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.
Subject(s)
COVID-19ABSTRACT
BACKGROUND: Data from molecular docking, in-vitro experiments and 2 published small clinical studies suggested a potential therapeutic benefit for the anti-hepatitis C drugs, sofosbuvir (SOF) and daclatasvir (DCV), to repurpose for the treatment of COVID-19. We planned this study to evaluate efficacy and safety of dual SOF/DCV as add-on treatment to the standard of care (SOC) in patients with COVID-19, initially hospitalized to a non-intensive care setting.METHODS: Eighty nine consecutive eligible patients presenting to a single center in Cairo were included in the study and randomly assigned to two treatment groups. The experimental group was treated with the SOC therapy (as per the Egyptian ministry of health protocol) in addition to one 400 mg tablet SOF and one 60 mg DCV daily for 10 days; while the control group was treated with the SOC therapy alone. Baseline clinical, laboratory and imaging data were measured and followed up for 21 days. Data were compared between the two treatment groups.FINDINGS: The proportion of cumulative clinical recovery in the experimental group at day 21 was numerically greater than the control group (40/44 (91%; CI: 78.8-96.4%) versus 35/45 (77.8%; 63.7-87.5%)). The Hazard Ratio (HR) for time to clinical recovery adjusted for baseline severity by a Cox-regression model was statistically significant: HR: 1.59 (CI: 1.001-2.5), signifying nearly 1.6 times higher probability of clinical recovery in the experimental group than the control at any time point during the study. Concordantly, the experimental group also showed trends to greater numerical improvement in other efficacy endpoints including the mean 8 points ordinal scale score, the mean severity of lung lesions score and the case fatality rate (4.5% versus 11.1%) than the control group. All these effects, though did not reach statistical significance at the study sample size, but being all concordant with the HR, they support the study concept. No serious or severe adverse events were reported in both groups and the treatment was well tolerated.INTERPRETATION: This study provides support to the potential benefits and safety of sofosbuvir combined with daclatasvir in the treatment of COVID-19. It is hoped to encourage further large sized multinational studies to confirm these encouraging results.Trial Registration: The study protocol was registered in the German clinical trial database repository (DRKS00022203) before the study initiation.Funding Statement: This study was funded by Pharco Corporate.Declaration of Interests: SH and OE are employees of Pharco, SH holds stock in Pharco. MY, AH conducted clinical studies and provided consultations for Pharco. Others have nothing to declare. Ethics Approval Statement: The study protocol was reviewed and approved by the Research Ethics Committee of Faculty of Medicine, Alexandria University (IRB00007555) and the Central Egyptian Ministry of Health and People Research Ethics Committee according to the Declaration of Helsinki. All subjects gave written informed consent before any treatment interventions were performed.