ABSTRACT
Background: The combination of sofosbuvir (SOF) and daclatasvir (DCV) has shown preliminary efficacy for patients with COVID-19 in five open-label studies with small sample sizes. This larger trial aimed to assess if the addition of sofosbuvir and daclatasvir to standard care improved clinical endpoints in hospitalized patients with moderate or severe COVID-19. Methods: This was a placebo-controlled, randomized clinical trial in adults with moderate or severe COVID-19 admitted to 19 hospitals in Iran. Patients were randomized to SOF/DCV 400/60mg once-daily or placebo in addition to standard of care. Patients were included if they had positive PCR or diagnostic chest CT, O 2 saturation <95%, and compatible symptoms. The primary endpoint was discharge from hospital within 10 days of first treatment. The trial is registered on Iran Registry of Clinical Trials under IRCT20200624047908N1 available at https://www.irct.ir/trial/49198.Results: Between July and October 2020, 1083 patients were allocated to either the SOF/DCV treatment arm (n=541) or matching placebo (n=542). The primary endpoint was achieved by 358 / 541 (66%) in the SOF/DCV arm and 370 /542 (68%) in controls (relative risk = 0.97, 95% CI = 0.89-1.05). The in-hospital death rates were 58/541 (11%) in the SOF/DCV group versus 53/542 (10%) in the placebo group (relative risk = 1.1, 95% CI = 0.77 to 1.56). Conclusions: We observed no significant effect of SOF/DCV versus placebo on the rate of hospital discharge or survival in hospitalized COVID-19 patients. However, the patient population was generally severe cases that may have been too advanced for antiviral drugs to be effective. Trial Registration: Iran Registry of Clinical Trials under IRCT20200624047908N1 available at https://www.irct.ir/trial/49198.Funding: This trial was sponsored by Abadan University of Medical Sciences and funded by the International Treatment Preparedness Coalition (grant number ITPC-2020)Declaration of Interests: S.Merat has received travel grants from and is a stockholder of Fanavaran Rojan Mohaghegh Daru Co. ANB and HNB are stockholders of Fanavaran Rojan Mohaghegh Daru Co. All other authors: none to declare.Ethics Approval Statement: The study protocol has been approved by the Abadan Faculty of Medicine Sciences Institutional Review Board and the Iranian Registry of Clinical Trials (IRCT) registry team.
Subject(s)
COVID-19ABSTRACT
Ivermectin is an antiparasitic drug being investigated for repurposing to SARS-CoV-2. In-vitro, ivermectin showed limited antiviral activity and a COVID-19 animal model demonstrated pathological benefits but no effect on viral RNA. This meta-analysis investigated ivermectin in 18 randomized clinical trials (2282 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. In six randomized trials of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-0.52]; p=0.0002); 14/650 (2.1%) deaths on ivermectin; 57/597 (9.5%) deaths in controls) with favorable clinical recovery and reduced hospitalization. Many studies included were not peer reviewed and meta-analyses are prone to confounding issues. Ivermectin should be validated in larger, appropriately controlled randomized trials before the results are sufficient for review by regulatory authorities.