COVID-19 Treatment in South Africa

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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COVID-19

Intervention / Treatment
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* Other: Standard of care (Paracetamol)
* Drug: Artesunate-amodiaquine
* Drug: Pyronaridine-artesunate
* Drug: Favipiravir plus Nitazoxanide
* Drug: Sofosbuvir/daclatasvir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age from 18 to 65 years of age, inclusive, at the time of signing the informed consent. Willing and able to provide informed consent. 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. 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. 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. Body weight ≥45 kg. Access to reliable video conference, telephone, direct/text messaging, or other device permitting real-time, reliable information transfer. Exclusion Criteria: Pregnant or lactating women. Known hypersensitivity or specific contraindications to the use of any of the active drugs in the treatment arms, or similar compounds. Signs of respiratory distress prior to randomization, including: respiratory rate >24 breaths/min SpO2 <95% in room air. Resting pulse rate ≥120 beats/min. High likelihood of hospitalization in the opinion of the attending clinician. QTcF >470 msec for females, or >450 msec for males, at screening. Serum potassium <3.5 mmol/L at screening. 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]). Known chronic kidney disease (Stage IV or receiving dialysis). Known cirrhosis (Child-Pugh Class B or greater). Known macular degeneration, or other known retinal diseases, or 4-aminoquinolone-induced visual impairment. Currently receiving, or recently received (within 60 days prior to randomization) treatment with any of the drugs in the treatment arms. Currently receiving, or recently received (within 30 days prior to randomization) treatment with any antimalarial drugs. 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. 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. Inability/unlikely to be in the study area for the duration of the 28 day follow-up period. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm A<br>Paracetamol (SOC) | Other: Standard of care (Paracetamol)<br>* SOC - 2 tablets (1000 mg) to be taken 6-hourly as needed<br>|
| Experimental: Arm B<br>SOC plus Artesunate-Amodiaquine | Drug: Artesunate-amodiaquine<br>* SOC plus artesunate-amodiaquine (ASAQ) - 2 tablets (200/540 mg artesunate/amodiaquine) daily for 3 days<br>|
| Experimental: Arm C<br>SOC plus Pyronaridine-Artesunate | Drug: Pyronaridine-artesunate<br>* 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<br>|
| Experimental: Arm D<br>SOC plus Favipiravir plus Nitazoxanide | Drug: Favipiravir plus Nitazoxanide<br>* 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<br>|
| Experimental: Arm E<br>SOC plus Sofosbuvir/daclatasvir | Drug: Sofosbuvir/daclatasvir<br>* SOC plus sofosbuvir/daclatasvir (SOF/DCV) 1 tablet (400 mg/60 mg sofosbuvir/daclatasvir) daily for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of SARS-CoV-2 clearance | Defined as the proportion of participants with a negative nasal swab | Day 7 | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Pyramax, Pyronaridine, Artesunate, Chloroquine, Zinc, Amodiaquine, Favipiravir, Nitazoxanide, Sofosbuvir, Daclatasvir