COVID-19 Treatment in South Africa

• ClinicalTrials.gov Identifier: NCT04532931
• Recruitment Status: Completed
• First Posted: August 31, 2020
• Last Update Posted: September 20, 2021
• Sponsor: Shin Poong Pharmaceutical Co. Ltd.
• Collaborator: Medicines for Malaria Venture
• Information provided by (Responsible Party): Shin Poong Pharmaceutical Co. Ltd.

Tracking Information

• First Submitted Date: August 26, 2020
• First Posted Date: August 31, 2020
• Last Update Posted Date: September 20, 2021
• Actual Study Start Date: September 3, 2020
• Actual Primary Completion Date: August 5, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 28, 2020)

Incidence of SARS-CoV-2 clearance [ Time Frame: Day 7 ]

Defined as the proportion of participants with a negative nasal swab

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 28, 2020)

• Incidence of SARS-CoV-2 clearance [ Time Frame: Day 10, 14, 21, 28 ]
  Defined as the proportion of participants with a negative nasal swab
• Time to clearance of nasal SARS-CoV-2 [ Time Frame: Day 0, 3, 7, 10, 14, 21, 28 ]
  Defined as a negative swab
• Median quantity of SARS-CoV-2 [ Time Frame: Day 14 ]
  Detected from mid-nasal swabs by PCR
• Proportion of days with fever after randomization [ Time Frame: Day 28 ]
  Number of days with fever
• Proportion of days with respiratory symptoms after randomization [ Time Frame: Day 28 ]
  Number of days with respiratory symptoms
• FLU-PRO© Plus [ Time Frame: 14 days ]
  FLU-PRO© Plus questionnaire scores and FLU-PRO© Plus Global Additional Daily Diary Items *The Influenza Patient-Reported Outcome instrument (FLU-PRO© Plus)
• Serious adverse events [ Time Frame: Day 28 ]
  Serious adverse events
• Adverse events resulting in treatment discontinuation [ Time Frame: Day 28 ]
  Adverse events
• Adverse events considered related to the investigational products [ Time Frame: Day 28 ]
  Related adverse events
• LRTI [ Time Frame: Day 28 ]
  Resting SpO2<93% sustained for 2 readings 2 hours apart AND presence of subjective dyspnea or cough in participants with access to SpO2
• Maximum score on WHO Ordinal Scale for Clinical Improvement during study participation [ Time Frame: Day 28 ]
  score 0(Uninfected)~ score 8(Dead)
• Cumulative incidence of hospitalization [ Time Frame: Day 28 ]
  frequency of patients requiring time in hospital
• Days of hospitalization [ Time Frame: Day 28 ]
  length of hospital stay
• Cumulative incidence of mortality [ Time Frame: Day 28 or later if participant is hospitalized at the time of Day 28 ]
  incidence of death

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: COVID-19 Treatment in South Africa
• Official Title: Phase 2, Exploratory, Single Center, Randomized, Open Label, Adaptive Clinical Trial to Compare Safety and Efficacy of Four Different Experimental Drug Regimens to Standard of Care for the Treatment of Symptomatic Outpatients With COVID-19
• Brief Summary: This exploratory study is a randomized, single center, open label study of four different experimental treatment arms versus standard of care for the treatment of SARS-CoV-2 infection in symptomatic outpatients with mild disease at the time of enrollment.
• Detailed Description: This phase 2, exploratory study will be an adaptive, randomized, open label, trial for treatment of individuals in an outpatient settings with mild SARS-CoV-2 infection. The primary outcome is focused on the evaluation of efficacy of the proposed experimental drugs in reducing upper respiratory viral shedding, defined as viral clearance (i.e., negative swab) on Day 7. Key secondary outcomes focus on other measures of viral shedding, safety evaluation, progression to LRTI (defined by resting blood oxygen saturation level [SpO2] <93% sustained for two readings two hours apart and presence of subjective dyspnoea or cough), disease severity, clinical resolution rate, and cumulative incidence of hospitalization or mortality at Day 28.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: COVID-19

Intervention

• Other: Standard of care (Paracetamol)
  SOC - 2 tablets (1000 mg) to be taken 6-hourly as needed
• Drug: Artesunate-amodiaquine
  SOC plus artesunate-amodiaquine (ASAQ) - 2 tablets (200/540 mg artesunate/amodiaquine) daily for 3 days
• Drug: Pyronaridine-artesunate
  SOC plus pyronaridine-artesunate (PA) Weight 45 to <65 kg: 3 tablets (540/180 mg pyronaridine/artesunate) daily for 3 days Weight ≥65 kg: 4 tablets (720/240 mg pyronaridine/artesunate) daily for 3 days
• Drug: Favipiravir plus Nitazoxanide
  SOC plus favipiravir plus nitazoxanide (FPV-NTZ) Favipiravir: 1600 mg 12-hourly for 1 day then 600 mg 12-hourly for 6 days Nitazoxanide: 2 tablets (1000 mg) 12-hourly for 7 days
• Drug: Sofosbuvir/daclatasvir

  SOC plus sofosbuvir/daclatasvir (SOF/DCV)

  1 tablet (400 mg/60 mg sofosbuvir/daclatasvir) daily for 7 days

Study Arms

• Placebo Comparator: Arm A
  Paracetamol (SOC)
  Intervention: Other: Standard of care (Paracetamol)
• Experimental: Arm B
  SOC plus Artesunate-Amodiaquine
  Intervention: Drug: Artesunate-amodiaquine
• Experimental: Arm C
  SOC plus Pyronaridine-Artesunate
  Intervention: Drug: Pyronaridine-artesunate
• Experimental: Arm D
  SOC plus Favipiravir plus Nitazoxanide
  Intervention: Drug: Favipiravir plus Nitazoxanide
• Experimental: Arm E
  SOC plus Sofosbuvir/daclatasvir
  Intervention: Drug: Sofosbuvir/daclatasvir

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 16, 2021): 192
• Original Estimated Enrollment (submitted: August 28, 2020): 250
• Actual Study Completion Date: August 23, 2021
• Actual Primary Completion Date: August 5, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age from 18 to 65 years of age, inclusive, at the time of signing the informed consent.
2. Willing and able to provide informed consent.
3. Women of reproductive potential must be using a highly effective method of contraception for at least 28 days prior to enrolment and must be able and willing to continue its use throughout the duration of the study.
4. Men must agree to use condoms when engaging in heterosexual sex during the study and for the period up to 91 days after the last dose of study medication. Men who are not randomized to a treatment arm including favipiravir (or another arm identified as having teratogenic potential through semen) will no longer need to adhere to this after randomization.
5. Laboratory confirmed SARS-CoV-2 infection, and any of the following self-reported symptoms within 72 hours prior to randomization: fever or chills, cough, myalgia, sore throat, shortness of breath, or new onset of anosmia or ageusia.
6. Body weight ≥45 kg.
7. 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. Known hypersensitivity or specific contraindications to the use of any of the active drugs in the treatment arms, or similar compounds.

3. Signs of respiratory distress prior to randomization, including:

   • respiratory rate >24 breaths/min
   • SpO2 <95% in room air.
4. Resting pulse rate ≥120 beats/min.
5. High likelihood of hospitalization in the opinion of the attending clinician.
6. QTcF >470 msec for females, or >450 msec for males, at screening.
7. Serum potassium <3.5 mmol/L at screening.
8. History of clinically significant cardiovascular disease (including arrhythmias, QT-interval prolongation, torsades de pointes (TdP), history of coronary artery disease with graft or stent procedures/surgery, cardiac failure [class 2 or higher using the New York Heart Association functional classification]).
9. Known chronic kidney disease (Stage IV or receiving dialysis).
10. Known cirrhosis (Child-Pugh Class B or greater).
11. Known macular degeneration, or other known retinal diseases, or 4-aminoquinolone-induced visual impairment.
12. Currently receiving, or recently received (within 60 days prior to randomization) treatment with any of the drugs in the treatment arms.
13. Currently receiving, or recently received (within 30 days prior to randomization) treatment with any antimalarial drugs.
14. Currently on treatment with drugs with known arrhythmogenic potential, or those known to induce significant QT-interval prolongation or TdP, as detailed in Appendix 6.
15. Currently on treatment for tuberculosis (or on treatment with rifampicin for any other indication), or on treatment with a protease inhibitor-based antiretroviral regimen, or efavirenz, or carbamazepine.
16. Inability/unlikely to be in the study area for the duration of the 28 day follow-up period.
17. 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.
18. 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.
19. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: South Africa

Administrative Information

• NCT Number: NCT04532931
• Other Study ID Numbers: SP-PA-COV-202
• 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

• Plan to Share IPD: No

• Current Responsible Party: Shin Poong Pharmaceutical Co. Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: Shin Poong Pharmaceutical Co. Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Medicines for Malaria Venture
• Investigators: Not Provided
• PRS Account: Shin Poong Pharmaceutical Co. Ltd.
• Verification Date: September 2021