Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial.

Background: This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19.

Methods: This phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18-65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV). The primary endpoint was the incidence of viral clearance, i.e., the proportion of patients with a negative SARS-CoV-2 RT-PCR on day 7, compared to SOC using a log-binomial model in the modified intention-to-treat (mITT) population.

Findings: The mITT population included 186 patients: mean age (SD) 34.9 (10.3) years, body weight 78.2 (17.1) kg. Day 7 SARS-CoV-2 clearance rates (n/N; risk ratio [95% CI]) were: SOC 34.2% (13/38), ASAQ 38.5% (15/39; 0.80 [0.44, 1.47]), PA 30.3% (10/33; 0.69 [0.37, 1.29]), FPV + NTZ 27.0% (10/37; 0.60 [0.31, 1.18]) and SOF-DCV 23.5% (8/34; 0.47 [0.22, 1.00]). Three lower respiratory tract infections occurred (PA 6.1% [2/33]; SOF-DCV 2.9% [1/34]); two required hospitalisation (PA, SOF-DCV). There were no deaths. Adverse events occurred in 55.3% (105/190) of patients, including one serious adverse event (pancytopenia; FPV + NTZ).

Interpretation: There was no statistical difference in viral clearance for any regimen compared to SOC. All treatments were well tolerated.

Funding: Medicines for Malaria Venture, with funding from the UK Foreign, Commonwealth and Development Office, within the Covid-19 Therapeutics Accelerator in partnership with Wellcome, the Bill and Melinda Gates Foundation, and Mastercard.