid19
• SARS-CoV Infection

Intervention

• Drug: Nitazoxanide
  Nitozoxanide 1 tablet (500 mg) taken 12-hourly with food for the first week, followed by 2 tablets (1000 mg) taken 12-hourly with food thereafter. (Participants that fail to tolerated the 1000 mg 12-hourly dose may revert back to the lower dose.)
• Drug: Sofosbuvir/Daclatasvir
  Sofosbuvir/daclatasvir 400mg/60 mg sofosbuvir/daclatasvir fixed dose combination 1 tablet daily

Study Arms

• No Intervention: Arm A: No pharmacological intervention (PPE only)
  No intervention
• Active Comparator: Arm B: Nitazoxanide (NTZ)
  Nitozoxanide administered
  Intervention: Drug: Nitazoxanide
• Active Comparator: Arm C: Sofosbuvir/daclatasvir (SOF/DCV).
  Sofosbuvir/daclatasvir administered
  Intervention: Drug: Sofosbuvir/Daclatasvir

• Publications *: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 21, 2020): 1950
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: February 28, 2022
• Actual Primary Completion Date: February 28, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age ≥18 years of age, inclusive, at the time of signing the informed consent.
2. Willing and able to provide informed consent via an electronic process.
3. Healthcare worker employed at a participating institution that has been identified as high-risk for SARS-CoV-2 exposure (may include doctors, nurses, nurse aids, radiographers, physiotherapists, phlebotomists, technicians, porters, cleaners, laboratory or other personnel identified as being at high risk of exposure), CHW involved in the collection of samples for the identification of SARS-CoV-2 through PCR, and inner city inhabitants at high risk for SARS-CoV-2 exposure due to the nature of their work and frequent use of public transport (may include essential services employees such as fire fighters, law enforcement officers, grocery store employees; and non healthcare workers using public transport at least three times a week).
4. Women of reproductive potential must be using a highly effective method of contraception prior to enrolment or must be willing to start a method at enrolment and continue its use throughout the duration of the study.
5. Body weight ≥45 kg.
6. Access to reliable video conference, telephone, direct/text messaging, or other device permitting real-time, reliable information transfer.

Exclusion Criteria:

1. Pregnant or lactating women.
2. PCR and/or serology confirmed SARS-Cov-2 infection at screening.
3. Current symptoms of COVID-19 disease (including, but not limited to, fever or chills, cough, myalgia, sore throat, shortness of breath, or new onset of anosmia or ageusia, or diarrhea).

4. Self-reported presence or history of any of the following conditions:

   • Chronic kidney disease (Stage IV or receiving dialysis)
   • Cirrhosis (Child-Pugh Class B or greater)
   • Porphyria cutanea tarda.
5. Currently on treatment for epilepsy or other seizure disorder.
6. Currently on treatment with a protease inhibitor-based antiretroviral regimen, or efavirenz, or on treatment with amiodarone, carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin,St. John's wort or any herbal products which may potentially decrease the concentration of the IMP.
7. Known hypersensitivity or specific contraindications to the use of any of the active drugs in the treatment arms or similar compounds.
8. Current enrolment in another COVID-19 prevention trial.
9. History of alcohol abuse within the last 6 months.
10. Having history or have risk factors for brady-arrhythmias (those with undiagnosed cardiac conditions).
11. History of malignancies in the last 5 years, excluding in-situ or non-invasive malignancies.
12. Concurrent or recent (within 3 months) participation in other research with a compound likely to interfere with any of the investigational products.
13. 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 volunteer or the objectives of the study. The Investigator should make this determination in consideration of the volunteer's medical history.
14. Inability or unwillingness to be followed up for the study period.
15. 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. (Personnel employed at a study site, but not directly involved in the conduct of the study, who would like to participate in the study, may only do so if they are enrolled in the study through a different site at which they are not employed.)
16. Participant is judged by the Investigator to be at significant risk of failing to comply with the provisions of the protocol as to cause harm to self or seriously interfere with the validity of the study results.
17. Confirmed vaccination against SARS-Cov-2.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: South Africa

Administrative Information

• NCT Number: NCT04561063
• Other Study ID Numbers: EZ-SS-025
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Professor Francois Venter, University of Witwatersrand, South Africa
• Original Responsible Party: Willem Daniel Francois Venter, University of Witwatersrand, South Africa, Divisional Director: Ezintsha
• Current Study Sponsor: University of Witwatersrand, South Africa
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Simiso Sokhela; Ezintsha

• PRS Account: University of Witwatersrand, South Africa
• Verification Date: June 2022