This exploratory study is a randomized, single center, open label study of four different experimental treatment arms versus standard of care for the treatment of SARS-CoV-2 infection in symptomatic outpatients with mild disease at the time of enrollment.
This phase 2, exploratory study will be an adaptive, randomized, open label, trial for
treatment of individuals in an outpatient settings with mild SARS-CoV-2 infection. The
primary outcome is focused on the evaluation of efficacy of the proposed experimental drugs
in reducing upper respiratory viral shedding, defined as viral clearance (i.e., negative
swab) on Day 7. Key secondary outcomes focus on other measures of viral shedding, safety
evaluation, progression to LRTI (defined by resting blood oxygen saturation level [SpO2] <93%
sustained for two readings two hours apart and presence of subjective dyspnoea or cough),
disease severity, clinical resolution rate, and cumulative incidence of hospitalization or
mortality at Day 28.
Other: Standard of care (Paracetamol)
SOC - 2 tablets (1000 mg) to be taken 6-hourly as needed
Drug: Artesunate-amodiaquine
SOC plus artesunate-amodiaquine (ASAQ) - 2 tablets (200/540 mg artesunate/amodiaquine) daily for 3 days
Drug: Pyronaridine-artesunate
SOC plus pyronaridine-artesunate (PA) Weight 45 to <65 kg: 3 tablets (540/180 mg pyronaridine/artesunate) daily for 3 days Weight ≥65 kg: 4 tablets (720/240 mg pyronaridine/artesunate) daily for 3 days
Drug: Favipiravir plus Nitazoxanide
SOC plus favipiravir plus nitazoxanide (FPV-NTZ) Favipiravir: 1600 mg 12-hourly for 1 day then 600 mg 12-hourly for 6 days Nitazoxanide: 2 tablets (1000 mg) 12-hourly for 7 days
Drug: Sofosbuvir/daclatasvir
SOC plus sofosbuvir/daclatasvir (SOF/DCV)
1 tablet (400 mg/60 mg sofosbuvir/daclatasvir) daily for 7 days
Inclusion Criteria:
1. Age from 18 to 65 years of age, inclusive, at the time of signing the informed
consent.
2. Willing and able to provide informed consent.
3. Women of reproductive potential must be using a highly effective method of
contraception for at least 28 days prior to enrolment and must be able and willing to
continue its use throughout the duration of the study.
4. Men must agree to use condoms when engaging in heterosexual sex during the study and
for the period up to 91 days after the last dose of study medication. Men who are not
randomized to a treatment arm including favipiravir (or another arm identified as
having teratogenic potential through semen) will no longer need to adhere to this
after randomization.
5. Laboratory confirmed SARS-CoV-2 infection, and any of the following self-reported
symptoms within 72 hours prior to randomization: fever or chills, cough, myalgia, sore
throat, shortness of breath, or new onset of anosmia or ageusia.
6. Body weight ≥45 kg.
7. Access to reliable video conference, telephone, direct/text messaging, or other device
permitting real-time, reliable information transfer.
Exclusion Criteria:
1. Pregnant or lactating women.
2. Known hypersensitivity or specific contraindications to the use of any of the active
drugs in the treatment arms, or similar compounds.
3. Signs of respiratory distress prior to randomization, including:
- respiratory rate >24 breaths/min
- SpO2 <95% in room air.
4. Resting pulse rate ≥120 beats/min.
5. High likelihood of hospitalization in the opinion of the attending clinician.
6. QTcF >470 msec for females, or >450 msec for males, at screening.
7. Serum potassium <3.5 mmol/L at screening.
8. History of clinically significant cardiovascular disease (including arrhythmias,
QT-interval prolongation, torsades de pointes (TdP), history of coronary artery
disease with graft or stent procedures/surgery, cardiac failure [class 2 or higher
using the New York Heart Association functional classification]).
9. Known chronic kidney disease (Stage IV or receiving dialysis).
10. Known cirrhosis (Child-Pugh Class B or greater).
11. Known macular degeneration, or other known retinal diseases, or
4-aminoquinolone-induced visual impairment.
12. Currently receiving, or recently received (within 60 days prior to randomization)
treatment with any of the drugs in the treatment arms.
13. Currently receiving, or recently received (within 30 days prior to randomization)
treatment with any antimalarial drugs.
14. Currently on treatment with drugs with known arrhythmogenic potential, or those known
to induce significant QT-interval prolongation or TdP, as detailed in Appendix 6.
15. Currently on treatment for tuberculosis (or on treatment with rifampicin for any other
indication), or on treatment with a protease inhibitor-based antiretroviral regimen,
or efavirenz, or carbamazepine.
16. Inability/unlikely to be in the study area for the duration of the 28 day follow-up
period.
17. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of drugs, or which may jeopardize the safety of
the volunteer or the objectives of the study. The Investigator should make this
determination in consideration of the volunteer's medical history.
18. Personnel (e.g. investigator, sub-investigator, research assistant, pharmacist, study
coordinator or anyone mentioned in the delegation log) directly involved in the
conduct of the study.
19. Participant is judged by the Investigator to be at significant risk of failing to
comply with the provisions of the protocol as to cause harm to self or seriously
interfere with the validity of the study results.
Ezintsha, Wits Reproductive Health & HIV Institute University of the Witwatersrand
Johannesburg, South Africa