Four Different Experimental Drug Regimens to Standard of Care for the Treatment of Symptomatic Outpatients With COVID-19

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Artesunate-amodiaquine; Drug: Pyronaridine-artesunate; Drug: Favipiravir plus Nitazoxanide; Drug: Sofosbuvir/daclatasvir; Drug: Paracetamol

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
• Enrollment (Actual): 192
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Johannesburg, South Africa
    • Ezintsha, Wits Reproductive Health & HIV Institute University of the Witwatersrand

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Paracetamol (SOC); 500 mg oral tablets. Two tablets taken at 6-hour intervals as needed, in all treatment arms (in addition to any investigative treatment)	Drug: Paracetamol; SOC - 2 tablets (1000 mg) to be taken 6-hourly as needed; Other Names: Control treatment (SoC)
Experimental: Artesunate-amodiaquine (ASAQ); Fixed dose combination tablets containing 100 mg artesunate and 270 mg amodiaquine. Participants received two tablets once daily for 3 days	Drug: Artesunate-amodiaquine; SOC plus artesunate-amodiaquine (ASAQ) - 2 tablets (200/540 mg artesunate/amodiaquine) daily for 3 days; Other Names: ASAQ
Experimental: Pyronaridine-artesunate (PA); Fixed dose combination tablets containing 180 mg pyronaridine and 60 mg artesunate, given once daily for 3 days. Participants weighing 45 to <65 kg received 3 tablets per dose, those ≥65 kg received 4 tablets per dose	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; Other Names: PA
Experimental: Favipiravir plus nitazoxanide (FPV-NTZ); Free combination of favipiravir 200 mg and 400 mg tablets and nitazoxanide 500 mg tablets. Participants received favipiravir as a loading dose of 1600 mg twice daily for 1 day followed by 600 mg twice daily for 6 days, and nitazoxanide 1000 mg twice daily, with food, for 7 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; Other Names: FPV-NTZ
Experimental: SOC plus Sofosbuvir/daclatasvir; Fixed dose combination tablets containing 400 mg sofosbuvir and 60 mg daclatasvir. Participants received 1 tablet once daily for 7 days	Drug: Sofosbuvir/daclatasvir; SOC plus sofosbuvir/daclatasvir (SOF/DCV) 1 tablet (400 mg/60 mg sofosbuvir/daclatasvir) daily for 7 days; Other Names: SOF/DCV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of SARS-CoV-2 Clearance	Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of SARS-CoV-2 Clearance		Day 3, 10, 14, 21, 28
Time to Clearance of Nasal SARS-CoV-2		Day 0, 3, 7, 10, 14, 21, 28
Estimated Viral Load of SARS-CoV-2 Detected by Quantitative RT-PCR	baseline and day14, Day 14 value minus baseline value	Day 14
Poisson Regression for Proportion of Days With Fever After Randomization		Day 28
Percentage of Days With Respiratory Symptoms After Randomization	"Percentage of total study days in which participants experienced respiratory symptoms until day 28. Percentage calculated as (No. of days with respiratory symptoms) ÷ (No. of days observation) x 100"	from randomization to end of study (until day 28)
FLU-PRO Plus Questionnaire Scores and FLU-PRO Plus Global Additional Daily Diary Items Over the First 14 Days	baseline and day 14, Day 14 value minus baseline value The FLU-PRO(inFLUenza Patient-Reported Outcome) Plus questionnaire was completed daily during the first 14 days, at Day 21 and at Day 28. From these items six domain scores for the body areas Nose, Throat, Eyes, Chest/Respiratory, Gastrointestinal, and Body/Systemic could be computed ranging from 0 (symptom free) to 4 (very severe symptoms). Total Score Range for FLU-PRO Plus; Score range per item: 0 (no symptoms) to 4 (very severe symptoms). A higher score indicates worse symptoms.; Total score calculation: The mean (average) of all item scores is used. (Minimum score: 0, Maximum score: 4)	14 days
Serious Adverse Events		Day 28
Adverse Events		Day 28
Related Adverse Events		Day 28
LRTI		Day 28
Maximum Score on WHO Ordinal Scale for Clinical Improvement During Study Participation		Day 28
Cumulative Incidence of Hospitalization		Day 28
Days of Hospitalization	Total number of hospitalization days for hospitalized participants in each group	Day 28
Cumulative Incidence of Mortality, Measured at Day 28 or Later if Participant is Hospitalized at the Time of Day 28		at Day 28 or later if participant is hospitalized at the time of Day 28 for up to 2 months

Collaborators and Investigators

• Sponsor: Shin Poong Pharmaceutical Co. Ltd.
• Collaborators: Medicines for Malaria Venture
• Investigators: Principal Investigator: Francois Venter, PhD, Ezintsha, Wits Reproductive Health & HIV Institute University of the Witwatersrand

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2020
• Primary Completion (Actual): August 5, 2021
• Study Completion (Actual): August 23, 2021

Study Registration Dates

• First Submitted: August 26, 2020
• First Submitted That Met QC Criteria: August 28, 2020
• First Posted (Actual): August 31, 2020

Study Record Updates

• Last Update Posted (Actual): July 28, 2025
• Last Update Submitted That Met QC Criteria: July 8, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: COVID-19; Favipiravir; Chloroquine; Sofosbuvir; Daclatasvir; Zinc; Nitazoxanide; Artesunate; Amodiaquine; Pyramax; Pyronaridine
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; Anti-Infective Agents; Antineoplastic Agents; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Antiviral Agents; Analgesics, Non-Narcotic; Analgesics; Antipyretics; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Sofosbuvir; Artesunate; Pyronaridine tetraphosphate, artesunate drug combination; Acetaminophen; Nitazoxanide; Favipiravir; Pyronaridine; Amodiaquine
• Other Study ID Numbers: SP-PA-COV-202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No