Background There is currently no validated, effective, safe treatment for severe illness caused by SARS-CoV-2. CVO PLUS CURATIF (CVO+C) is a capsule formulation of two compounds of plant origin with anti-inflammatory and antiviral activities in vitro: artemisinin and 1,8-cineole. These compounds have been repurposed for possible use as an oral treatment against COVID-19. Methods We performed a phase 3 randomized clinical trials on patients over the age of 18 years with SARS-CoV-2 infection confirmed by RT-PCR and mild-to-moderate symptoms. Patients were randomly assigned to receive CVO+C (3 capsules per day) or placebo for 15 days. The primary outcome was the proportion of patients testing negative for SARS-CoV-2 by RT-PCR on day 28 and an absence of severe and serious adverse events. Recovery time, and biological parameters on days 7, 14, 21 and 28 of the trial were considered as secondary outcomes. The safety outcomes considered were adverse events on treatment. Results In total, 1,576 individuals underwent RT-PCR screening for SARS-CoV-2 infection during the study period. Positive test results were obtained for 591 subjects, 339 of whom met the inclusion criteria for this study. The final analysis included 339 subjects: 132 from the CVO+C arm and 144 from the placebo arm. Treatment efficacy differed significantly (p=0.011) between the CVO+C arm (87.1%, 95% CI: 81.3%-92.9%, with 70.45% of patients cured by day 14) and the placebo arm (75.0%, 95% CI: 67.8% - 82.1%), with an OR of 2.25. The median time to recovery was 14 days for the CVO+C group and 21 days for the placebo group. A total of 72 incidences of mild and moderate adverse events, 14 severe adverse events and no serious adverse events were observed in both groups. ConclusionCVO+C was effective for the treatment of mild-to-moderate COVID-19. None of the patients in the CVO+C arm displayed progression to the severe form of COVID-19. Liver kidney and metabolic functions were preserved in all patients.Trial registration: Registered at Pan African Clinical Trials Registry: (No. PACTR202103601407640, date of approval: 24/03/2021) and approved by the ethics committee of the Ministry of Public Health of Madagascar (approval No. 216 MINSANP/SG/AGMED/CERBM, 17/12/2020)