Clinical Effectiveness and Safety of Sofosbuvir–Velpatasvir as Add-on Treatment for COVID-19 Patients: Study Protocol and Preliminary Data for the Randomized Controlled Trial

Objectives: COVID-19 is a worldwide health problem. Although the most infected patients experience a mild-to-moderate disease, some patients (especially older people) develop pulmonary distress with fatal lung failure and multi-organ damage. There is currently no known effective treatment for this disease. Sofosbuvir, an FDA-approved drug for the treatment of hepatitis C virus, is also able to inhibit other members of positive strand RNA viruses with conserved polymerase and may be helpful for the treatment of SARS-CoV-2. The goal of the current trial is to determine the usefulness of “standard of care (SOC) plus hydroxychloroquine and lopinavir/ritonavir” vs. “SOC plus a combination of lopinavir/ritonavir hydroxychloroquine and sofosbuvir/velpatasvir” in patients hospitalized with COVID-19. 
The Design of Clinical Trial: In this randomized controlled trial, patients over 18 years who have been diagnosed with COVID-19 by the positive SARS-CoV-2 reverse transcriptase–polymerase chain reaction (RT–PCR) test or compatible chest computed tomography (CT) scan were candidates for the study. Eighty patients from Kermanshah province, West of Iran were allocated to treatment with SOC plus hydroxychloroquine and lopinavir/ritonavir (dual therapy) or SOC plus a combination of hydroxychloroquine and lopinavir/ ritonavir and sofosbuvir/velpatasvir (triple therapy) for 10 days. Allocation was conducted using simple randomization. The primary outcomes were reducing mortality up to 28 days after hospitalization. Adverse events were handled and reported in accordance with the Good Clinical Practice guidelines. 
Participants: Patients who were hospitalized with COVID-19 (with positive SARS-CoV-2 RT–PCR test and/or compatible chest CT scan) were screened for eligibility at Farabi Hospital, Kermanshah University of Medical Sciences (KUMS), Kermanshah, Iran. 
Intervention and Comparator: Both arms received active treatment and none was given placebo. The intervention arm received hydroxychloroquine 400 mg single dose and lopinavir–ritonavir (400 and 100 mg) twice daily plus sofosbuvir–velpatasvir (400 and 100 mg) once daily orally, plus SOC for 10 days. The comparator arm received hydroxychloroquine 400 mg single dose and lopinavir–ritonavir (400 and 100 mg) twice daily orally, plus SOC for 10 days. SOC includes oxygen therapy, non-invasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and corticosteroids. 
Primary Outcomes: The main outcomes are reducing mortality until 28 days after hospitalization. Other outcomes can be found in full protocol file. 
Randomization: For the purpose of allocation sequence generation, using an Excel file (randomnumbers table) and simple random allocation, 80 included patients entered to the study, 40 patients in each group (1:1 ratio). In order to maintain the allocation sequence concealment, the details of treatment for each patient were contained in a sealed envelope, labeled by the numbers from 1 to 80. In fact, our study was a randomized open label clinical trial in which all the physicians and nurses plus all patients were aware of the type of treatment.
Blinding: Our study was a randomized open label clinical trial in which all the physicians and nurses plus all patients were aware of the type of treatment. 
Numbers to be Randomized (Sample Size): Eighty included patients entered to the study, 40 patients in each group using simple random allocation. 
Trial Status: The finalized protocol version 1.5 was used in the trial study and the recruitment/intervention process started on April 11, 2020, finished on May 11, and the related follow-up finished on June 8, 2020.
Registry of Clinical Trial: This clinical trial has been registered on March 30, 2020 under IRCT number 46790, in the Iranian Registry of Clinical Trials (https://www.irct.ir/ trial/46790) and by KUMS under Grant No. 990097. 
Full Protocol: The full protocol and other details are attached as a Supplementary File (full protocol), accessible from the journal website. 
Preliminary Data: The sofosbuvir/velpatasvir regimen does not improve survival, clinical improvement, and duration of hospitalization in hospitalized COVID-19 patients.