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
Phase: PHASE2
Conditions: COVID-19
Sponsor: Shin Poong Pharmaceutical Co. Ltd.

  
 
 
 
 
 
 
SP-PA-COV-202 
 
 
A phase 2, exploratory, single center, randomized, open label, adaptive clinical trial to 
compare the safety and efficacy of four different experimental drug regimens to standard 
of care for the treatment of symptomatic outpatients with COVID-19 
 
 
Short Title: 
COVID-19 Treatment South Africa 
Phase: 
2 
Protocol Version and Approval Date: 
Version 4, 17 Nov 2020 
Sponsor: 
Shin Poong Pharm. Co., Ltd. 
161 Yoksam-ro, Gangnam-gu 
Seoul, 06246 
Republic of Korea 
Funder: 
Medicines for Malaria Venture 
ICC – Block G, 3rd Floor 
20, Route de Pré-Bois 
PO Box 1826 
1215 Geneva 15 
Switzerland 
Principal Investigator: 
Professor Francois Venter PhD, FCP, DTM&H, Dip HIV 
Divisional Director: Ezintsha, Wits Reproductive Health 
& HIV Institute 
University of the Witwatersrand 
5th Floor, Building D 
Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg 
 
 
 
CONFIDENTIAL 
Property of Shin Poong Pharm. Co., Ltd. 
May not be used, divulged, published, or otherwise disclosed without consent 

20 Nov 2020
Stephan Duparc
20 Nov 2020

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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE ............................................................................................................... 2 
SPONSOR / FUNDER SIGNATORY APPROVAL PAGE ..................................................................................... 3 
ABBREVIATIONS AND TERMS ..................................................................................................................... 6 
SYNOPSIS 
 ....................................................................................................................................... 8 
1. 
SCHEDULE OF ACTIVITIES ................................................................................................................... 15 
2. 
INTRODUCTION ................................................................................................................................. 18 
2.1 
Background ........................................................................................................................................... 19 
2.2 
Study Rationale ..................................................................................................................................... 19 
2.2.1 
COVID-19 and antiviral approaches ............................................................................................. 19 
2.2.2 
Drug selection .............................................................................................................................. 20 
2.2.3 
Dose selection ............................................................................................................................. 22 
2.2.4 
Study design ................................................................................................................................ 23 
2.2.5 
Pharmacokinetic-pharmacodynamic assessments ...................................................................... 23 
2.3 
Benefit/Risk Assessment ....................................................................................................................... 23 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................................................. 24 
4. 
STUDY DESIGN ................................................................................................................................... 25 
4.1 
Overall Design ....................................................................................................................................... 25 
4.2 
Participant and Study Completion ........................................................................................................ 26 
5. 
STUDY POPULATION .......................................................................................................................... 26 
5.1 
Inclusion Criteria ................................................................................................................................... 27 
5.2 
Exclusion Criteria ................................................................................................................................... 27 
5.3 
Co-enrollment Guidelines ..................................................................................................................... 28 
6. 
TREATMENTS ..................................................................................................................................... 28 
6.1 
Treatments Administered ..................................................................................................................... 28 
6.2 
Risks to the Participants ........................................................................................................................ 29 
6.2.1 
Management of participants to limit risks of SARS-CoV-2 transmission ..................................... 30 
6.3 
Dose Modification and Toxicity Management ...................................................................................... 31 
6.4 
Method of Treatment Assignment ........................................................................................................ 32 
6.5 
Blinding ................................................................................................................................................. 32 
6.6 
Preparation / Handling / Storage / Accountability ................................................................................ 32 
6.7 
Treatment Compliance .......................................................................................................................... 32 
6.8 
Concomitant Therapy ............................................................................................................................ 32 
6.8.1 
Prohibited medications ............................................................................................................... 32 
6.8.2 
Precautionary medications .......................................................................................................... 33 
6.9 
Treatment After the End of the Study .................................................................................................. 34 
7. 
DISCONTINUATION/WITHDRAWAL CRITERIA ..................................................................................... 34 
7.1 
Discontinuation of Study Treatment ..................................................................................................... 34 
7.2 
Withdrawal from the Study................................................................................................................... 34 
7.3 
Lost to Follow-up ................................................................................................................................... 35 
8. 
STUDY ENCOUNTERS ......................................................................................................................... 35 
8.1 
Screening Evaluation: Day 0 (-1 day window) ....................................................................................... 35 
8.2 
Enrollment/Randomization/Start of Treatment: Day 1 ........................................................................ 36 
8.3 
Treatment Continuation and Follow-Up: Day 2 to Day 14 (±2)............................................................. 37 
8.4 
Late Follow-Up: Day 21 (±2) .................................................................................................................. 39 
8.5 
End-of-Study: Day 28 ............................................................................................................................ 39 
9. 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................................... 40 
9.1 
Efficacy Assessments ............................................................................................................................. 40 
9.1.1 
Mid-nasal swab and saliva specimen .......................................................................................... 40 
9.1.2 
Participant surveys ...................................................................................................................... 41 
9.1.3 
WHO Ordinal Scale for Clinical Improvement ............................................................................. 41 
9.2 
Adverse Events ...................................................................................................................................... 41 
9.2.1 
Definition ..................................................................................................................................... 42 
9.2.2 
Serious adverse events ................................................................................................................ 42 
9.2.3 
Treatment-related AEs and SAEs ................................................................................................. 43 

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9.3 
Treatment of Overdose ......................................................................................................................... 43 
9.4 
Pregnancy .............................................................................................................................................. 43 
9.5 
Other Safety Assessments ..................................................................................................................... 43 
9.6 
Serological and Other Assessments ...................................................................................................... 44 
9.7 
PK Assessments ..................................................................................................................................... 44 
9.8 
Biohazard Containment ........................................................................................................................ 45 
10. DATA MANAGEMENT ........................................................................................................................ 45 
11. STATISTICAL CONSIDERATIONS .......................................................................................................... 45 
11.1 Sample Size Determination ................................................................................................................... 45 
11.2 Populations for Analyses ....................................................................................................................... 46 
11.3 Statistical Analyses ................................................................................................................................ 46 
11.3.1 
Efficacy analyses .......................................................................................................................... 47 
11.3.2 
Secondary endpoints ................................................................................................................... 47 
11.3.3 
Exploratory endpoints ................................................................................................................. 48 
11.3.4 
Combined study analysis ............................................................................................................. 48 
12. STUDY MONITORING ......................................................................................................................... 48 
12.1 Safety Review Team .............................................................................................................................. 48 
12.2 Independent Monitor ........................................................................................................................... 48 
12.3 Data Monitoring Committee ................................................................................................................. 49 
12.4 Scientific Advisory Committee .............................................................................................................. 49 
13. ETHICAL CONSIDERATIONS ................................................................................................................ 49 
13.1 Regulatory and Ethical Considerations ................................................................................................. 49 
13.2 Informed Consent Process .................................................................................................................... 50 
13.3 Study Records........................................................................................................................................ 50 
13.4 Confidentiality ....................................................................................................................................... 50 
13.5 Blood Volume ........................................................................................................................................ 51 
14. REFERENCES ...................................................................................................................................... 52 
APPENDICES 
 ....................................................................................................................................... 56 
APPENDIX 1: 
STUDY GOVERNANCE ...................................................................................................... 56 
APPENDIX 2: 
CONTACT DETAILS ........................................................................................................... 57 
APPENDIX 3:  
THE INFLUENZA PATIENT-REPORTED OUTCOME INSTRUMENT (FLU-PRO© PLUS) .............. 60 
APPENDIX 4: 
DAILY SURVEY ................................................................................................................. 62 
APPENDIX 5: 
WHO ORDINAL SCALE FOR CLINICAL IMPROVEMENT ....................................................... 65 
APPENDIX 6: 
PROHIBITED CONCOMITANT MEDICATIONS ..................................................................... 66 
 
 
 

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ABBREVIATIONS AND TERMS 
Term 
Definition 
ACE2 
Angiotensin-converting enzyme 2 
ACT 
Artemisinin-based combination therapy 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AQ 
Amodiaquine 
ASAQ 
Artesunate-amodiaquine 
AST 
Aspartate aminotransferase 
COVID-19 
Coronavirus disease 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DEAQ 
Desethylamodiaquine 
DMC 
Data Monitoring Committee 
EC50 
Half-maximal effective concentration 
eCRFs 
Electronic case report forms 
Eligible 
Qualified for enrollment into the study based upon inclusion/exclusion criteria 
FLU-PRO 
Influenza patient-reported outcome 
FPV-NTZ 
Favipiravir plus nitazoxanide 
GCP 
Good Clinical Practice 
IATA 
International Air Transport Association 
ICF 
Informed consent form 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LRTI 
Lower respiratory tract infection 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
Mpro 
Main protease 
NSAID 
Non-steroidal anti-inflammatory drug 
PA 
Pyronaridine-artesunate 
Participant(s) 
Term used throughout the protocol to denote the enrolled individual(s) 
PBPK 
Physiologically based pharmacokinetics 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic(s) 
PPE 
Personal protection equipment 
PY 
Pyronaridine 
QTcF 
QT-interval corrected for heart rate in accordance with Fridericia’s formula 
PKPD 
Pharmacokinetic-pharmacodynamic 
RCT 
Randomized controlled trial 
RdRp 
RNA-dependent RNA-polymerase 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 

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SAHPRA 
South African Health Products Regulatory Authority 
SARS-CoV 
Severe acute respiratory syndrome coronavirus 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SmPC 
Summary of product characteristics 
SoA 
Schedule of activities 
SOC 
Standard of care 
SOF/DCV 
Sofosbuvir/daclatasvir 
SpO2 
Oxygen saturation 
TdP 
Torsades de pointes 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 
 
 

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SYNOPSIS 
Title 
A phase 2, exploratory, single center, randomized, open label, adaptive clinical 
trial to compare the safety and efficacy of four different experimental drug 
regimens to standard of care for the treatment of symptomatic outpatients with 
COVID-19. 
Short Title 
COVID-19 Treatment South Africa 
Rationale 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes 
mild illness confined to the upper respiratory tract in approximately 80% of 
people but can cause severe lower respiratory tract infection (LRTI) in 20%, 
particularly among those in high-risk groups, defined by advanced age (>60 years) 
and presence of comorbidities (e.g., cardiopulmonary disease, hypertension, 
diabetes mellitus, obesity, renal disease). Progression to LRTI appears to 
frequently result in hospitalization for supplemental oxygen therapy and may 
lead to a need for ventilator respiratory support and ultimately death. Given the 
rapid spread of the SARS-CoV-2 pandemic, interventions that avert adverse 
patient outcomes and reduce the strain on the medical system are urgently 
needed. In addition, prolonged viral shedding has been noted after infection, 
especially soon after infection; therapeutic strategies that can effectively reduce 
viral shedding, and potentially onward transmission, have the potential to shift 
the trajectory of the pandemic. 
 
As of the beginning of May 2020, no therapeutic agents had been approved for 
the treatment of COVID-19, although many scientists and researchers have 
proposed a number of potentially suitable existing drugs based on in vitro, pre-
clinical, or limited clinical studies. These agents have potential benefits but also 
have inherent risks and limitations (e.g., adverse reactions and scalability of 
supply). There is an urgent need for controlled and adequately powered clinical 
studies in relevant patient populations to guide policy makers, regulators and 
other clinical trialists on prioritized drugs, including a path toward future 
evaluations as data become available. This study intends to rapidly provide data 
to inform early decision-making and/or support combined analysis with other 
concurrently run studies. 
 
Our understanding of the viral pathogenesis of SARS-CoV-2 remains limited. 
However, it appears that the virus cell entry depends on the binding of the viral 
spike (S) proteins to cellular receptors, and on S protein priming by host cell 
proteases. SARS-CoV-2, like SARS-CoV, uses the same receptor angiotensin 
converting enzyme 2 (ACE2) on pulmonary epithelial cells for entry and the 
transmembrane serine protease 2 for S protein priming [1]. The receptor binding 
domain of lineage B betacoronaviruses is a single, continuous domain that 
contains all of the structural information necessary to interact with the host 
receptor. Fusion is mediated at the cell membrane, delivering the viral 
nucleocapsid inside the cell for subsequent replication. A recent retrospective 
analysis of 85 patients with laboratory-confirmed COVID-19 also indicated that 
SARS-CoV-2 infects human kidney tubules and induces acute tubular damage in 
some patients [2], and 2–11% of patients exhibit liver comorbidities [3]. COVID-
19 has also been associated with multiple direct and indirect cardiovascular 
complications including acute myocardial injury, myocarditis, arrhythmias, and 
venous thromboembolism [4,5]. Therefore, therapeutic options that provide 
antiviral concentrations of drug(s) within the systemic circulation as well as other 
affected organs are likely to be required. 
 
Medications to treat and/or prevent SARS-CoV-2 need to inhibit aspects of the 
viral life cycle, ultimately blocking replication. Already-approved and available 

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medications are ideal for immediate evaluation for SARS-CoV-2 infection 
treatment and prevention. Clinical studies are already ongoing for SARS-CoV-2 
using 
various 
repurposed 
antiviral 
medicines 
(https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-
research-on-novel-coronavirus-2019-ncov). 
 
Drugs were selected for this study on the basis of an analysis of the human 
pharmacokinetics of all agents reported to have anti-SARS-CoV-2 activity in vitro. 
Specifically, the human maximum plasma concentration (Cmax) and predicted 
(calculated) maximum lung concentration after administration of the licensed 
doses were used to assess whether concentrations would exceed those required 
to inhibit at least 50% of SARS-CoV-2 replication in vitro (EC50) for at least some 
of the dosing interval. The full analysis has been published [6] and was 
supplemented by in-house data for 4-aminoquinolines available at MMV [7]. 
 
All study drugs, with the exception of pyronaridine, were predicted to provide 
concentrations with at least some antiviral activity in plasma, with favipiravir and 
nitazoxanide providing the greatest plasma ratios over their reported activity (see 
figure beneath). 
 
 
 
Similarly, based on the calculated lung concentrations, all study drugs were also 
predicted to reach concentrations with some activity in lung, but predicted lung 
exposures for amodiaquine and pyronaridine were estimated to be profoundly 
higher than the reported anti-SARS-CoV-2 EC50 (see figure beneath). For 
amodiaquine, desethylamodiaquine and pyronaridine, this is supported by PBPK 
simulations which predict a high distribution of the compounds into the lungs. 
 
 
 
These data alone support the rationale for assessing these agents in combination 
for COVID-19 therapy. 
 
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 

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(defined by resting blood oxygen saturation level [SpO2] <93% sustained for two 
readings two hours apart and presence of subjective dyspnea or cough), disease 
severity, clinical resolution rate, and cumulative incidence of hospitalization or 
mortality at Day 28. 
 
Assessment of an initial virological impact will inform further evaluation in a 
subsequent, separate, confirmatory, phase 3 trial to evaluate the efficacy of 
promising experimental drugs in terms of clinical outcomes. 
Design 
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 enrolment.  
Population 
Women and men from 18 to 65 years of age, inclusive, with self-reported 
symptoms of COVID-19 for no more than 72 hours prior to screening AND who 
test positive for SARS-CoV-2 at screening or during the 2 days prior to screening, 
will be enrolled. The eligibility criteria have been set to identify participants with 
mild COVID-19 disease in accordance with national guidelines [8]. 
 
The following eligibility criteria will be used to select study participants. 
 
Inclusion criteria: 
1. Age from 18 to 65 years of age, inclusive, at the time of signing the 
informed consent form. 
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 with onset no more than 72 hours prior to screening 
informed consent, and still present at randomization: fever or chills, cough, 
myalgia, sore throat, headache, conjunctivitis, shortness of breath, nausea, 
diarrhea, new onset of anosmia or ageusia, or other symptoms recognized 
in local and international guidelines as typical of mild COVID-19. 
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. Duration of self-reported symptoms of COVID-19 for more than 96 hours or 
four calendar days (whichever is greater) prior to randomisation. 
4. Signs of respiratory distress prior to randomization, including: 
o 
respiratory rate >24 breaths/min 
o 
SpO2 <95% in room air. 
5. Resting pulse rate ≥120 beats/min. 
6. High likelihood of hospitalization in the opinion of the attending clinician. 
7. QTcF >470 msec for females, or >450 msec for males, at screening. 
8. Serum potassium < 3.5 mmol/L at screening. 

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9. 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]). 
10. Known chronic kidney disease (Stage IV or receiving dialysis). 
11. Known cirrhosis (Child-Pugh Class B or greater). 
12. Known macular degeneration, or other known retinal diseases, or 4-
aminoquinolone-induced visual impairment. 
13. Currently receiving, or recently received (within 60 days prior to 
randomization) treatment with any of the drugs in the experimental 
treatment arms (Arms B to E). 
14. Currently receiving, or recently received (within 30 days prior to 
randomization) treatment with any antimalarial drugs. 
15. 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. 
16. 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. 
17. Inability/unlikely to be in the study area for the duration of the 28 day 
follow-up period. 
18. 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. 
19. 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. 
20. 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. 
 
Volunteers may be re-screened if they are found not to have COVID-19 at the 
time of the initial screening, but develop a further, and separate acute illness 
suggestive of COVID-19 at a later stage again. 
 
Participants will be counseled about the preliminary in vitro data on the activity 
of the planned treatment arms against SARS-CoV-2 and equipoise regarding 
efficacy in humans, given that there are only limited data from an uncontrolled 
study at this time. 
Interventions 
The following treatment arms are planned:  
• Arm A: Standard of care (SOC) 
• Arm B: SOC plus artesunate-amodiaquine (ASAQ) 
• Arm C: SOC plus pyronaridine-artesunate (PA) 
• Arm D: SOC plus favipiravir plus nitazoxanide (FPV-NTZ) 
• Arm E: SOC plus sofosbuvir/daclatasvir (SOF/DCV) 
 
Based on the availability of the investigational drugs, a decision may be made to 
proceed with fewer than five arms initially, and to commence the remaining arms 
as soon as the relevant investigational products are available. 
 
Current standard of care (SOC) will serve as the control arm and will also be 
provided to all participants in accordance with local guidelines which are subject 

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to change. Any changes to recommended SOC will be discussed by the study 
scientific advisory committee to determine the impact on existing assessments 
and treatment arms. At the time of drafting this protocol, SOC comprises 
paracetamol 1 g 6-hourly taken orally as needed. Other optional symptomatic 
therapies (e.g., throat lozenges) may also be provided based on availability and 
need, and participants will be advised to rest. 
Objectives and 
Endpoints 
Primary Objective 
• To test the efficacy of each 
treatment regimen compared to 
SOC alone in reducing SARS-CoV-2 
viral shedding. 
Primary Endpoint 
• Incidence of SARS-CoV-2 clearance 
(defined as the proportion of 
participants with a negative SARS-
CoV-2 RT-PCR test) on Day 7. 
Secondary Objectives 
• To test the efficacy of each 
treatment regimen compared to 
SOC alone in reducing SARS-CoV-2 
viral shedding as determined by 
viral culture 
Secondary Endpoints 
• Incidence of SARS-CoV-2 clearance 
on Day 7 (defined as the 
proportion of participants with 
negative SARS-CoV-2 viral cultures 
on both Day 7 and Day 10 in the 
subset of participants for whom 
these assessments are performed 
and results are available) 
• To test the efficacy of each 
treatment regimen compared to 
SOC alone in reducing late SARS-
CoV-2 viral shedding 
• Incidence of SARS-CoV-2 clearance 
(defined as the proportion of 
participants with negative SARS-
CoV-2 RT-PCR tests) on Days 10, 
14, 21 and 28 
• To test the efficacy of each 
treatment compared to SOC alone 
in reducing the duration of SARS-
CoV-2 viral shedding 
• Time to clearance of SARS-CoV-2, 
defined as a negative SARS-CoV-2 
RT-PCR test (samples collected 
Days 0, 3, 7, 10, 14, 21 and 28) 
• To test whether each treatment 
regimen is associated with 
decreased viral shedding over 14 
days compared to SOC alone 
• Estimated viral load of SARS-CoV-2 
detected by quantitative RT-PCR 
• To test whether each treatment 
regimen decreases the resolution 
rate for symptomatic SARS-CoV-2 
infection/COVID-19 disease 
compared to SOC alone 
• Proportion of days with fever after 
randomization 
• Proportion of days with respiratory 
symptoms after randomization 
• FLU-PRO© Plus questionnaire 
scores and FLU-PRO© Plus Global 
Additional Daily Diary Items over 
the first 14 days 
• To test the safety of each 
treatment regimen compared to 
SOC alone for treatment of 
outpatients with SARS-CoV-2 
infection 
• Serious adverse events (including 
death and hospitalization) 
• Adverse events resulting in 
treatment discontinuation 
• Adverse events considered related 
to the investigational products 

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• To test the efficacy of each 
treatment regimen compared to 
SOC alone to prevent progression 
to LRTI 
• LRTI, defined by resting SpO2<93% 
sustained for 2 readings 2 hours 
apart AND presence of subjective 
dyspnea or cough 
• To test whether each treatment 
regimen has an effect on disease 
severity compared to SOC alone 
• Maximum score on WHO Ordinal 
Scale for Clinical Improvement 
during study participation 
• To test the efficacy of each 
treatment regimen compared to 
SOC alone in reducing 
hospitalization  
• Cumulative incidence of 
hospitalization at Day 28 
• To test whether each treatment 
regimen has an effect on the 
duration of hospitalization among 
persons who become hospitalized 
with COVID-19 disease, compared 
to SOC 
• Days of hospitalization 
• To test the efficacy of each 
treatment regimen compared to 
SOC alone in reducing mortality. 
• Cumulative incidence of mortality, 
measured at Day 28 or later if 
participant is hospitalized at the 
time of Day 28. 
Exploratory Objectives 
• To investigate drug exposure of 
the study drugs in patients with 
COVID-19 
Exploratory Endpoints 
• Plasma/whole blood Cmin 
concentrations on Day 3 (Arms B 
and C) and Day 7 (Arms B to E) 
• To explore the relationship 
between efficacy and plasma or 
whole blood concentrations of the 
study drugs for each treatment 
regimen 
• Viral clearance 
• Categorical secondary endpoints 
related to efficacy 
• Plasma/whole blood Cmin 
concentrations on Day 7 
• To explore the immune response 
in symptomatic patients infected 
with SARS-CoV-2 
• Seroconversion as assessed by 
means of a validated serological 
assay still to be determined 
 
• To explore the relationship 
between sample RT-PCR results, 
their cycle threshold values, and 
corresponding viral culture results 
for SARS-CoV-2. 
• SARS CoV-2 qualitative and 
quantitative RT-PCR results and 
cycle threshold values from all 
relevant time points, and viral 
culture results from screening, Day 
7 and Day 10 in the subset of 
participants for whom viral culture 
is performed. 
Sample Size 
Assuming that the percentage of participants with viral clearance by Day 7 is 20% 
in the control arm (Arm A), a sample size of 50 participants per arm will provide 
at least 80% power to detect an increase in viral clearance to 50% for a new 
treatment. This assumes a two-sided, 5% type 1 error rate and a loss to follow up 
rate of 20%. The assumptions for this calculation are supported by a published 
analysis of a trial of favipiravir (FPV) versus lopinavir/ritonavir (LPV/RTV), where 
the percentage with viral clearance by Day 7 was 65% for favipiravir versus 20% 
for LPV/RTV [9]. Issues of multiplicity have not been considered in this 
exploratory study. 

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The aim of this exploratory study is to demonstrate similar high proportions of 
viral clearance for new candidate treatments. Demonstration of these benefits in 
any study treatment arms would justify taking these forward into a subsequent, 
separate, confirmatory, phase 3 trial, while dropping those arms which fail to 
achieve an improved rate of viral clearance versus the control treatment. 
Duration 
Twenty-eight days of clinical follow-up per participant unless follow-up of an 
unresolved serious adverse event necessitates an extended follow-up period. 
Site 
Administrative Institution: 
Ezintsha, Wits Reproductive Health & HIV Institute (Wits RHI) 
University of the Witwatersrand 
5th Floor, Building D 
Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg 
 
Main Site: 
Building C 
Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg 
 
Satellite Site: 
Charlotte Maxeke Johannesburg Academic Hospital 
Area 585, Level 8, Jubilee Road 
Johannesburg, 2193 
South Africa 

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1. 
SCHEDULE OF ACTIVITIES 
Procedure 
Screen
-ing 
Enroll-
ment 
Treatment and Follow-Up Period 
(Including self-quarantine as required in accordance with local guidelinesa) 
Late Follow-Up 
EOS 
Day 
0 (-1)b 
Day  
1 
Day  
2 
Day  
3 (+1) 
Days  
4-6 
Day  
7 (±1) 
Days  
8-9 
Day 
10 (±1) 
Days 
11-13 
Day 
14 (±2) 
Days 
15-20 
Day 
21 (±2) 
Day  
28 (±2)c 
Screening informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of COVID-19 symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy and lactation status and urine 
pregnancy testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Mid-nasal swab and saliva specimene 
Xf 
 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
Xg 
Blood for serum potassium 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 48-hour “Flu Pack”h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteriai 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Main informed consent, optional storage consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Past and current medical conditions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications, including contraception 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, including weight and height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (temperature, pulse, RR, SpO2) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG, including assessment of QTcF intervalj 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
Blood collection for serologyl 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Optional blood collection for samples for storagem 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Participant collected daily vitals (temperature, 
pulse and respiratory rate)n 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Participant collected daily SpO2o 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Completion of daily surveyp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Completion of FLU-PRO© Plus questionnaireq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
WHO Ordinal Scale for Clinical Improvementr 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
Study therapy 
 
Xs 
Xs 
Xs 
Xs 
Xs 
 
 
 
 
 
 
 
PK sampling 
 
 
 
Xt 
 
Xu 
 
 
 
 
 
 
 
Contact with study clinician or staffv 
X 
X 
X 
X 
(Xw) 
X 
(Xw) 
X 
(Xw) 
X 
(Xw) 
X 
X 
Adverse event reviewx 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Return of unused IMP and empty containers 
 
 
 
 
 
 
 
 
 
 
 
 
Xy 

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EOS: end of study; PK: pharmacokinetics; SOC: standard of care; SpO2: oxygen saturation; RR: respiratory rate; WHO: World Health Organization. 
Note: Participants who stop study product should continue study participation off study product with continued evaluations as per the schedule of activities. The reason for study 
product discontinuation should be recorded. 
a Current local guidelines specify a quarantine duration for patients with mild COVID-19 of 10 days from onset of symptoms provided resolution of fever has occurred and other 
symptoms are improving [8]. Instructions to participants will be updated if the local guidelines are updated without amending the protocol. 
b Screening will be conducted at the study site. A window period of -1 day may apply as long as COVID-19 symptoms are not present for more than 96 hours or 4 calendar days 
(whichever is greater) prior to randomization. Study personnel will wear personal protective equipment during all interactions, and participants and study personnel will be 
instructed to adhere to local guidance for COVID-19-related safety measures. Screening (Day 0) and Day 1 evaluations may occur on the same calendar day depending on the 
availability of the RT-PCR test results. 
c For participants who are hospitalized at the time of the scheduled Day 28 visit, the last visit will be approximately 3 days after discharge. 
d Urine pregnancy test for women of reproductive potential only. 
e Or other specimen depending on best practice recommendations and the availability of a suitable, validated assay. 
f Participants that have tested positive for SARS-CoV-2 infection (RT-PCR) in the 2 days prior to screening and have laboratory confirmation of this require a mid-nasal swab and 
saliva specimen (or other specimen as identified) for RT-PCR quantification and viral culture of SARS-CoV-2 at screening only. 
g Participants will be visited by laboratory personnel or a study team member or community healthcare worker (CHW), or may report to the site if the quarantine period has been 
completed, to facilitate this. Laboratory personnel/study personnel/CHWs will wear personal protective equipment during all required interactions, and participants and 
laboratory personnel/study personnel/CHWs will be instructed to adhere to local guidance for COVID-19-related safety measures. Qualitative RT-PCR for SARS-CoV-2 will be 
performed at all time points. Quantitative RT-PCR will be performed at all time points up to and including Day 14. Viral culture will be performed at Day 7 and Day 10 only. 
h 48-Hour “flu pack” to be dispensed to all participants in accordance with local standard operating procedures and current national treatment guideline.  
i Eligibility criteria related to age, duration of COVID-19 symptoms, pregnancy status, qualitative RT-PCR and potassium results will be assessed on Day 0 or when the Day 0 results 
are available; all other eligibility criteria will be assessed on Day 1 after completion of the relevant assessments. 
j Using a validated method. 
k Participants who meet all eligibility criteria will be randomized to receive study treatment. Study treatment packs will be dispensed or delivered to participants, or collected by 
participants from the site. 
l Blood samples (5 mL at each time point) will be collected for serological testing in accordance with emerging, validated assays from randomized participants. 
m Blood samples (up to 20 mL at each time point) will be collected from randomized participants providing optional consent for this. Samples will be stored at -70 °C for a period of 
up to 2 years. The samples will be used for future testing in accordance with emerging disease-related data, and suitable, validated assays. 
n The Day 1 assessments will be performed by randomized participants under observation of the site personnel. Assessments will be recorded utilizing a mobile phone/tablet 
application, or other device, or diary, or during a telephonic or in person interaction (once the quarantine period has completed) with the site personnel. Assessments may be 
performed by study personnel if an in person visit is conducted after completion of the quarantine period. 
o The Day 1 assessment will be performed by randomized participants under observation of the site personnel. To be measured after at least 5 minutes resting in a sitting or supine 
position. Participants with an SpO2 <93% will repeat the assessment 2 hours later. If the repeat assessment is <93%, they will contact the site immediately to report this. All 
results will be recorded utilizing a mobile phone/tablet application, or other device, or diary, or during a telephonic or in person interaction (once the quarantine period has 
completed) with the site personnel. 
p To be recorded during a telephonic or in person (once the quarantine period has completed) interaction with the site personnel, or utilizing a mobile phone/tablet application, or 
other device, or diary. The daily survey will consist of the FLU-PRO© Plus Global Additional Daily Diary Items (related to general well-being, overall severity of symptoms, and 

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ability to perform usual daily activies) as well as other general daily diary questions related to study drug administration, recording of vital signs and SpO2 measurements, 
review of concomitant medications, and information related to possible adverse events. 
q The Influenza Patient-Reported Outcome instrument (FLU-PRO© Plus). To be recorded during a telephonic or in person (once the quarantine period has completed) interaction 
with the site personnel, or utilizing a mobile phone/tablet application, or other device, or diary. 
r To be performed by study team personnel. The Day 1 assessment should be performed prior to the first dose of IMP. 
s To be taken as prescribed, for up to 7 days depending on the treatment arm to which the participant is randomized. Includes SOC for all treatment arms. 
t A Day 3 PK sample will be drawn from participants in the ASAQ and PA arms in accordance with the timing in Section 9.7. 
u A Day 7 PK sample will be drawn from all participants in the experimental arms (Arms B to E) in accordance with the timing in Section 9.7. 
v To be performed utilizing a web-conference, telephone call or text/direct messaging, or in person if the quarantine period has been completed. 
w These evaluations will be as needed/requested by study participant. 
x Serious adverse events, adverse events resulting in treatment discontinuation, and all other AEs, including those judged by the site Investigator to be related to the administered 
treatment regimens. 
y Or anytime from Day 7 if an earlier contact visit takes place. 

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2. 
INTRODUCTION 
This is a randomized, single center, open label, adaptive, exploratory trial for the treatment of severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults with mild disease not requiring 
hospital admission. The trial will compare four different experimental treatment arms to SOC. 
Assessments will be conducted to assess the effect of each dosing regimen in decreasing viral shedding. 
Evaluations include SARS-CoV-2 viral shedding, progression to lower respiratory tract infection (LRTI), and 
safety and tolerability. A plasma or whole blood sample will be collected from each participant on Day 7 
in order to assess plasma concentrations at the primary endpoint, and on Day 3 from participants in the 
artesunate-amodiaquine and pyronaridine-artesunate arms. 
Enrolment to each of the planned, currently identified study arms (Arms A to E) will commence as soon 
as the relevant drugs are available after study initiation (i.e., different treatment arms may be opened up 
at different times depending on the availability of the IMPs). 
Up to 250 eligible adults (18 to 65 years of age) will be randomized in an equal allocation ratio to receive 
one of the following therapies: 
• 
Arm A: Standard of care (SOC) 
• 
Arm B: SOC plus artesunate-amodiaquine (ASAQ) 
• 
Arm C: SOC plus pyronaridine-artesunate (PA) 
• 
Arm D: SOC plus favipiravir plus nitazoxanide (FPV-NTZ) 
• 
Arm E: SOC plus sofosbuvir/daclatasvir (SOF/DCV). 
Current SOC will be provided to all participants in accordance with local guidelines which are subject to 
change. Any changes to recommended SOC will be discussed by the study Scientific Advisory Committee 
to determine the impact on existing assessments and treatment arms. At the time of drafting this protocol, 
SOC comprises paracetamol 1 g 6-hourly taken orally as needed. Other optional symptomatic therapies 
(e.g., throat lozenges) may also be provided based on availability and need, and participants will be 
advised to rest. 
During the study, participants will take the IMP associated with the treatment arm to which they are 
randomized, and will perform the following: 
• 
Complete daily vital signs assessments (temperature, pulse rate and respiratory rate). Participants will 
also measure SpO2 daily and evaluate themselves for symptoms and signs of LRTI. 
• 
Complete surveys that will include questions about general well-being, respiratory and systemic 
symptoms, adherence to the study medication dosing schedule, review of adverse events (AEs) and 
concomitant medications, and other issues which may emerge as important to track on a daily basis. 
Additional assessments (collection of mid-nasal swabs and saliva samples [or other specimen depending 
on best practice recommendations and the availability of suitable, validated assays] for qualitative and 
quantitative reverse transcription polymerase chain reaction [RT-PCR] and viral culture detection of SARS-
CoV-2, AE evaluation, PK sampling and clinical improvement assessment) will be performed by study team 
personnel or laboratory personnel. 

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2.1 
Background 
SARS-CoV-2 is a coronavirus novel to the human population and discovered in December 2019; it is 
currently the cause of a global pandemic [11,12,13]. The World Health Organization (WHO) named the 
novel coronavirus SARS-CoV-2 and the disease caused by the virus COVID-19. 
SARS-CoV-2 has spread rapidly across the world, with the first case confirmed in South Africa on 5 March 
2020. As of 30 June 2020, there were 151,209 confirmed cases in South Africa, with 2,657 deaths [14]. 
Despite scale up in screening and testing, accurate reporting is limited by availability of diagnostic testing. 
WHO declared the COVID-19 pandemic a Public Health Emergency of International Concern on 30 January 
2020 [15], and a pandemic on 11 March 2020 [16]. The United States declared a national emergency on 
13 March 2020 [17], and South Africa declared a national state of disaster on 15 March 2020 [18]. 
Severe pneumonitis and most deaths have occurred in the elderly or in persons with underlying 
pulmonary or cardiac comorbidities, hypertension or diabetes. In healthy adults, including pregnant 
women, infection with SARS-CoV-2 can be asymptomatic, or cause a febrile, self-limited respiratory 
infection in the majority of cases. The disease can be severe, however, in a small percentage of patients. 
Infection appears less symptomatic in children and younger adults [19]. Manifestations of COVID-19 in 
persons with comorbidities, such as HIV infection, tuberculosis or chronic malaria, are not well-
characterized. Nevertheless, the burden of this pandemic to the global health and economic systems is 
expected to be substantial. No acquired immunity to this novel viral infection appears to exist in the 
human population globally, and no effective treatment or preventative agent is licensed at this time. 
As with many infectious epidemics, household contacts, first responders, caregivers, and medical 
personnel attending persons with COVID-19 are at high risk of infection. The incubation time requires 14 
days of quarantine for exposed individuals not wearing personal protective equipment [20], and on 
3 March 2020, WHO declared a global shortage of personal protective equipment, leaving doctors, nurses, 
and other frontline workers dangerously ill-equipped to care for COVID-19 patients [21]. Extensive 
absences from the care network and health system will degrade the ability to care not only for those with 
COVID-19 but also for routine healthcare issues as well. At the height of local epidemic, the already 
stretched health care system is expected to become overburdened with patients with respiratory illness. 
To date, rigorous self-isolation and lockdown have been required to contain SARS-CoV-2, leading entire 
societies to abruptly stop normal life. Interventions are urgently needed to stop viral spread and to 
decrease the morbidity and mortality associated with the infection. The ability to stop viral replication to 
prevent transmission of the virus and to prevent LRTI, which is associated with need for hospitalization 
and possibly mechanical ventilatory support, will be of benefit to the individual, the hospital system, and 
the health of the public. 
2.2 
Study Rationale 
2.2.1 
COVID-19 and antiviral approaches 
SARS-CoV-2 is a novel betacoronavirus of zoonotic origin, similar to the coronaviruses severe acute 
respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-
CoV). Based on current evidence, case fatality rate for SARS-CoV-2 is about 3%, which is significantly lower 
than that of SARS-CoV (10%) and MERS-CoV (40%) [22]. However, SARS-CoV-2 has potentially higher 
transmissibility (R0: 1.4 to 5.5) than both SARS-CoV (R0: 2 to 5) and MERS-CoV (R0: <1). 
Our understanding of the viral pathogenesis of SARS-CoV-2 remains limited. However, it appears that the 
virus cell entry depends on the binding of the viral spike (S) proteins to cellular receptors, and on S protein 

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priming by host cell proteases. SARS-CoV-2, like SARS-CoV, uses the same receptor angiotensin converting 
enzyme 2 (ACE2) on pulmonary epithelial cells for entry and the transmembrane serine protease 2 for 
S protein priming [1]. The receptor binding domain of lineage B betacoronaviruses is a single, continuous 
domain that contains all of the structural information necessary to interact with the host receptor. Fusion 
is mediated at the cell membrane, delivering the viral nucleocapsid inside the cell for subsequent 
replication. A recent retrospective analysis of 85 patients with laboratory-confirmed COVID-19 also 
indicated that SARS-CoV-2 infects human kidney tubules and induces acute tubular damage in some 
patients [2], and 2–11% of patients exhibit liver comorbidities [3]. COVID-19 has also been associated with 
multiple direct and indirect cardiovascular complications including acute myocardial injury, myocarditis, 
arrhythmias, and venous thromboembolism [4,5]. Therefore, therapeutic options that provide antiviral 
concentrations of drug(s) within the systemic circulation as well as other affected organs are likely to be 
required. 
Medications to treat and/or prevent SARS-CoV-2 need to inhibit aspects of the viral life cycle, ultimately 
blocking replication. Already-approved and available medications are ideal for immediate evaluation for 
SARS-CoV-2 infection treatment and prevention. Clinical studies are already ongoing for SARS-CoV-2 using 
various repurposed antiviral medicines (https://www.who.int/emergencies/diseases/novel-coronavirus-
2019/global-research-on-novel-coronavirus-2019-ncov). 
2.2.2 
Drug selection 
Drugs were selected for this study on the basis of an analysis of the human pharmacokinetics of all agents 
reported to have anti-SARS-CoV-2 activity in vitro. Specifically, for all drugs considered with the exception 
of SOF/DCV, the human maximum plasma concentration (Cmax) and predicted maximum lung 
concentration after administration of the licensed doses were used to assess whether concentrations 
would exceed those required to inhibit at least 50% of SARS-CoV-2 replication in vitro (EC50). The full 
analysis has been published [6] and was supplemented by in-house data for 4-aminoquinolines available 
at MMV [7]. 
 
 
Figure 1:  Anti-SARS-CoV-2 activity in plasma (a) and lung (b) for various drug candidates 
 
These drugs, with the exception of pyronaridine, were predicted to provide concentrations with at least 
some antiviral activity in plasma, with favipiravir and nitazoxanide providing the greatest plasma ratios 
over their reported activity (Figure 1a). Similarly, based on the calculated lung concentrations, these drugs 
were also predicted to reach concentrations with some activity in lung, but predicted lung exposures for 
a) 
b) 

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amodiaquine and pyronaridine were estimated to be profoundly higher than the reported anti-SARS-CoV-
2 EC50 (Figure 1b)  
These data alone support the rationale for assessing these agents in combination for COVID-19 therapy. 
Additional rationale is as follows. 
2.2.2.1 
Artesunate-amodiaquine (Arm B) and pyronaridine-artesunate (Arm C) 
Amodiaquine (AQ), desethylamodiaquine (DEAQ, primary active metabolite of AQ), and pyronaridine (PY) 
are active against SARS-CoV-2 (Vero76 cell assay) in vitro with plasma/blood EC50 of 1.8 µM, <0.3 µM and 
0.7 µM, respectively [7]. Moreover, PBPK modelling of lung penetration indicates AQ, DEAQ and PY to be 
well-distributed to lungs, with a Cmax lung/plasma ratio of 13 for AQ and 40 for DEAQ, and Cmax lung/blood 
ratio of 44 for PY, supporting the selection of these compounds for this trial [7]. 
In contrast with AQ and PY, the available data on the activity of artesunate against SARS-CoV-2 are limited 
[23,24]. The inclusion of artesunate in treatment arms B and C is therefore largely driven by the availability 
of AQ and PY as existing fixed-dose combinations with artesunate (ASAQ and PA) with established safety, 
tolerability and efficacy in malaria. 
2.2.2.2 
Favipiravir and nitazoxanide (Arm D) 
Favipiravir has already demonstrated benefits as a therapeutic agent for COVID-19 in a randomized 
controlled trial [10]. 
Nitazoxanide, is a thiazolide antiparasitic medicine used for the treatment of cryptosporidiosis and 
giardiasis that cause diarrhea [25,26], and also has reported activity against anaerobic bacteria, protozoa 
and other viruses [27]. Importantly, rapid deacetylation of nitazoxanide in blood means that the major 
systemic species of the drug in vivo is tizoxanide, which has not yet been studied for anti-SARS-CoV-2 
activity. Notwithstanding, tizoxanide has been shown to exhibit similar in vitro inhibitory activity to 
nitazoxanide for rotaviruses [28], hepatitis B and C viruses [29,30], other coronaviruses, noroviruses [31] 
and influenza viruses [32,33]. As another respiratory virus, previous work on influenza may be useful to 
gain insight into the expected impact of nitazoxanide for SARS-CoV-2. Accordingly, the drug has been 
shown to selectively block the maturation of the influenza hemagglutinin glycoprotein at the post-
translational stage [33,34] and a previous phase 2b/3 trial demonstrated a reduction in symptoms and 
viral shedding at a dose of 600 mg twice daily compared to placebo in patients with uncomplicated 
influenza [35]. Other potential benefits of nitazoxanide in COVID-19 may derive from its impact upon the 
innate immune response that potentiates the production of type 1 interferons [33,36] and 
bronchodilation of the airways through inhibition of TMEM16A ion channels [37]. 
No significant adverse drug-drug interactions are expected when favipiravir and nitazoxanide are 
administered together (https://www.covid19-druginteractions.org/). 
2.2.2.3 
Sofosbuvir / daclatasvir (Arm E) 
The combination of sofosbuvir 400mg once daily and daclatasvir 60g once daily is normally used to treat 
hepatitis C and has an excellent safety profile. 
SARS-CoV-2 replication and transcription depends on a number of key enzymes, notably RNA-dependent 
RNA-polymerase (RdRp), Main Protease (Mpro) and Helicase. The structure of SARS-CoV-2 RdRp and Mpro 
have been analyzed and published in high resolution and are attractive targets against which to model 
antiviral drugs [38,39]. Some in silico [40,41] and in vitro [42,43] studies of sofosbuvir and daclatasvir have 

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predicted that these and other nucleoside/nucleotide analogues will bind strongly to the SARS-CoV-2 
RdRp enzyme and inhibit its function [40,43]. This is the same proposed mechanism of action of both 
remdesivir and favipiravir. 
One study predicts sofosbuvir and remdesivir both would have equal binding energy to SARS-CoV-2 RdRp 
of -7.5Kcal/mol. Another study predicts molecular docking score to SARS-CoV-2 RdRp of -4.41Kcal/mol 
and -5.16Kcal/mol, respectively with a binding energy of -34.1Kcal/mol and -36.3Kcal/mol, respectively 
[44]. 
However, in silico results are not always concurrent, as computer models use different formulas and make 
different assumptions, and in vitro analyses use different cell lines and have different laboratory 
conditions. One deep learning model suggested that daclatasvir would have a binding strength to SARS-
CoV-2 RdRp of 23.31Kd which is similar to remdesivir (20.17Kd) [45]. However, another modelling study 
comparing the binding strength of 88 antiviral drugs with SARS-CoV-2 Mpro, found daclatasvir to be one 
of the weakest binders to the enzyme (MolDock Score -45.44) [46]. 
Pharmacokinetics 
Whilst the IC50 of remdesivir is thought to be 0.85 +/- 0.41 μM [47] the IC50 of sofosbuvir and daclatasvir 
in SARS-Cov-2 has not yet been published. One study found that sofosbuvir failed to prevent COVID-19-
induced cellular death in vitro [48]. Sofosbuvir and daclatasvir are both licensed for use in hepatitis C virus 
(HCV) [48]. The IC50 of sofosbuvir across HCV genotypes is thought to range from 0.7 to 2.6 µM [49]. 
Knowledge of sofosbuvir pharmacokinetics in other viruses is crucial in guiding sufficient dosing regimens 
against SARS-CoV-2 and ensuring the success of repurposed antivirals. Many studies in silico, in vitro and 
in animals have shown sofosbuvir to have action against other members of the Flaviviridae and 
Togaviridae family (other positive-strand RNA viruses) such as yellow fever, Zika, dengue and Chikungunya 
(CHIKV) viruses [50,51,52,53]. Sofosbuvir inhibited yellow fever viral replication in vitro with an EC50 of 
around 5 μM [50]. In another study, sofosbuvir showed inhibition of three Zika virus strains in Huh-7 and 
Jar cells, with EC50 of 1 μM to 5 μM [51]. Furthermore, sofosbuvir possesses anti-dengue activity and 
demonstrated aggressive in vitro reduction of viral yield with an EC90 of 0.4 μM in HepG2 cells [52]. Ferreira 
et. al. [53] investigated the pharmacology of sofosbuvir on CHIKV-infected astrocytes and Huh-7 
hepatoma cells in vitro, demonstrating that sofosbuvir inhibits CHIKV replication (EC50 17 ± 5 μM and 2.7 
± 0.5 μM, respectively). Results from these studies highlight sofosbuvir’s broad potential antiviral activity. 
In the light of the mentioned evidence it is reasonable to believe that sofosbuvir could be effective in 
treating COVID-19. In Iran, there are currently eight registered randomized clinical trials looking at the 
effectiveness of sofosbuvir in combination with daclatasvir or ledipasvir for treatment against COVID-19, 
with a total sample size of 510. Results from these are expected from May 2020 onwards [54]. Six out of 
the eight trials are assessing the combination of sofosbuvir/daclatasvir. 
2.2.3 
Dose selection 
Assessment of human maximum plasma concentrations and modelling of predicted maximum lung 
concentrations of candidate drugs was done based on the doses for which these drugs are currently 
licensed (with respect to their known therapeutic indications). Therefore, the safety and tolerability are 
well understood at these doses and they are deemed appropriate for this study. 
The adult dose of nitazoxanide for diarrhea in immunocompetent patients with amebiasis, 
cryptosporidiosis, or giardiasis is 500 mg twice daily with food. However, for diarrhea in AIDS patients, 
1000 mg twice daily with food can be used for 14 days or until diarrhea resolves. This 1000 mg twice daily 

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dose has been selected for this study on the basis that modelling suggests a higher proportion of patients 
will achieve plasma and lung exposures above the EC90 target at this dose [55]. 
2.2.4 
Study design 
In the absence of approved drug therapies for the treatment of COVID-19, this phase 2, exploratory trial 
aims to efficiently evaluate and prioritize multiple candidate therapeutics selected for clinical evaluation 
based on their known safety in humans, available pre-clinical activity against SARS-CoV-2, 
pharmacokinetic properties, and potential ease of delivery to low-resource settings.  
The study offers an approach where an initial assessment of potential benefit can be made before 
enrolling a large number of participants in a confirmatory clinical trial with selected treatment(s). The 
overarching goal of the proposed study is to evaluate the effect of the proposed experimental drugs on 
viral shedding. Assessment of an initial virological impact will inform further evaluation in a subsequent, 
confirmatory, phase 3 trial to evaluate the efficacy of promising experimental drugs on clinical outcomes 
such as prevention of lower respiratory tract infection, duration of hospitalization, and mortality. 
2.2.5 
Pharmacokinetic-pharmacodynamic assessments 
PK assessments in initial trials are critical to garner essential information about the exposure-response 
relationship for COVID-19 treatment and prevention. Given ethical concerns regarding the exposure of 
study personnel to highly infectious patients, intense PK sampling is not possible in the context of this 
study. Minimum plasma (or whole blood in the case of pyronaridine) concentrations (Cmin) are well 
understood to be the best PK surrogate parameters for assessing PKPD effects in viral infections due to 
the speed at which viruses replicate in the presence of subtherapeutic drug concentrations. The sampling 
strategy in this study has therefore been developed to maximize the value of isolated samples. Minimum 
concentration (Cmin) on Day 7 will be assessed in all participants in the experimental arms to coincide with 
the primary endpoint, and on Day 3 in participants in the ASAQ and PA arms. 
2.3 
Benefit/Risk Assessment 
COVID-19 disease can be unpredictable in its severity. An 18.7% mortality rate has been observed among 
hospitalized cases in South Africa [56]. The elderly (>60 years of age) and those with medical comorbidities 
(e.g., cardiopulmonary disease, hypertension, diabetes mellitus and renal disease) are at highest risk of 
poor outcomes [11,12,13]. Transmission in younger persons, however, amplifies infection in communities, 
putting susceptible persons at risk. There is no proven drug for treatment of those with COVID-19 disease, 
although preliminary data for remdesivir is promising.  
All of the planned interventions have been demonstrated to be tolerable and safe at the proposed, 
clinically tested doses. Participants will also be provided with standard of care treatment in accordance 
with local, existing guidelines, which will also serve as a control arm. 
QT-interval prolongation is associated with the 4-aminoquinolone compounds. For this reason, patients 
at high risk of developing QT-interval prolongation (those with a history of arrhythmias or other significant 
cardiovascular disease, those with QT-interval prolongation at baseline, those with low serum potassium 
levels at baseline, and those on treatment with other drugs known to cause QT-interval prolongation) will 
be excluded at screening. Concomitant administration of other drugs known to cause significant QT-
interval prolongation is also prohibited during the study. 

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Thus, the potential benefit-to-risk ratio for testing the proposed interventions as treatment, is favorable 
in this population. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To test the efficacy of each treatment regimen 
compared to SOC alone in reducing SARS-CoV-2 
viral shedding. 
• Incidence of SARS-CoV-2 clearance (defined as the 
proportion of participants with a negative SARS-
CoV-2 RT-PCR test) on Day 7. 
Secondary 
• To test the efficacy of each treatment regimen 
compared to SOC alone in reducing SARS-CoV-2 
viral shedding determined by viral culture 
• Incidence of SARS-CoV-2 clearance on Day 7 
(defined as the proportion of participants with 
negative SARS-CoV-2 viral cultures on both Day 7 
and Day 10 in the subset of participants for whom 
these assessments are performed and results are 
available) 
• To test the efficacy of each treatment regimen 
compared to SOC alone in reducing late SARS-CoV-
2 viral shedding 
• Incidence of SARS-CoV-2 clearance (defined as the 
proportion of participants with negative SARS-CoV-
2 RT-PCR tests) on Days 10, 14, 21 and 28 
• To test the efficacy of each treatment compared to 
SOC alone in reducing the duration of SARS-CoV-2 
viral shedding 
• Time to clearance of SARS-CoV-2, defined as a 
negative SARS-CoV-2 RT-PCR test (samples 
collected Days 0, 3, 7, 10, 14, 21 and 28) 
• To test whether each treatment regimen is 
associated with decreased viral shedding over 14 
days compared to SOC alone 
• Estimated viral load of SARS-CoV-2 detected by 
quantitative RT-PCR 
• To test whether each treatment regimen decreases 
the resolution rate for symptomatic SARS-CoV-2 
infection/COVID-19 disease compared to SOC 
alone 
• Proportion of days with fever after randomization 
• Proportion of days with respiratory symptoms 
after randomization 
• FLU-PRO© Plus questionnaire scores and FLU-PRO© 
Plus Global Additional Daily Diary Items over the 
first 14 days 
• To test the safety of each treatment regimen 
compared to SOC alone for treatment of 
outpatients with SARS-CoV-2 infection 
• Serious adverse events (including death and 
hospitalization) 
• Adverse events resulting in treatment 
discontinuation 
• Adverse events considered related to the 
investigational products 
• To test the efficacy of each treatment regimen 
compared to SOC alone to prevent progression to 
LRTI 
• LRTI, defined by resting SpO2<93% sustained for 2 
readings 2 hours apart AND presence of subjective 
dyspnea or cough 
• To test whether each treatment regimen has an 
effect on disease severity compared to SOC alone 
• Maximum score on WHO Ordinal Scale for Clinical 
Improvement during study participation 
• To test the efficacy of each treatment regimen 
compared to SOC alone in reducing hospitalization 
• Cumulative incidence of hospitalization at Day 28 

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• To test whether each treatment regimen has an 
effect on the duration of hospitalization among 
persons who become hospitalized with COVID-19 
disease, compared to SOC 
• Days of hospitalization 
• To test the efficacy of each treatment regimen 
compared to SOC alone in reducing mortality. 
• Cumulative incidence of mortality, measured at 
Day 28 or later if participant is hospitalized at the 
time of Day 28. 
Exploratory 
• To investigate drug exposure of the study drugs in 
patients with COVID-19 
• Plasma/whole blood Cmin concentrations on Day 3 
(Arms B and C) and Day 7 (Arms B to E) 
• To explore the relationship between efficacy and 
plasma or whole blood concentrations of the study 
drugs for each treatment regimen 
• Viral clearance 
• Categorical secondary endpoints related to efficacy 
• Plasma/whole blood Cmin concentrations on Day 7 
• To explore the immune response in symptomatic 
patients infected with SARS-CoV-2 
• Seroconversion as assessed by means of a 
validated serological assay still to be determined 
• To explore the relationship between sample RT-
PCR results, their cycle threshold values, and 
corresponding viral culture results for SARS-CoV-2. 
• SARS CoV-2 qualitative and quantitative RT-PCR 
results and cycle threshold values from all relevant 
time points, and viral culture results from 
screening, Day 7 and Day 10 in the subset of 
participants for whom viral culture is performed. 
 
4. 
STUDY DESIGN 
4.1 
Overall Design 
The overarching goal of this study is to assess the efficacy of interventions to reduce virus shedding among 
adult outpatients with mild SARS-CoV-2 infection. Confirmation of the initial virological impact on the 
clinical progression of COVID-19 should be obtained in a subsequent, separate, phase 3 trial focused on 
prevention of LRTI, and reduction of hospitalization and mortality. 
This is a randomized, single center, open label, exploratory, adaptive trial. The trial will commence four 
experimental interventions (Arms B to E) to assess the efficacy as measured by a reduction in viral 
shedding compared to SOC (Arm A). Participants will be randomized to one of these treatment arms in a 
1:1:1:1:1 ratio. 
Initially, this study will enroll up to 250 eligible adults (18 to 65 years of age inclusive) who have RT-PCR-
confirmed SARS-CoV-2 infection and self-reported symptoms of COVID-19 (50 per arm). The sample size 
calculations and statistical power are detailed in Section 11.1). Eligible participants will be enrolled and 
randomized in an equal allocation ratio to study treatment arms. The recruitment rate will be assessed on 
a weekly basis starting at the end of the second week after the first eligible participant is recruited and 
randomized. The DMC may advise increasing the sample size target, should a higher dropout rate than 
expected be observed. This would be based on a blind review of the pooled, observed recruitment and 
dropout rates, and the final sample size target, if applicable. The interim monitoring plan (written by the 
study Statistician) will define the strategy for potential sample size re-assessment (based on the the 
observed overall dropout rate) in order to preserve the pre-specified power of 80%. If this study 
demonstrates high rates of viral clearance for new candidate treatments, demonstration of these benefits 

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would then justify taking selected treatments into a subsequent, separate, phase 3, confirmatory trial 
with a larger sample size, powered on a new endpoint of clinical recovery. 
Other unspecified additional treatment modalities may be incorporated into this protocol, based on 
emerging data. These will be added through protocol amendments, which will define additional sample 
size needs and any potential change to randomization (e.g., changing the randomization ratio, 
continuation/discontinuation of any of the existing arms, etc.). Details regarding sample size calculation, 
statistical power, and statistical methods are provided in Section 10. 
Participants will be counseled about the preliminary in vitro data on the activity of the experimental 
interventions against SARS-CoV-2, and equipoise regarding efficacy in humans, given that there are only 
limited data available at this time. This counselling will be serially updated as new, clear data become 
available. 
Blood samples will be drawn from participants for SARS-CoV-2 antibody testing using emerging, validated 
assays. Blood samples will also be collected from participants offering optional consent for storage and 
future testing defined by emerging disease-related data and hypotheses and suitable, validated assays. 
An amendment to this protocol will be drafted to describe the assessment of other outcomes based on 
emerging data in this rapidly developing field. 
An independent DMC will be convened for this study with expertise in COVID-19 or respiratory viruses, 
emerging epidemics, as well as biostatistics. The purpose of the DMC is to monitor the study for social 
harms, safety and efficacy. The DMC will also review the blinded sample size re-assessment plan and 
proposed sample size changes in a blinded manner if required. 
4.2 
Participant and Study Completion 
As an initial target, 250 participants will be randomly assigned to one of the five study treatment arms (at 
least 50 participants per treatment arm). This sample size target may increase based on blinded sample 
size re-assessment. 
A participant is considered to have completed the study if he/she has completed all phases of the study 
including the last scheduled procedure shown in the Schedule of Activities (SoA) in Section 1. 
The study will be considered complete when sufficient number of participants have completed the study 
to enable appropriate evaluation of the primary endpoint. 
5. 
STUDY POPULATION 
Women and men from 18 to 65 years of age, inclusive, with self-reported symptoms of COVID-19 for no 
more than 72 hours prior to screening informed consent and who test positive for SARS-CoV-2 at 
screening or during the two days prior to screening, will be enrolled. The eligibility criteria have been set 
to identify participants with mild COVID-19 disease in accordance with national guidelines [8]. 
Potential participants will be recruited from surrounding COVID-19 testing stations and from patients 
presenting to local healthcare facilities. Volunteers who are interested in participating in the trial may be 
consented for pre-screening to assess potential eligibility. Those eligible for screening, will be invited to 
participate in the informed consent process as described in Section 13.2. Written or electronic informed 
consent will be obtained prior to any screening procedures. 
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted. 

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The following eligibility criteria will be used to select study participants. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study if all of the following criteria apply: 
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 with 
onset no more than 72 hours prior to screening informed consent, and still present at 
randomization: fever or chills, cough, myalgia, sore throat, headache, conjunctivitis, shortness of 
breath, nausea, diarrhea, new onset of anosmia or ageusia, or other symptoms recognized in local 
and international guidelines as typical of mild COVID-19. 
6. Body weight ≥45 kg. 
7. Access to reliable video conference, telephone, direct/text messaging, or other device permitting 
real-time, reliable information transfer. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria are met: 
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. Duration of self-reported symptoms of COVID-19 for more than 96 hours or four calendar days 
(whichever is greater) prior to randomisation. 
4. Signs of respiratory distress prior to randomization, including: 
o 
respiratory rate >24 breaths/min 
o 
SpO2 <95% in room air. 
5. Resting pulse rate ≥120 beats/min. 
6. High likelihood of hospitalization in the opinion of the attending clinician. 
7. QTcF >470 msec for females, or >450 msec for males, at screening. 
8. Serum potassium <3.5 mmol/L at screening. 
9. 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]). 
10. Known chronic kidney disease (Stage IV or receiving dialysis). 
11. Known cirrhosis (Child-Pugh Class B or greater). 
12. Known macular degeneration, or other known retinal diseases, or 4-aminoquinolone-induced visual 
impairment. 

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13. Currently receiving, or recently received (within 60 days prior to randomization) treatment with any 
of the drugs in the experimental treatment arms (Arms B to E). 
14. Currently receiving, or recently received (within 30 days prior to randomization) treatment with any 
antimalarial drugs. 
15. 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. 
16. 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. 
17. Inability/unlikely to be in the study area for the duration of the 28 day follow-up period. 
18. 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. 
19. 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. 
20. 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. 
Volunteers may be re-screened if they are found not to have COVID-19 at the time of the initial screening, 
but develop a further, and separate acute illness suggestive of COVID-19 at a later stage again. 
5.3 
Co-enrollment Guidelines 
Participants may be co-enrolled in other research studies, provided that these are observational studies 
where no interventions are offered only. Any other exception requires approval of the Principal 
Investigator; if a participant clinically worsens, such as requiring hospitalization, such an exception will be 
automatically granted for participation in other offered treatment studies. The study team should be 
consulted for co-enrollment in studies that do not meet this guidance or if there are questions about 
eligibility for co-enrollment. For any co-enrolled study, the total volume of blood samples collected across 
the two studies should not exceed 480 mL over any eight week period. 
6. 
TREATMENTS 
Study treatment is defined as any investigational treatment or marketed product to be administered to a 
study participant according to the study protocol. 
6.1 
Treatments Administered 
The following treatments are planned: 
Arm A: 
Study Treatment Name 
Paracetamol (SOC) 
Dosage Formulation 
Tablet 500 mg 
Route of Administration 
Oral 
Dosing Instructions 
2 tablets (1000 mg) to be taken 6-hourly as needed 

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Arm B: 
SOC as described in Arm A plus experimental treatment as follows: 
Study Treatment Name 
Artesunate-amodiaquine (ASAQ) 
Dosage Formulation 
100/270 mg artesunate/amodiaquine fixed dose combination, uncoated tablets 
Route of Administration 
Oral 
Dosing Instructions 
2 tablets (200/540 mg artesunate/amodiaquine) daily for 3 days 
Arm C: 
SOC as described in Arm A plus experimental treatment as follows: 
Study Treatment Name 
Pyronaridine-artesunate (PA) 
Dosage Formulation 
180/60 mg pyronaridine tetraphosphate/artesunate fixed dose combination, film-
coated tablets 
Route of Administration 
Oral 
Dosing Instructions 
For participants with body weight 45 to <65 kg: 
3 tablets (540/180 mg  
 
 
 
 
 
 
 
 
pyronaridine/artesunate) daily 
 
 
 
 
 
 
 
 
for 3 days 
For participants with body weight ≥65 kg 
 
4 tablets (720/240 mg  
 
 
 
 
 
 
 
 
pyronaridine/artesunate) daily 
 
 
 
 
 
 
 
 
for 3 days 
Arm D: 
SOC as described in Arm A plus experimental treatment as follows: 
Study Treatment Name 
Drug 1: Favipiravir 
Drug 2: Nitazoxanide 
Dosage Formulation 
200 mg and 400 mg film-coated tablets  
500 mg tablets 
Route of Administration 
Oral 
Oral 
Dosing Instructions 
1600 mg 12-hourly for 1 day,  
then 
600 mg 12-hourly for 6 days 
2 tablets (1000 mg) 12-hourly for 7 days; 
to be taken with food. 
Arm E: 
SOC as described in Arm A plus experimental treatment as follows: 
Study Treatment Name 
Sofosbuvir/daclatasvir 
Dosage Formulation 
400mg/60 mg sofosbuvir/daclatasvir fixed dose combination, film coated tablets 
Route of Administration 
Oral 
Dosing Instructions 
1 tablet (400 mg/60 mg sofosbuvir/daclatasvir) daily for 7 days 
6.2 
Risks to the Participants 
Administration of IMP in this study will be for a short duration (up to 7 days) at doses that are well-
described and have been shown to be well-tolerated in clinical studies. Risks to participants are therefore 
expected to be well-controlled.  

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Since both COVID-19 and many drugs are known to be associated with liver injury, all participants will be 
advised of the clinical signs and symptoms of hepatotoxicity and will be requested to report the 
emergence of any of these urgently. 
In evaluating individual risks to participants, the relevant Summaries of Product Characteristics (SmPCs) 
for each IMP should be reviewed. Documented risks related to different components of the treatment 
arms include, but are not limited to, the following. 
Artesunate-amodiaquine: 
Amodiaquine has been shown to prolong the QT-interval in some patients. 
Pyronaridine-artesunate: 
PA has been associated with a transient increase in transaminases in a small number of patients treated 
for acute malaria and in Caucasian, healthy volunteers. No associated clinical signs and symptoms of 
hepatotoxicity have been observed or reported. 
Favipiravir: 
Early embryonic deaths and teratogenicity have been observed in pre-clinical studies with favipiravir. 
Participants will be counselled with regard to this prior to study participation and will be required to agree 
to use of suitable contraception (Section 5.1). Women of reproductive potential will require a negative 
urine pregnancy test to be eligible for study participation. 
Nitazoxanide: 
No specific risks to participants are predicted at the proposed dose to be administered during this study. 
Sofosbuvir: 
Cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens 
are used in combination with amiodarone, which is an exclusion criterion for participation in this study. 
Daclatasvir: 
Cases of severe bradycardia and heart block have been observed when daclatasvir-containing regimens 
are used in combination with amiodarone, which is an exclusion criterion for participation in this study. 
Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycemia, 
after initiating treatment. 
6.2.1 
Management of participants to limit risks of SARS-CoV-2 transmission 
To limit the transmission of SARS-CoV-2, the following measures will be employed: 
• 
Participants will engage in visits and site personnel contact using telemedicine, telephone or 
text/direct messaging as far as is possible. 
• 
For any necessary physical interactions, study and laboratory personnel will be instructed to wear 
personal protection equipment (PPE) at all times, and participants and laboratory/study personnel 
will be instructed to adhere to national and regional guidance for COVID-19-related safety measures. 
• 
The organization of each study site will be in accordance with national and regional guidelines for 
limiting the spread of COVID-19, and will be such that contact between persons with potential SARS-
CoV-2 infection and other patients is restricted. 

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• 
To limit exposure in waiting rooms and pharmacies, daily vital signs will be self-monitored by 
participants and medications will be delivered to participants at homes where possible. 
• 
To limit community exposure to trial participants infected with SARS-CoV-2, participants will be 
required to self-quarantine in accordance with national and regional guidelines for the required 
duration and transported to study site with a study vehicle in line with national infection control 
guidelines. 
6.3 
Dose Modification and Toxicity Management 
If any study therapy dose is missed, it should be taken as soon as possible. If it is less than 4 hours before 
the next dose is scheduled, the missed dose should be skipped and documented as such in the participant 
daily survey. 
Modification for toxicities is discussed below. Only toxicities related to study medications provided 
through the study will be considered in this section. 
Grade 1 or 2 
Participants who develop Grade 1 or 2 toxicity (per Division of Acquired Immunodeficiency Syndrome 
[DAIDS] Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1, July 
2017 [https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf]) that is considered by 
the site Investigator to be related to the study medication, may continue study treatment at the discretion 
of the site Investigator with close follow up. If a participant chooses to discontinue study treatment, the 
site should notify the Safety Review Team within 7 days. These participants will remain on study, off study 
treatment, and have all evaluations performed. 
Grade 3 
• 
Participants who develop a Grade 3 toxicity thought by the site Investigator to be related to study 
drug should have study product withheld, and the site should consult with the Safety Review Team 
via the Medical Monitor. The participant should be re-evaluated every 2 days until the AE returns to 
Grade ≤2, at which time study drug may be reintroduced at the discretion of the site Investigator in 
consultation with the Safety Review Team. 
• 
Participants experiencing a Grade 3 toxicity requiring permanent discontinuation of study product 
should be followed up weekly until resolution of the toxicity. These participants will remain on study, 
off study treatment, and have all evaluations performed per the SoA. 
Grade 4 
• 
Participants who develop a Grade 4 toxicity will have study product permanently discontinued, and 
the site should notify the Principal Investigator and the Safety Review Team via the Medical Monitor 
within 72 hours. 
• 
Participants experiencing Grade 4 toxicity requiring permanent discontinuation of study product 
should be followed up weekly until resolution of the AE or return to baseline. These participants will 
remain on study, off study treatment, and have all evaluations performed per the SoA. 
Specific Management of Toxicities Related to Study Drugs 
All possible drug toxicities will be managed on a case-by-case basis. Grade 2 and above toxicities will be 
discussed with one of the study physicians in their role as a site Investigator. All Grade 3 and above 

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toxicities will be reported to the Principal Investigator and Medical Monitor. Case management and 
follow-up will, at a minimum, be in accordance with the above-mentioned guidelines. 
All AEs (whether or not considered drug-related) will be reported during the study, and all serious adverse 
events (SAEs) and suspected, unexpected, serious adverse reactions (SUSARs) will be reported in 
accordance with applicable regulations and requirements (Section 9.2.2). 
6.4 
Method of Treatment Assignment 
Participants will be randomized using a centralized, automated randomization system (IVRS/IWRS) to one 
of the five treatment arms (Arms A to E) in a 1:1:1:1:1 ratio. The randomization plan will be adaptive based 
on treatment arms available for participant allocation and will be overseen by the study Statistician. 
6.5 
Blinding 
No blinding will be performed to conceal treatment identification for the study. The study will be open-
label to participants and study personnel. 
6.6 
Preparation / Handling / Storage / Accountability 
Drugs should be stored at room temperature, as per package insert. Records must be maintained that 
document receipt, release for dosing, disposal, or return to the Sponsor. 
Details of all drug-related procedures surrounding shipping, receipt, storage, handling, preparation, 
dispensing and accountability will be documented in the Pharmacy Manual. 
6.7 
Treatment Compliance 
Study drug (and home monitoring kits) will either be dispensed to participants at the site or delivered to 
participants at their homes. In cases where study supplies are delivered, participants will be contacted to 
ensure that they received the box of study supplies and took their first dose of medication. All participants 
will be asked to complete a daily survey to gather information regarding treatment administration. 
Medication errors, including under-dosing, will be recorded in the survey. 
Consultation via tele-medicine, text/direct messaging, or telephone will be available to provide support 
to the participant to complete study procedures. 
6.8 
Concomitant Therapy 
Participants will be asked about concomitant medications at the screening/baseline evaluation visit. 
During the study, participants will be asked to complete a daily survey that includes information regarding 
any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that the participant receives during the study. At each contact, the Investigator should 
question the participant about any medication taken.  
6.8.1 
Prohibited medications 
Participants will be advised to consult the study clinician before commencing any new concomitant 
medications during the study. 

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The use of the following drugs is prohibited during the study (Appendix 6): 
• 
Drugs with known arrhythmogenic potential, or known to induce significant QT-interval prolongation 
or TdP (detailed in Appendix 6) 
• 
Protease inhibitor-based antiretroviral regimens, or efavirenz 
• 
Rifampicin 
• 
Carbamazepine. 
6.8.2 
Precautionary medications 
Use of medications classified as precautionary is not study prohibitory but will be discussed with the study 
clinician and the participant. The study clinician will review all previous and concomitant medications 
taken by study participants to evaluate possible drug-drug interactions and ensure that unacceptable risks 
do not result from these. The relevant SmPCs for the applicable study drugs and previous/concomitant 
medications will be used as a reference. 
Known interactions to be considered include, but are not limited to, the following: 
Artesunate-amodiaquine:  
Drugs known to prolong the QT interval should be used with caution. In the absence of clinical data, ASAQ 
is not recommended to be administered concomitantly with drugs known to inhibit CYP2A6 (e.g., 
methoxsalen, pilocarpine, tranylcypromine) and/or CYP2C8 (e.g., trimethoprim, ketoconazole, ritonavir, 
saquinavir, lopinavir, gemfibrozil, montelukast). 
Pyronaridine-artesunate: 
Caution is advised when co-administering PA with metoprolol given in cardiac failure. A possible dose 
adjustment of metoprolol may be required. Dihydroartemisinin administration may result in a slight 
decrease in CYP1A2 activity. Caution is therefore, advised when PA is administered concomitantly with 
medicinal products metabolized by this enzyme that have a narrow therapeutic index, such as 
theophylline. 
Favipiravir: 
Favipiravir should be used with caution when administered together with pyrazinamide, repaglinide, 
theophylline, and famciclovir. 
Nitazoxanide: 
Caution should be used when administering nitazoxanide concurrently with other highly plasma protein-
bound drugs with narrow therapeutic indices. 
Sofosbuvir: 
Medicinal products that are strong (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin and St 
John's wort) or moderate (e.g., modafinil, oxcarbazepine and rifapentine ) P-glycoprotein (P-gp) inducers 
in the intestine may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect. Co-
administration with such medicinal products is not recommended. The concomitant administration of 
protease inhibitors can result in increased plasma concentrations of sofosbuvir and is not recommended. 

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Daclatasvir: 
Strong inducers of CYP3A4 and P-gp (e.g., phenytoin, carbamazepine, oxcarbazepine, phenobarbital, 
rifampicin, rifabutin, rifapentine, systemic dexamethasone, and St John’s wort) may lead to lower 
exposure and loss of efficacy of daclatasvir. The concomitant administration of protease inhibitors can 
result in increased plasma concentrations of daclatasvir and is not recommended. 
Daclatasvir is an inhibitor of P-gp, organic anion transporting polypeptide (OATP) 1B1, OCT1 and breast 
cancer resistance protein (BCRP). Administration of daclatasvir may increase systemic exposure to 
medicinal products that are substrates of P-gp, OATP 1B1, OCT1 or BCRP, which could increase or prolong 
their therapeutic effect and adverse reactions. Caution should be used if the medicinal product has a 
narrow therapeutic range. 
6.9 
Treatment After the End of the Study 
No additional treatment will be provided at the end of the study. 
7. 
DISCONTINUATION/WITHDRAWAL CRITERIA 
7.1 
Discontinuation of Study Treatment 
Study treatment will be discontinued for the following reasons: 
• 
Hospitalization (at the discretion of the inpatient provider, hospitalized participants may continue to 
receive study treatment if maintained on the originally randomized treatment regimen) 
• 
Requirement for prohibited concomitant medications or other contraindication to study product 
• 
Occurrence of an AE requiring discontinuation of study product 
• 
Request by participant to terminate study treatment 
• 
Clinical reasons believed by the physician to be life-threatening or place the participant at undue risk, 
even if not addressed in Section 6.3. 
Participants who stop study product should continue study participation off study product with continued 
evaluations as per the SoA. The reason for study product discontinuation should be recorded. 
Hospitalized participants will be followed through hospitalization and the last visit will be within 3 days of 
discharge if this occurs after Day 28. 
7.2 
Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request or may be withdrawn 
at any time for the following reasons: 
o 
At the request of the primary care provider if he/she thinks the study is no longer in the best 
interest of the participant 
o 
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 
o 
At the discretion of the Institutional Review Board/Ethics Committee or government agencies as 
part of their duties, Investigator, or industry supporter. 

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• 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such withdrawal of consent. 
• 
If a participant withdraws from the study, he/she may request destruction of any samples taken and 
not tested. This must be documented by the Investigator in the site study records. 
• 
If possible and agreed to by the participant, assessments detailed for the EOS visit on Day 28 (SoA) 
should be completed at the time of study discontinuation if a participant withdraws from the study. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to comply with required study procedures: 
• 
The site must attempt to contact the participant as soon as possible and counsel the participant on 
the importance of maintaining the assigned procedure schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the Investigator or designee must make every effort 
to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a visit to 
the participant’s place of residence by a member of the study team). These contact attempts should 
be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
8. 
STUDY ENCOUNTERS 
The current COVID-19 pandemic has placed a significant burden on the healthcare system. Contact 
between study participants and study personnel will be limited as far as is possible. Study personnel will 
be instructed to wear PPE during all interactions, and participant and study personnel will be instructed 
to adhere to national and regional guidance for COVID-19-related safety measures. 
For this study, data collection will be self-conducted where possible to minimize the impact of non-ill 
participants within the healthcare system and the risks of SARS-CoV-2 transmission. If the participant is 
assessed as eligible during the screening visit, contact between study participants and study personnel 
will occur via tele-medicine, text/direct messaging or telephone as far as is possible. 
Participants will be instructed to seek clinical care should they manifest any signs or symptoms of LRTI 
requiring medical intervention and notify their physician about trial participation. Any participant who’s 
clinical condition deteriorates during the study, will be hospitalised if required in accordance with the 
national guidelines for clinical management of patients with COVID-19 [8]. 
8.1 
Screening Evaluation: Day 0 (-1 day window) 
Presenting patients will be assessed for study eligibility through screening conducted at the site. 
Day 0 evaluations and procedures are as follows: 
• 
Screening informed consent for all eligibility assessments to be conducted on Day 0 (may be taken 
electronically) 
• 
Collection of demographic information 

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• 
Collection of information on the duration of COVID-19 symptoms 
• 
Pregnancy and lactation status, and a urine pregnancy test for women of reproductive potential 
(women will be considered to be of reproductive potential unless they have been surgically sterilized 
[by hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy or tubal ligation], or 
are post-menopausal [age-appropriate spontaneous amenorrhea for ≥12 months in the absence of 
oral contractive use for >12 months) 
• 
Collection of a mid-nasal swab and saliva sample (or other sample depending on best practice 
recommendations) for RT-PCR detection and quantification of SARS-CoV-2 and viral culture 
• 
Collection of blood sample for serum potassium concentration 
• 
Dispensing of a 48-hour “flu pack” for symptomatic management of COVID-19 symptoms 
(paracetamol 1 g 6-hourly to be taken orally as needed and other optional symptomatic therapies 
[e.g., throat lozenges] based on availability and need). 
Once available, participants will be contacted to inform them of their test results, and those with a positive 
SARS-CoV-2 RT-PCR test result, a serum potassium ≥ 3.5 mmol/L, and otherwise eligible in terms of 
assessments conducted on Day 0, will be invited to return for an enrollment visit on Day 1. 
8.2 
Enrollment/Randomization/Start of Treatment: Day 1 
Patients who present for the Day 1 visit will be invited to take part in the study (pending additional 
confirmation of eligibility), and to provide informed consent for this and the remaining eligibility 
assessments in accordance with the main study informed consent form (ICF) prior to any further 
procedures being conducted. The main study informed consent may be taken electronically. 
Eligibility will continue to be assessed at the Enrollment Visit on Day 1 in accordance with the following 
assessments: 
• 
Collection of past and current medical conditions 
• 
Collection of concomitant medication information, including contraception usage 
• 
Weight and height assessment 
• 
Abbreviated, symptom-directed, physical examination to include as least the following: 
o 
General examination 
o 
Heart and lungs 
• 
Vital signs (temperature, pulse, and respiratory rate) 
• 
SpO2 assessment 
• 
ECG, including assessment of QTcF-interval 
• 
Check of inclusion and exclusion criteria. 
Thereafter, the following will be conducted for patients meeting all eligibility criteria: 
• 
Participants will be randomized to one of the treatment arms in accordance with the study 
randomization schedule. 
• 
Each participant will receive a monitoring kit containing a thermometer and an SpO2 monitor. 

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• 
Participants will be instructed as to how to: 
o 
Measure daily vital signs (temperature, pulse and respiratory rate) 
o 
Measure daily SpO2 (and repeat SpO2 if the scheduled reading is <93%) 
o 
Complete the FLU-PRO© Plus questionnaire 
o 
Complete the daily survey (comprising the FLU-PRO© Plus Global Additional Daily Diary Items and 
other general daily diary questions). 
• 
A mobile data collection application will be installed on the participant’s mobile device (for 
participants that have their own, compatible, mobile device). 
• 
A blood sample will be collected for: 
o 
SARS-CoV-2 serology 
o 
Storage for future testing (only in participants providing optional consent for this). 
• 
Participants will perform the following assessments under observation of the site personnel (and 
record data using telemedicine or relay this to the site personnel for transcribing): 
o 
Vital signs (temperature, pulse and respiratory rate) 
o 
SpO2 measurement 
o 
The FLU-PRO© Plus questionnaire 
o 
The daily survey (comprising the FLU-PRO© Plus Global Additional Daily Diary Items and other 
general daily diary questions). 
• 
A study team member will complete the WHO Ordinal Scale for Clinical Improvement survey. 
• 
IMP for the full course of treatment will be dispensed to participants (either at the study site, or via 
courier or study personnel delivery). Participants will be instructed to commence their study 
treatment on the same day. 
Prior to completion of the visit, the following will be done: 
• 
Participants will be instructed to seek clinical care at any stage throughout the study should they 
develop signs or symptoms of respiratory distress. If needed, direct hospital referral may be facilitated 
by the site personnel in accordance with the national guidelines for clinical management of patients 
with COVID-19 [8]. 
• 
Participants will be advised that, at any stage during the study, they may request additional contact, 
including via telemedicine or telephone, with the study clinician or staff to discuss developing 
symptoms or AEs, or if they need to clarify study procedures. 
Screening, enrollment and randomization procedures (Day 0 and Day 1) can take place on the same 
calendar day in the unlikely event that the RT-PCR result is available rapidly. 
8.3 
Treatment Continuation and Follow-Up: Day 2 to Day 14 (±2) 
A study team member will be available via telemedicine, text/direct messaging, or telephone to provide 
support for completion of study procedures.  

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On Relevant Study Treatment Days: 
• 
Participants will take their study treatment until completion as per the dosing schedule described in 
Section 6.1. 
On Days 2 to 14 (±2) inclusive: 
• 
Participants will complete the following assessments (and record data using telemedicine, 
telephonically or via text/direct messaging): 
o 
Vital signs (temperature, pulse and respiratory rate) 
o 
SpO2 measurement 
o 
The FLU-PRO© Plus questionnaire 
o 
The daily survey (comprising the FLU-PRO© Plus Global Additional Daily Diary Items and other 
general daily diary questions). 
On Day 2: 
• 
Contact with the study clinician or staff will be conducted via telemedicine or telephone. Participants 
will be clinically assessed for signs and symptoms of respiratory distress and will have in person 
assessment of AEs. 
On Days 3 (±1), 7 (±1), 10 (±1), and 14 (±2): 
• 
Contact with the study clinician or staff will be conducted via telemedicine or telephone, or may be in 
person if the relevant quarantine period has been completed in accordance with local guidelines. 
Participants will be clinically assessed for signs and symptoms of respiratory distress and will have in 
person assessment of AEs. 
• 
Participants will be visited by a study team member, laboratory personnel or a CHW, or may report to 
the site if the relevant quarantine period has been completed, for collection of a mid-nasal swab and 
saliva sample (or other sample depending on best practice recommendations) for RT-PCR detection 
and quantification of SARS-CoV-2 (Days 3, 7, 10 and 14) and viral culture (Days 7 and 10). 
On Days 3 and 7: 
• 
Participants in the ASAQ and PA treatment arms will have a plasma and/or whole blood PK sample 
collected on Day 3 prior to the last dose of IMP and approximately 24 hours after the previous IMP 
dose. 
• 
Participants in the experimental treatment arms (Arms B to E) will have a single plasma and/or whole 
blood PK sample collected on Day 7 prior to their last dose of IMP (if relevant) and relative to the 
previous dose of IMP administered as follows: 
o 
24 (±2) hours post-dose for SOF/DCV 
o 
96 (±2) hours post dose for ASAQ, PA 
o 
12 (±1) hours post dose for FPV-NTZ. 
On Days 7 (±1) and 14 (±2): 
• 
A study team member will complete the WHO Ordinal Scale for Clinical Improvement survey. 

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8.4 
Late Follow-Up: Day 21 (±2) 
The following will be performed: 
• 
Contact with the study clinician or staff will be conducted via telemedicine or telephone. Participants 
will be clinically assessed for signs and symptoms of respiratory distress and will have in person 
assessment of AEs. As needed, additional contact with the study clinician or staff will be conducted at 
the request of the participant (e.g., if developing concerning symptoms or an AE) or if needed to clarify 
study procedures or follow-up symptoms. 
• 
Participants will complete the following assessments (and record data using telemedicine, 
telephonically or via text messaging): 
o 
Vital signs (temperature, pulse and respiratory rate) 
o 
The FLU-PRO© Plus questionnaire 
o 
The daily survey (comprising the FLU-PRO© Plus Global Additional Daily Diary Items and other 
general daily diary questions). 
• 
Participants will report to the site, or be visited by a study team member, laboratory personnel or a 
CHW for collection of a mid-nasal swab and saliva sample (or other sample depending on best practice 
recommendations) for RT-PCR detection of SARS-CoV-2. 
• 
A study team member will complete the WHO Ordinal Scale for Clinical Improvement survey. 
A study team member will be available via telemedicine, text/direct messaging, or telephone to provide 
support for completion of study procedures. 
8.5 
End-of-Study: Day 28 
The following will be performed: 
• 
Contact with the study clinician or staff will be conducted via telemedicine or telephone or in person. 
Participants will be clinically assessed for signs and symptoms of respiratory distress and will have in 
person assessment of AEs. 
• 
Participants will complete the following assessments (and record data using telemedicine, 
telephonically, via text messaging or in person): 
o 
Vital signs (temperature, pulse and respiratory rate); these may be assessed by the site personnel 
if an in person visit is conducted 
o 
The FLU-PRO© Plus questionnaire 
o 
The daily survey (comprising the FLU-PRO© Plus Global Additional Daily Diary Items and other 
general daily diary questions). 
• 
Participants will report to the site or be visited by a study team member or CHW for the following: 
o 
Collection of a mid-nasal swab and saliva sample (or other sample depending on best practice 
recommendations) for RT-PCR detection of SARS-CoV-2 
o 
Collection of blood for SARS-CoV-2 serology 
o 
Collection of blood for storage for future testing (only in participants providing optional consent 
for this). 

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• 
A study team member will complete the WHO Ordinal Scale for Clinical Improvement survey. 
• 
Unused IMP, empty IMP containers and SpO2 monitors will either be returned to the site by the 
participant, or collected by courier or a member of the study team (if not already returned at an earlier 
time point). 
For participants who are hospitalized on Day 28, the Day 28 procedures will be performed within 3 days 
after discharge from the hospital. 
A study team member will be available via telemedicine, text/direct messaging, or telephone to provide 
support for completion of study procedures. 
Clinical outcomes will be confirmed through appropriate health records, if possible. 
Participant reimbursement may be performed in accordance with local standards. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA. 
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor (via the Medical Monitor or 
chairperson of the SRT) immediately upon occurrence or awareness to determine if the participant 
should continue or discontinue study treatment. 
• 
All screening and enrollment evaluations (demographic data, duration of COVID-19 symptoms, 
pregnancy and lactation status, mid-nasal swab and saliva sample, confirmation of positive SARS-CoV-
2 result, serum potassium, medical history, previous and concomitant medication usage, weight and 
height, abbreviated, symptom-directed physical examination, study personnal assessment of vital 
signs and SpO2, and ECG and QTcF evaluation) must be completed prior to randomization, and 
reviewed to confirm that potential participants meet all eligibility criteria. The Investigator will 
maintain a screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management and obtained before 
signing of the informed consent form (ICF) may be utilized for screening or baseline purposes provided 
that the procedures meet the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
• 
Blood samples will only be collected for SARS-CoV-2 serological assays (in accordance with emerging, 
suitable and validated assays), for a screening serum potassium assessment, for a maximum of two 
PK samples, and for storage for future testing (in participants offering optional consent for this only). 
The maximum amount of blood collected from any participant over the duration of the study is 
expected to be 71 mL but should not exceed 480 mL even if additional safety assessments are 
required. 
9.1 
Efficacy Assessments 
9.1.1 
Mid-nasal swab and saliva specimen 
Mid-nasal swabs and saliva specimens (or other site depending on best practice recommendations and 
the availability of suitable, validated assays) will be collected from all potentially eligible volunteers at 

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screening on Day 0 for viral detection (and quantification and viral culture if the participant is 
subsequently enrolled). Additional mid-nasal swabs and saliva samples will be collected on Days 3, 7, 10, 
14, 21 and 28. Participants will report to the site or be visited by a study team member, laboratory 
personnel or a CHW to facilitate swab collection. 
Swab kits may contain either viral transport media, 0.9% saline, or phosphate-buffered saline, which have 
been shown to be equivalent for storage of SARS-CoV-2 samples based on validated assays [57]. Saliva 
samples will be collected in suitable sterile containers. Previous testing has demonstrated that respiratory 
viral ribonucleic acid (RNA) is stable in room temperature for up to 1 week. 
Swabs will be subjected to RNA amplification and tested for SARS-CoV-2. Qualitative assays will be 
performed at all time points. Additional quantitative assays for viral load will be performed at screening 
and on Days 3, 7, 10 and 14. Viral culture will be performed on samples from enrolled participants 
collected at screening, Day 7 and Day 10. 
Further details regarding mid-nasal swab and saliva sample (or other biological samples depending on the 
availability of suitable, validated assays) collection, handling and processing, as well as the testing 
laboratory, assays and methods to be used, will be documented in the Laboratory Manual. 
9.1.2 
Participant surveys 
Participants will be asked to complete the the following surveys during the study: 
• 
The FLU-PRO© Plus questionnaire [58,59,60] to assess the symptomatic extent of their illness 
(Appendix 3) 
• 
The daily survey (Appendix 4) that includes: 
o 
The FLU-PRO© Plus Global Additional Daily Diary Items (related to general well-being, overall 
severity of symptoms, and ability to perform usual daily activies) 
o 
General daily diary items (related to study drug administration, recording of vital signs and SpO2 
measurements, review of concomitant medications, and information related to possible adverse 
events). 
These surveys will be completed electronically using telemedicine, or telephonically during an interview 
with a study team member. 
9.1.3 
WHO Ordinal Scale for Clinical Improvement 
A study team member will complete the WHO Ordinal Scale for Clinical Improvement (Appendix 5) after 
contact (via telemedicine or telephone) on relevant study days. 
9.2 
Adverse Events 
Participants will be asked to complete the daily survey (Appendix 4) that includes information on any 
symptoms that they are experiencing. In addition, AE review by a staff member (via telemedicine, 
telephone, or text/direct messaging) will be performed. 
All AEs must be recorded on the electronic case report forms (eCRFs). 
AEs will be recorded from the time of informed consent until the end-of-study visit (Day 28). SAEs 
occurring after the reporting period that the Investigator becomes aware of must be reported as 
described in Section 9.2.2 if the Investigator considers the event to be related to the IMP administered. 

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9.2.1 
Definition 
An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant 
administered a pharmaceutical product, which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory 
findings), symptom, or disease temporally associated with the use of an investigational product, whether 
or not considered related to the product. 
AEs may include the onset of new illnesses and the exacerbation of pre-existing medical conditions. An 
AE can include an undesirable medical condition occurring at any time, including baseline or washout 
periods, even if no study treatment has been administered. 
9.2.2 
Serious adverse events 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening (immediate risk of death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (with the exception of 
hospitalization due to progressive COVID-19 disease) 
• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require intervention to prevent one of the 
other outcomes listed in the definition above. 
All AEs that are recorded must have their severity graded. To grade AEs, sites should refer to the DAIDS 
AE Grading Table, corrected Version 2.1, July 2017, which can be found on the DAIDS Regulatory Support 
Center website at https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. 
The Investigator will report all SAEs to the Sponsor through the Qualified Person for Pharmacovigilance 
(QPPV) within 24 hours of the site personnel becoming aware of the event. The report should be in writing 
by email or fax with the Medical Monitor on copy and documented on a standard SAE Reporting Form. In 
addition to this, fatal or life-threatening SAEs must be reported immediately to the QPPV, irrespective of 
the extent of available AE information.  
Qualified Person Responsible for Pharmacovigilance: 
Dr Robert Miller 
Email:   
 
 
 
 
 
safety @artemidapharma.com 
Tel/Fax: 
 
 
 
 
 
+44 203 291 3032 
For all SAEs, the Investigator is obligated to pursue and provide information in accordance with the 
timeframes for reporting specified above. In addition, an Investigator may be requested to obtain specific 
additional follow-up information in an expedited fashion. This information may be more detailed than 
that captured on the AE case report form. In general, this will include a description of the AE in sufficient 
detail to allow for a complete medical assessment of the case and independent determination of possible 
causality. Information on other possible causes of the event, such as concomitant medications and 
illnesses must be provided. In the case of a participant death, a summary of autopsy findings (if available) 
must be submitted as soon as possible to the QPPV. 

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The Local Ethics Committee and Regulatory Authority will be notified of all SAEs in accordance with their 
requirements. 
Reporting and follow-up procedures are described in the Safety Management Plan. 
9.2.3 
Treatment-related AEs and SAEs 
A treatment-related AE is defined as any new AE that begins, or any preexisting condition that worsens in 
severity, after at least 1 dose of study treatment has been administered and is considered by the 
Investigator to be related to the study medication. 
All AEs and SAEs should have attribution recorded as treatment- or not treatment-related, in the judgment 
of the site Investigator. 
9.3 
Treatment of Overdose 
Overdose of any of the study interventions (including SOC) should be managed according to the product 
labeling information. Study drug overdose, including misuse or abuse of the product and medication 
errors, should be reported in the eCRF in the clinician notes. 
9.4 
Pregnancy 
All women of reproductive potential will be offered effective contraception for the duration of the study. 
While all efforts will be undertaken to prevent pregnancy among participants, or pregnancy in partners of 
male participants in Arm D, should a participant or partner of a participant from any study arm become 
pregnant during the study, she will be counselled (or invited for counselling if she is a participant’s partner) 
regarding the risks associated with known or potentially teratogenic study drugs, and undergo an 
informed consent process to confirm her continued participation in the study (if appropriate), and 
willingness to be followed through the pregnancy.  
Pregnancies occurring in participants enrolled in this study, or their partners, must be reported and 
followed to outcome. Reporting should be performed using a standard Pregnancy Reporting Form. The 
reporting procedure follows that described for SAEs in Section 9.2.2. 
Pregnancy alone is not regarded as an AE unless there is a possibility that the study drug may have 
interfered with the effectiveness of a contraceptive medication. Elective abortions without complications 
should not be considered AEs unless they were therapeutic abortions. Hospitalization for normal delivery 
of a healthy newborn should not be considered an SAE. Pregnancy is not considered an SAE unless there 
is an associated outcome that meets one or more of the SAE criteria. Spontaneous abortions should 
always be reported as SAEs. 
Any pregnancy outcome considered to be an SAE should be reported within the timelines and using the 
procedures described in Section 9.2.2. 
9.5 
Other Safety Assessments 
ECG, including assessment of QTcF-interval (using a suitable, validated method) and serum potassium will 
be performed at screening to exclude patients at high risk of QT-interval prolongation from participation 
in the study. 
During the study, safety will be assessed through vital signs monitoring, SpO2 monitoring, and participant 
surveys, as shown in the SoA. 

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Participants will be asked to complete the FLU-PRO© Plus questionnaire and the daily survey (which 
includes the FLU-PRO© Plus Global Additional Daily Diary Items). Events qualifying as AEs will be recorded 
on the eCRF and reported as described in Section 9.2. 
9.6 
Serological and Other Assessments 
Blood samples will be collected from all randomized participants at baseline on Day 1, and on Day 28 for 
serological testing in accordance with emerging, suitable and validated assays. 
An additional blood sample will also be collected from participants offering optional consent for storage 
of samples at -70 °C for a period of up to 2 years. These samples will be used for future testing in 
accordance with emerging, disease-related data and suitable, validated assays. 
Additional details regarding sample collection, processing and storage will be described in the Laboratory 
Manual. 
9.7 
PK Assessments 
The aim of the PK assessments is to gather essential information about the exposure-response 
relationship for COVID-19 treatment and prevention. The sampling strategy in this study has been 
developed to maximize the value of isolated samples. Minimum concentration (Cmin) on Day 7 will be 
assessed in all participants in the experimental arms (Arms B to E) to coincide with the primary endpoint, 
and on Day 3 in participants in the ASAQ and PA arms (Arms B and C). 
A single plasma and/or whole blood PK sample will be collected on these days. The timing of the sample 
collections will be as follows: 
• 
Day 3 samples for participants in the ASAQ and PA arms will be collected prior to the last dose of IMP 
and approximately 24 hours after the previous IMP dose. 
• 
Day 7 samples for participants in all experimental arms (Arms B to E) will be collected prior to the last 
dose of IMP (if IMP administration is still scheduled for Day 7) and relative to the previous dose of IMP 
administered as follows: 
o 
24 (±2) hours post-dose for SOF/DCV 
o 
96 (±2) hours post dose for ASAQ, PA 
o 
12 (±1) hours post dose for FPV-NTZ. 
The basic requirements for PK sampling are as follows: 
1. Accurate record of the time of IMP administration (for the dose administered prior to the blood 
sampling) (dd:mm:yy; hh:mm) 
2. Accurate recording of the time of blood sampling (dd:mm:yy; hh:mm). 
Blood samples will be collected and processed as outlined in the study-specific Laboratory Manual. 
Additional details regarding storage and shipment will be also be described in the Laboratory Manual. 
Details of PK analytical procedures will be described in the Analytical Plan. 

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9.8 
Biohazard Containment 
As the transmission of SARS-CoV-2 and other respiratory droplet pathogens can occur through contact 
with respiratory droplets and contaminated surfaces, precautions will be employed by all personnel in the 
handling of all specimens for this study. 
All dangerous goods and materials, including diagnostic specimens and infectious substances, must be 
transported using packaging mandated by national and regional regulations.  
Details of these procedures will be described in the Laboratory Manual and will comply with relevant IATA 
Dangerous Goods Regulations. 
10. 
DATA MANAGEMENT 
The Investigator will maintain paper or electronic source documentation for all study participants. 
Participant information will be captured in an eCRF. The Clinical Data Management System will comply 
with regulatory guidelines and requirements for electronic systems. 
Data validation and quality control procedures will be detailed in the Data Management Plan. 
Medical history and AE data will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1 or later. Concomitant medications will be coded using the latest 2020 release of the WHO 
Drug Dictionary in effect at the time of study start. 
11. 
STATISTICAL CONSIDERATIONS 
11.1 
Sample Size Determination 
Primary Endpoint of Viral Clearance 
Assuming that the percentage of participants with viral clearance by Day 7 is 20% in the control arm (Arm 
A), a sample size of 50 participants per arm will provide at least 80% power to detect an increase in viral 
clearance to 50% for a new treatment regimen. This assumes a two-sided, 5% type 1 error rate and a loss 
to follow up rate of 20%. The assumptions for this calculation are supported by a published analysis of a 
trial of favipiravir versus lopinavir/ritonavir, where the percentage with viral clearance by Day 7 was 65% 
for favipiravir (FPV) versus 20% for lopinavir/ritonavir (LPV/RTV) [9]. Issues of multiplicity have not been 
considered in this exploratory study. 
 

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Figure 2:  Kaplan-Meier survival curves for time to viral clearance per treatment 
 
The aim of this exploratory study is to demonstrate similar high proportions of viral clearance for new 
candidate treatments. Demonstration of these benefits in any study treatment arms would justify taking 
these specific arms forward into a subsequent, separate, confirmatory, phase 3 trial, with a new endpoint 
of clinical recovery. 
11.2 
Populations for Analyses 
For analysis purposes, the following populations are defined and will be described in greater detail in the 
trial Statistical Analysis Plan: 
Population 
Description 
Safety Analysis Set 
All enrolled participants who receive at least one dose of randomized 
treatment  
Modified Intention to Treat 
(mITT) 
All enrolled participants with confirmed SARS-CoV-2 infection who receive at 
least one dose of randomized treatment  
As Treated 
All enrolled participants who complete the course of randomized treatment 
and have viral load results available on Day 7 
11.3 
Statistical Analyses 
The Statistical Analysis Plan will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, the detailed analytical plans with endpoints and 
procedures for accounting for missing, unused, and spurious data. 
An Interim Monitoring Plan will also be developed to describe approaches for re-estimation of sample size 
in order to preserve the pre-specified power of 80%. 
This section presents a brief summary of the planned statistical analyses of the primary and secondary 
endpoints (Section 3). 

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11.3.1 
Efficacy analyses 
Demographic characteristics (age, sex, race) of each study group will be tabulated. 
The mean age (plus range and standard deviation) by sex of the enrolled participants, as a whole and per 
group, will be calculated. 
Primary analyses: The primary analyses will be conducted on the mITT population overall. Participants 
randomized to each active treatment will be compared to participants randomized to SOC (Arm A). The 
primary analysis will make use of all participants randomized to SOC, whether contemporaneously 
enrolled or not. Due to anticipated heterogeneity in risk of disease progression, pre-specified baseline 
variables, including age, body mass index (BMI), and days of symptoms at time of enrollment will be 
included in the model to increase precision. 
Sensitivity analysis: The primary analyses will be repeated, replacing randomization arm by actual 
treatment to account for possible off-label use of and noncompliance to the investigational products. 
Subgroup analyses: All subgroup analyses will be pre-specified in the Statistical Analysis Plan. Any further 
subgroup analyses will be considered ad hoc. 
Missing Data: Due to the design of the study and retention activities, measurable outcomes are expected 
for all participants. However, in the unlikely event of a missing test result, the missing data will be imputed. 
11.3.2 
Secondary endpoints 
All secondary endpoints will be assessed in the mITT population overall and by treatment arm. 
Endpoints related to SpO2 will be calculated for all participants that had SpO2 ≥95% on Day 1. 
11.3.2.1 Safety analyses 
All safety analyses will be performed on the Safety Analysis Set. SAEs, AEs, treatment-related AEs, and 
discontinuations due to AEs will be compared by study group. 
11.3.2.2 Hospitalization 
Hospitalization rates between the groups will be compared using logistic regression stratified by site. 
Number of days hospitalized will be described graphically and by median and interquartile rage. 
11.3.2.3 Disease severity 
Disease severity, as measured by the WHO Ordinal Scale for Clinical Improvement (Appendix 5), will be 
compared between the groups using a proportional odds model. 
11.3.2.4 Symptom resolution 
Days with fever after randomization, respiratory symptoms after randomization, and Sp02<93% after 
randomization will be modeled using Poisson regression stratified by site with an offset for number of 
days of observation. 
Data from the FLU-PRO© Plus questionnaire (Appendix 3) and the FLU-PRO© Plus Global Additional Daily 
Diary Items (Appendix 4) will be analysed in accordance with guidance from Leidos Biomedical Research, 
Inc. Details will be described in the Statistical Analysis Plan. 

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11.3.3 
Exploratory endpoints 
Limited sparse PK sampling will be conducted in all participants in the experimental arms of the study 
using Cmin plasma and/or whole blood concentrations tailored to each of the main study drugs. For the 
majority of drugs this will be conducted on Day 7 only, to minimize exposure of healthcare staff to 
infectious patients through site visits. For long half-life drugs such as pyronaridine and amodiaquine that 
will only be dosed during the first days of the study, an additional plasma and/or whole blood Cmin sample 
will be collected pre-dose on Day 3 to ensure robust quantification of drugs and/or their major circulating 
active metabolite. 
A number of potential analyses are possible with these plasma or whole blood concentration data. 
Correlations of Cmin with time to undetectable virus will be analyzed by Cox regression and the difference 
in proportions for other endpoints can be evaluated using Pearson’s chi-square or Fisher’s exact test (as 
appropriate). If warranted, differences in plasma and whole blood concentrations between individuals 
defined as “responders” versus those defined as “non-responders” to therapy will be assessed using a 
ttest, in the case that differences in response to therapy between participants is evident. 
11.3.4 
Combined study analysis 
This protocol is based on a model protocol for consideration by multiple institutions as they evaluate the 
efficacy of experimental treatments for SARS-CoV-2 infection. Individual participant data from similar 
studies may be pooled into a combined study analysis. De-identified data from the present study will be 
made available for these purposes in accordance with the funder’s open access policy 
(https://www.gatesfoundation.org/how-we-work/general-information/open-access-policy). 
12. 
STUDY MONITORING 
12.1 
Safety Review Team 
The Safety Review Team (SRT) will monitor the conduct of the study through monthly summary reports 
of arms of accrual, baseline characteristics, AEs, laboratory results and protocol deviations. On a weekly 
basis, the Medical Monitor (one of the members of the SRT) will review by-arm summaries of premature 
study discontinuations and premature study treatment discontinuations (and reasons) and AEs. 
A detailed description of the operational aspects of the Safety Review Team will be documented in the 
Safety Review Team Charter. 
12.2 
Independent Monitor 
Study conduct will be monitored by an independent monitor. Monitors will conduct remote monitoring 
and will visit the sites as required. Review of individual participant records, including consent forms, eCRFs, 
supporting data, laboratory specimen records, and endpoints through laboratory and medical records 
(physicians’ progress notes, nurses’ notes, individuals’ hospital charts) will be performed as detailed in 
the Clinical Monitoring Plan, to ensure protection of study participants, compliance with the protocol, and 
accuracy and completeness of records. The monitors also will inspect the sites’ regulatory files to ensure 
that regulatory requirements are being followed, and the sites’ pharmacies to review product storage and 
management. 

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The Clinical Monitoring Plan will describe these activities and will take into consideration necessary 
adaptations to ensure the safety of the monitor with regard to infection control and the fact that physical 
access to sites may be limited. 
12.3 
Data Monitoring Committee 
An independent DMC will be convened for this study with expertise in respiratory viruses, antiviral 
therapies and shedding, and emerging epidemics. A biostatistician will also form part of the DMC. The 
purpose of the DMC is to monitor the study for safety, social harms, and efficacy. The DMC will evaluate 
the progress of the project, including periodic assessments of accrual, retention, safety, performance and 
variation of the project site, and other factors that can affect project implementation. 
The DMC will review and approve modifications to the overall enrollment target based on the observed 
drop-out rate. Due to the anticipated rapid speed of enrollment and the short duration of the study, no 
formal interim analyses for futility will be performed. The DMC will review severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) endpoints. 
The DMC will conduct interim reviews as specified in the DMC Charter when adequate data have been 
accrued. Meetings will be convened by teleconference. Semi-blinded reports containing participant 
characteristics, AEs, SAEs, and other safety and efficacy data will be sent to the protocol team and DMC 
members the week prior to the DMC meeting. The DMC members will also receive pooled reports of 
accrual and retention rates to enable them to provide recommendations regarding a possible sample size 
increase in an un-biased way. 
The objectives and responsibilities of the DMC, and the DMC operational procedures will be detailed in 
the DMC Charter which will be ratified by the DMC members prior to the study start. 
12.4 
Scientific Advisory Committee 
A scientific advisory committee (SAC) will be established for this study. The scientific advisory committee 
will be consulted in the event of new evidence emerging that could impact the scientific rationale of the 
trial and might require: 
• 
changes to treatment arm drugs or doses or duration of IMP administration, or 
• 
changes to other aspects of the study design. 
13. 
ETHICAL CONSIDERATIONS 
13.1 
Regulatory and Ethical Considerations 
The study will be conducted according to GCP, the Belmont Report, the Declaration of Helsinki, and South 
Africa legal requirements regarding clinical trials. The study protocol and relevant supporting documents 
will be submitted for review and approval by the SAHPRA and the Human Research Ethics Committee 
(HREC) responsible for oversight of research conducted at the study site. The study protocol will be 
registered with the South African National Clinical Trial Registry (www.sanctr.gov.za) / National Human 
Research Ethics Committee (www.ethicsapp.co.za) and www.ClinicalTrial.gov. Six-monthly progress 
reports will be submitted to SAHPRA and HREC for the duration of the study, and as requested. Upon 
completion or premature termination of the study, the Investigator will provide HREC and SAHPRA with a 
summary of the study’s outcome, and any reports required. 

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13.2 
Informed Consent Process 
The principles of informed consent in the current edition of the Declaration of Helsinki will be 
implemented before any protocol-specified procedures or interventions are carried out. The pre-
screening consent form will describe any information that will be gathered or procedures that will be 
followed during pre-screening. The separate screening and main study electronic consent form(s) will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. Consent for storage of samples for future testing will also be requested, but will be optional. 
Failure to provide consent for sample storage will not exclude a volunteer from study participation. In the 
event of a female participant becoming pregnant, consent for follow-up of the pregnancy and outcome 
thereof will be requested. Potential participants will have the opportunity to have any questions answered 
before and after signing either the pre-screening consent form or the ICF. The informed consent process 
and all questions raised will be documented. 
The study staff who conduct the informed consent process will also sign the ICF(s). A copy of the consent 
form(s) will be given to the participant, and this fact will be documented in the participant’s record. 
A participant who is rescreened will sign new ICF(s); eligibility for the study must be re-checked prior to 
enrollment with regard to all other screening procedures. 
13.3 
Study Records 
The study site will establish a standard operating procedure for confidentiality protection. The site will 
ensure that study records including administrative documentation and regulatory documentation as well 
as documentation related to each participant enrolled in the study, including ICFs, locator forms, case 
report forms, notations of all contacts with the participant, and all other source documents are stored in 
a secure manner. 
13.4 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain participant confidentiality. The exceptions are SARS-CoV-2 testing results, which are 
subject to local and national reporting. This may be name-based depending on local requirements. Local 
public health may contact participants diagnosed with SARS-CoV-2 for the purpose of surveillance and 
contact notification. Participants will be informed prior to SARS-CoV-2 testing that results are reportable 
and may lead to contact by local public health if results are positive for infection. 
All records will be kept in a secure storage area with limited access. Clinical information will not be 
released without the written permission of the participant, except as necessary for monitoring, and 
auditing by the regulatory authorities or the Human Research Ethics Committee (HREC). 
The Principal Investigator or designee and all employees and co-workers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to those individuals for the purpose of the study. All 
computers are password-protected and records can only be accessed by authorized study staff. 

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13.5 
Blood Volume 
Anticipated blood draws for participants in the experimental treatment arms will amount to the following 
total blood volumes: 
Assessment 
Maximum volume per sample 
Maximum no. of samples 
Total volume 
Serum potassium 
5 mL 
1 
5 mL 
PK 
8 mL 
2 
16 mL 
Serology 
5 mL 
2 
10 mL 
Storage for future testing 
20 mL 
2 
40 mL 
TOTAL 
71 mL 
For participants in the SOC arm (Arm A), no PK samples will be drawn and the anticipated total blood 
volume drawn will therefore be 55 mL.  
Therefore, for all participants, even if the situation arises where multiple additional blood draws for 
unanticipated safety monitoring are required, the total volume drawn should not exceed 480 mL over an 
8 week period. 
 

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37. Miner K, Labitzke K, Liu B, et al. Drug Repurposing: The Anthelmintics Niclosamide and 
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49. Sovaldi® (sofosbuvir) tablets for oral use. FDA. FDA AccessData. Available 
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50. De Freitas et al. (2019) Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo. 
PLoS Negl Trop Dis 13(1): e0007072. https://doi.org/10.1371/journal. pntd.0007072 
51. Bullard-Feibelman, K., Govero, J., Zhu, Z., Salazar, V., Veselinovic, M., Diamond, M. and Geiss, B., 
2017. The FDA-approved drug sofosbuvir inhibits Zika virus infection. Antiviral Research, 137, 
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52. Gan, C., Lim, S., Chee, C., Yusof, R. and Heh, C., 2017. Sofosbuvir as treatment against 
dengue?. Chemical Biology & Drug Design, 91(2), pp.448-455. 
53. Ferreira A, Reis P, de Freitas C, et al. Beyond Members of the Flaviviridae Family, Sofosbuvir Also 
Inhibits Chikungunya Virus Replication. Antimicrobial Agents and Chemotherapy 2018; 
63(2):pp.e01389-18. 
54. Iranian Clinical Trial Registry. 2020 [online] Available at: https://www.irct.ir/ 
55. Rajoli R, Pertinez H, Arshad U, et al. Dose prediction for repurposing nitazoxanide in SARS-CoV-2 
treatment or chemoprophylaxis. medRxiv 2020.05.01.20087130; 
doi: https://doi.org/10.1101/2020.05.01.20087130. 
56. NICD COVID-19 Surveillance in Selected Hospitals, 14 May 2020. 
57. Rodino KG, Espy MJ, Buckwalter SP, et al. Evaluation of saline, phosphate buffered saline and 
minimum essential medium as potential 2 alternatives to viral transport media for SARS-CoV-2 
testing. J Clin Microbiol. 2020. 2020 Mar 30. 
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59. Powers JH, Bacci ED, Guerrero ML, et al. Evaluation of the performance properties of the 
InFLUenza Patient-Reported Outcome (FLU-PRO©) instrument. Value in Health. 2018 
Feb;21(2):210-218. 
60. Powers JH, Bacci ED, Leidy NK, et al. Performance of the inFLUenza Patient-Reported Outcome 
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APPENDICES 
APPENDIX 1: 
STUDY GOVERNANCE 
The following Investigators and Institutional Affiliations are established. Designees may be provided, as 
appropriate. 
Name 
Role  
Institution 
Francois Venter 
Principal Investigator 
Ezintsha, Wits Reproductive Health & HIV Institute 
University of the Witwatersrand 
5th Floor, Building D 
Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg 
South Africa 
Nomathemba Chandiwana 
Lead Investigator 
 
Main Site: 
Building C 
Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg 
 
Satellite Site: 
Charlotte Maxeke Johannesburg Academic Hospital 
Area 585, Level 8 
Jubilee Road 
Johannesburg, 2193 
South Africa 
 

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APPENDIX 2: 
CONTACT DETAILS 
Site 
Institution: 
 
 
Ezintsha, Wits Reproductive Health & HIV Institute 
Address: 
 
 
University of the Witwatersrand 
 
 
 
 
5th Floor, Building D 
 
 
 
 
Sunnyside Office Park 
 
 
 
 
32 Princess of Wales Terrace 
 
 
 
 
Parktown, Johannesburg 
Main Site: 
 
 
Building C 
 
 
 
 
Sunnyside Office Park 
 
 
 
 
32 Princess of Wales Terrace 
 
 
 
 
Parktown, Johannesburg 
 
 
 
 
South Africa 
Principal Investigator:  
Professor Francois Venter 
Email:  
 
 
fventer@ezintsha.org 
Telephone: 
 
 
+27 11 084 4983 
Lead Investigator: 
 
Nomathemba Chandiwana 
Email:  
 
 
nchandiwana@ezintsha.org 
Mobile:  
 
 
+27 76 164 3215 
Research Pharmacist: 
 
Lebohang Mphahlele 
Address: 
 
 
Wits RHI Yeoville Research Centre 
 
 
 
 
35 Bedford Street, Cnr Dunbar 
 
 
 
 
Yeoville, 2001 
 
 
 
 
South Africa 
Telephone: 
 
 
+27 11 358 5848 
IRB/Ethics Committee:  
Human Research Ethics Committee 
Research Administrator: 
Ms Jennifer Palmer 
(email: jpalmer@witshealth.co.za)  
Telephone: 
 
 
+27 11 274 9278 
 
Satellite Site 
Satellite Site: 
 
 
Charlotte Maxeke Johannesburg Academic Hospital 
 
 
 
 
Area 585, Level 8 
 
 
 
 
Jubilee Road 
 
 
 
 
Johannesburg, 2193 
 
 
 
 
South Africa 
 

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Sponsor 
Institution: 
 
 
Shin Poong Pharm. Co., Ltd. 
Address: 
 
 
161 Yoksam-Ro, Gangnam-Gu 
 
 
 
 
Seoul, 06246 
 
 
 
 
Republic of Korea 
Project Director: 
 
Jandee Kim 
Email:  
 
 
jdkim@shinpoong.co.kr 
Telephone: 
 
 
+82 10 6263 5261 
 
Funder 
Institution: 
 
 
Medicines for Malaria Venture 
Address: 
 
 
ICC – Block G, 3rd Floor 
 
 
 
 
20, Route de Pré-Bois 
 
 
 
 
PO Box 1826 
 
 
 
 
1215 Geneva 15 
 
 
 
 
Switzerland 
Chief Medical Officer:  
Stephan Duparc 
Email:  
 
 
duparcs@mmv.org 
Telephone: 
 
 
+41 22 555 0351 / +41 79 446 2956 
Project Director: 
 
Farouk Chughlay 
Email:  
 
 
chughlayf@mmv.org 
Telephone: 
 
 
+41 22 555 0355 / +41 79 123 4289 
Clinical Trial Manager:  
Julia Flynn 
Email:  
 
 
flynnj-consultants@mmv.org 
Telephone: 
 
 
+41 79 905 9203 
 
Cinical Research Organisation 
Institution: 
 
 
Triclinium Clinical Development (TCD) 
Address: 
 
 
Design House 
 
 
 
 
121 Amkor Road 
 
 
 
 
Lyttleton Manor 
 
 
 
 
Centurion, 0157 
 
 
 
 
South Africa 
Project Manager: 
 
Fiona Storer 
Email:  
 
 
fiona.storer@tcd-global.com 
Telephone: 
 
 
+27 12 664 1622 / +27 82 853 6791 
 

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Independent Medical Monitor 
Institution: 
 
 
HJ-Clinical Trial Consultancy 
Address: 
 
 
15 Oaklands, Fancourt 
 
 
 
 
George, 6529 
 
 
 
 
South Africa 
Medical Monitor: 
 
Hilary Johnstone 
Email:  
 
 
hjohnstone@hjclinical.com 
Telephone: 
 
 
+27 83 704 4929 
 
Pharmacovigilance 
Institution: 
 
 
Quanticate 
Address: 
 
 
Bevan House  9-11 Bancroft Court 
 
 
 
 
Hitchin 
 
 
 
 
Hertfordshire 
 
 
 
 
SG5 1LH 
 
 
 
 
United Kingdom 
QPPV:  
 
 
Robert Miller, Artemida Pharma 
Email:  
 
 
robert.miller@artemidapharma.com 
Telephone: 
 
 
+44 203 291 3032 / +44 782 655 5254 
 

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APPENDIX 3:  
THE INFLUENZA PATIENT-REPORTED OUTCOME INSTRUMENT (FLU-PRO© Plus) 
To be completed on D1-14, D21 and D28: 
 
 
Copyright © 2014- 2020 Leidos Biomedical Research, Inc.  All Rights Reserved 
 

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Copyright © 2014- 2020 Leidos Biomedical Research, Inc.  All Rights Reserved 
 
 

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APPENDIX 4: 
DAILY SURVEY 
To be completed on D1-14, D21 and D28 
FLU-PRO© Plus GLOBAL ADDITIONAL DAILY DIARY ITEMS: 
Copyright © 2014- 2020 Leidos Biomedical Research, Inc.  All Rights Reserved 
Items to be asked in daily diary through to Day 14, and on Days 21 and 28 along with the FLU-PRO 
symptom items 
1. Overall, how severe were your infection symptoms today? (Please select one response only) 
0 
No flu symptoms today 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Very severe 
2. Overall, how were your infection symptoms today compared to yesterday? (Please select one 
response only) 
1 
Much better 
2 
Somewhat better 
3 
A little better 
4 
About the same 
5 
A little worse 
6 
Somewhat worse 
7 
Much worse 
3. How much did your infection symptoms interfere with your usual activities today? (Please select one 
response only) 
1 
Not at all 
2 
A little bit 
3 
Somewhat 
4 
Quite a bit 
4. Have you returned to your usual activities today? 
1 
Yes 
0 
No 

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Clinical Study Protocol 
 
 
 
Version 4, 17 Nov 2020 
 
Page 63 of 66 
 
5. In general, how would you rate your physical health today? (Please select one response only) 
5 
Excellent 
4 
Very Good 
3 
Good 
2 
Fair 
1 
Poor 
6. Have you returned to your usual health today? 
1 
Yes 
0 
No 
5 
Very much 
 
GENERAL DAILY DIARY ITEMS: 
1. Have you taken your daily medication since the last survey? 
 
Yes 
 
No 
 
Not applicable 
2. Take your vitals: (time of day: 
: 
 hh:mm) 
• 
Pulse 
 
 
 
 beats per minute 
• 
Temperature 
 
 
 °C 
• 
Respiratory rate 
 
 breaths per minute 
• 
Oxygen saturation level  
 % 
3. Have you taken any other medications? 
 
Yes 
 
No 
If “yes”, describe:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Shin Poong Pharm. Co., Ltd. 
Confidential 
SP-PA-COV-202 
Clinical Study Protocol 
 
 
 
Version 4, 17 Nov 2020 
 
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4. Have you observed any change or new complaint since you last completed the survey? 
 
Yes 
 
No 
If “yes”, describe:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Confidential 
SP-PA-COV-202 
Clinical Study Protocol 
 
 
 
Version 4, 17 Nov 2020 
 
Page 65 of 66 
 
APPENDIX 5: 
WHO ORDINAL SCALE FOR CLINICAL IMPROVEMENT 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatory 
No limitation of activities 
1 
 
Limitation of activities 
2 
Hospitalized: mild disease 
Hospitalized, no oxygen therapy 
3 
 
Oxygen by mask or nasal prongs 
4 
Hospitalized: severe disease 
Non-invasive ventilation or high-flow oxygen 
5 
 
Intubation and mechanical ventilation 
6 
 
Ventilation + additional organ support (pressors, RRT, ECMO) 7 
Dead 
Death 
8 
WHO COVID-19 Core Protocol 
SOLIDARITY Trial 
Version 10.0, March 22, 2020 
 
 

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Confidential 
SP-PA-COV-202 
Clinical Study Protocol 
 
 
 
Version 4, 17 Nov 2020 
 
Page 66 of 66 
 
APPENDIX 6: 
PROHIBITED CONCOMITANT MEDICATIONS 
The following drugs are known to induce prolongation of the QT-interval. Their use is not permitted in 
conjunction with the study drugs. Participants using these drugs at baseline, or those anticipated to 
require these during the study, should not be enrolled in the study. 
• 
antiarrhythmics (e.g., amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, 
hydroquinidine, sotalol) 
• 
neuroleptics (e.g., phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, 
pimozide, or thioridazine) and antidepressant agents known to cause significant QT-interval 
prolongation (e.g., citalopram, escitalopram) 
• 
certain antimicrobial agents, including agents of the following classes: 
o 
macrolides (e.g,. erythromycin, clarithromycin) 
o 
fluroquinolones (e.g., moxifloxacin, sparfloxacin) 
o 
imidazole and triazole antifungal agents 
o 
pentamidine 
o 
saquinavir 
• 
certain non-sedating antihistamines (e.g., terfenadine, astemizole, mizolastine) 
• 
cisapride 
• 
droperidol 
• 
domperidone 
• 
bepridil 
• 
diphemanil 
• 
probucol 
• 
levomethadyl 
• 
methadone 
• 
vinca alkaloids 
• 
arsenic trioxide. 
Use of the following drugs is not permitted during the study due to potential drug-drug interactions. 
Participants using these drugs at baseline, or those anticipated to require these during the study, should 
not be enrolled in the study. 
• 
protease inhibitor-based antiretroviral regimens 
• 
efavirenz 
• 
rifampicin 
• 
carmabazepine.