key: cord-0751714-4lhgdvll authors: Abbass, Sherif; Kamal, Ehab; Salama, Mohsen; Salman, Tary; Sabry, Alyaa; Abdel‐Razek, Wael; Helmy, Sherine; Abdelgwad, Ahmed; Sakr, Neamt; Elgazzar, Mohamed; Einar, Mohamed; Farouk, Mahmoud; Saif, Mounir; Shehab, Ismail; El‐hosieny, Eman; Mansour, Mai; Mahdi, Doaa; Tharwa, El‐Sayed; Salah, Mostafa; Elrouby, Ola; Waked, Imam title: Efficacy and safety of sofosbuvir plus daclatasvir or ravidasvir in patients with COVID‐19: A randomized controlled trial date: 2021-08-24 journal: J Med Virol DOI: 10.1002/jmv.27264 sha: c902100b59d4dae65253043bff6e53adc15b2a47 doc_id: 751714 cord_uid: 4lhgdvll Only a few treatments are approved for coronavirus disease‐2019 (COVID‐19) infections, with continuous debate about their clinical impact. Repurposing antiviral treatments might prove the fastest way to identify effective therapy. This trial aimed to evaluate the efficacy and safety of sofosbuvir (SOF) plus daclatasvir (DCV) or ravidasvir (RDV) added to standard care (SOC) for patients with moderate and severe COVID‐19 infection. Multicentre parallel randomized controlled open‐label trial. One hundred and twenty eligible patients with moderate and severe COVID‐19 infection were randomized to one of the study arms. Ten days of treatment with SOF plus DCV or RDV in addition to the standard of care compared to SOC. Follow up in 7 days. Sum of the counted symptoms at 7 and 10 days, mean change in oxygen saturation level, viral negativity, and rate of intensive care unit (ICU) admission. Compared to SOC, the SOF‐DCV group experienced a significantly lower sum of the counted symptoms (fever, headache, generalized aches, or respiratory distress) combined with no evidence of deterioration (ICU admission and mechanical ventilation) on Days 7 and 10 of treatment. Oxygen saturation also significantly improved among the SOF‐DCV group compared to SOC starting from Day 4. The study also showed positive trends regarding the efficacy of SOF‐DCV with a lower incidence of mortality. On the other hand, adding SOF‐RDV to SOC did not show significant improvements in endpoints. The results support the efficacy and safety of SOF‐DCV as an add‐on to SOC for the treatment of moderate to severe COVID‐19 infections. Currently, no antiviral medication for COVID-19 treatment has been validated apart from remdesivir, which is the only medication approved by the FDA based on various reports, including randomized clinical trials. 3, 4 For this reason, repurposing of drugs approved for other diseases has been attempted. SARS-CoV-2 shares similarities with viral genomic replication mechanisms with other RNA viral families through RNAdependent RNA polymerase (RdRp). 5 Therefore, existing antivirals targeting the RdRp can potentially be repurposed for treating SARS-CoV-2. The hepatitis C (HCV) and SARS-CoV-2 RNA viruses use similar viral genome replication mechanisms. Direct antiviral agents against hepatitis C have shown laboratory activity against SARS-CoV-2, supported by a molecular docking experiment. 6 Using the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) model, the tight binding of sofosbuvir (SOF) to the coronavirus RdRp was identified. 7 Ledipasvir and velpatasvir were also found by virtual screening to be potential candidates to block another vital target in SARS-CoV-2 replication, the 3-chymotrypsin-like protease (3CLpro), also known as main protease (Mpro). 8 In another molecular docking model, elbasvir and ledipasvir showed similar binding potential against helicase, RdRp, and protease from both viruses. 9 SOF is the backbone of many approved anti-HCV regimens. Data from multiple trials and real-world experience proved that a combination of SOF with an NS5A inhibitor is effective, safe, and well-tolerated in treating patients with HCV. 10 In silico activity of SOF plus daclatasvir (DCV) is reported against SARS-CoV-2. [11] [12] [13] Similar to DCV, ravidasvir (RDV) has antiviral activity through NS5a inhibition. DCV and RDV are both safe and effective pan-genotypic NS5a inhibitors. 14 We proposed that SOF plus DCV (SOF-DCV) or RDV (SOF-RDV) could be repurposed antiviral treatments for COVID-19 because they could inhibit two SARS-CoV-2 replication enzymes. This study evaluated the role of adding SOF plus DCV (SOF-DCV) or RDV (SOF-RDV) to standard treatment compared to standard treatment in patients with SARS-CoV-2 infection. This study was a randomized, open-label, prospective trial to evaluate the safety and efficacy of SOF plus DCV (SOF-DCV) or RDV (SOF-RDV) in addition to standard treatment compared to standard treatment in Egyptian adults with COVID-19. This study was a phase III, randomized, open-label, prospective, controlled study. Patients were randomized (1:1:1) into three treatment groups: Group 1 (n = 40) received SOF-DCV in addition to the standard of care therapy for 10 days, Group 2 (n = 40) received SOF-RDV in addition to the standard of care therapy for 10 days, and Group 3 (n = 40) received the standard of care therapy without investigational medications. The data collected during the screening period included demographic data (age, gender, type of employment, income, level of education, smoking, alcohol intake, and marital status), medical and surgical history, concomitant medications, physical examinations, vital signs, standard 12-lead ECG, reverse-transcription polymerase chain reaction (RT-PCR) for SARS-COV-2 RNA through a nasopharyngeal swab (Genesig ® Real-time PCR assay; Primerdesign Ltd.), blood count, creatinine, total and direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gammaglutamyl transferase (GGT), sodium, potassium, glucose, total protein, albumin, ferritin, fibrinogen, and creatinine clearance (Cockcroft-Gault calculation), C-reactive protein (CRP), lactic dehydrogenase, HIV antibody, D-dimer, troponin, hepatitis C virus (HCV) antibody, and radiological examination (computerized tomography or X-ray of the chest). During the treatment period of 10 days, patients were followed up for their vital signs and disease progression daily. RT-PCR for COVID-19 was repeated on Days 7, 10 (end of experimental medication), 17 (7 days after the end of experimental medication) according to the practice of the study centers following the MoH standard procedures, and lab investigations were re-performed on Days 10 and 17. This study was conducted from September 2020 to March 2021 and followed the guidelines of the Declaration of Helsinki. The clinical sites' institutional review boards and ethics committees, and the Egyptian Ministry of Health approved the study. The trial is registered at the ISRCTN registry with registration number ISRCTN21085622. We included patients aged >18 years with laboratory-confirmed symptomatic COVID-19 as determined by PCR assay in any specimen collected <72 h before randomization, willing and able to provide written informed consent, and had the following disease severity grades: moderate (patients with respiratory rate ≥20 breaths/min, oxygen saturation measured through a pulse oximeter [SpO 2 ] ˃ 90% on room air and heart rate ≥90 beats/min), severe (not critical) (patients with clinical signs indicative of severe systematic illness with COVID-19; such as respiratory rate ≥30/min, heart rate ≥125/min, SpO 2 ≤ 90% on room air or PaO 2 / FiO 2 < 300). Degrees of severity of COVID-19 were defined according to WHO's COVID-19 disease severity classification. 15 We excluded patients with critically severe COVID-19 requiring invasive mechanical ventilation at screening, patients who have a severe concomitant illness, patients with hypersensitivity or contraindication to any of the drugs used in the study, patients with liver cirrhosis or elevated ALT, and/or AST above three times the upper limit of normal, patients with cardiac ischemia or clinically symptomatic cardiac abnormalities, patients with a history of any malignancy within the last 5 years, patients with a history of solid organ or bone marrow transplantation, patients who received treatment with any other investigational drug/device or involved in another clinical trial within 6 months before screening, people living with HIV, and pregnant or breastfeeding ladies. The study was conducted in four public hospitals dedicated at the time for COVID-19 patients in Egypt: Shebin Fever Hospital, Menouf Fever Hospital, Mahalla Fever Hospital, and the National Liver Institute. The investigational products were SOF 400 mg tablets The rate of SARS-COV-2 viral clearance by PCR on Day 9 of treatment with interferon-α plus lopinavir/ritonavir was 66.70% 17 ; while the rate of viral clearance among patients receiving the standard of care was 36.5%. 18 Assuming an α error of 0.05, a two-tail test, and a power of 0.85, a total of 102 patients (34 patients in each group) was appropriate to reject the null hypothesis that the virologic response rates for experimental and control subjects are equal with a probability of 0.85. To account for an expected dropout rate of 10%, a total of 120 patients (40 patients in each group) were randomized in a ratio of 1:1:1. The sample size was calculated using G*Power software version 3.1.9. Randomization was carried out centrally by a stratified block randomization technique using computer-generated sequences of three A total of 136 patients were screened for their eligibility for enrollment in this study between September 2020 to March 2021. Of them, 14 patients were ineligible for enrollment (screen failure), 2 withdrew their consent, and 120 patients were enrolled and randomized. All 120 randomized patients were included in the analysis of stated endpoints. Figure 1 shows the patients' flow diagram in the study according to the consolidated standards for reporting controlled randomized trials (CONSORT). Patients' baseline characteristics are presented in Table 1 . The three groups were almost homogenous regarding their demographics, comorbidities, and severity of the disease. The analysis was intention-to-treat and involved all patients who were randomly assigned. Adverse events (AEs) were significantly less reported among the SOF-DCV group than SOC, while the recorded number was nearly equal between SOC and SOF-RDV groups. Most of the reported events were related to the progression of the disease (death, ICU admission, and need for mechanical ventilation) ( Table 4 ). Death cases were notably less recorded among the SOF-DCV group compared to SOC. All mortalities were due to severe hypoxia leading to respiratory failure. Details of deaths are presented in Table 5 . There is no approved treatment for COVID-19 until now; there is an increasing list of antiviral agents extensively studied for their potential to be repurposed as a COVID-19 treatment. 20 In 2013, SOF was approved for treatment against HCV infection; it is a nucleotide analog that exerts its antiviral activity through nonstructural-5b (NS5b) inhibition. SOF acts as a substrate for HCV RNA-dependant-RNA-polymerase (RdRp), which incorporates into the newly synthesized viral RNA and terminates its synthesis resulting in inhibition of viral replication. 23 At the same time, DCV is an inhibitor for the nonstructural-5a (NS5a) protein which has several roles during the HCV replication cycle, including protein phosphorylation, RNA replication, and cell signaling. 24 Both HCV and SARS-CoV-2 share similarities between NS5a, and NS5b proteins, suggesting that both drugs could be effective antiviral drugs against SARS-CoV-2. 25 The combination of SOF and DCV is used for the treatment of chronic HCV with a high (>90%) sustained virologic response (SVR). 26 Enzymatic assays showed that SOF could act as a competitive inhibitor and chain terminator for SARS-CoV-2 RdRp, 27 patients. The study also showed that the addition of sub-inhibitory concentrations of DCV resulted in increased potency of SOF. 25 There is no available result of clinical studies evaluating the efficacy and safety of SOF-RDV among COVID-19 patients. A previous study by Esmat et al. 29 showed that a combination of SOF-RDV in addition to ribavirin was associated with a 95.3% response rate among HCV genotype-4 patients with or without cirrhosis. This is consistent with the STORM-C-1 trial, which reported that SOF-RDV is efficient and well-tolerated among different populations suffering from chronic HCV infection with or without comorbidities. 30 A recent molecular docking study suggested that RDV could be a potential antiviral drug against SARS-CoV-2 by inhibiting viral 3CLpro. 31 Nevertheless, in our study, we did not observe the superiority of a combination of SOF-RDV versus SOC. The current study was a randomized, open-label, prospective trial to evaluate the efficacy and safety of adding a combination of SOF plus SOF or RDV to standard medical care for COVID-19 patients. The results showed that there was a statistically significant reduction in the count of symptoms for the SOF-DCV arm on Days 7 and 10 compared with the SOC group. This statistically significant improvement was not reached in the SOF-RDV arm. By virtue of the natural history of the disease, significant improvement in oxygen saturation was observed over time for all study groups, with a consistently maintained significant benefit with SOF-DCV but not SOF-RDV versus SOC. In contrast to our findings, Roozbeh This study adds to the existing literature on the efficacy and safety of SOF-DCV combination to treat moderate to severe COVID-19 cases. SOF-DCV addition to the standard of care was found to improve clinical symptoms, oxygen saturation, and decrease ICU admission. The results highlight a potential for the combination to be integrated as an effective and safe antiviral agent to treat such cases. The study protocol was approved by the National Liver Institute ethical committee (NLI IRB 00003413) and by The Egyptian MoH IRB (IRB 0000687). Local ethics committees in the other three sites also approved the study protocol. The trial is registered at the ISRCTN registry with registration number ISRCTN21085622. We thank MARS Academy, Egypt for their assistance in statistical analysis. Also we extend our thank to TCD MENA monitoring team (Mohammed Ayman, Rehab Ahmed and Moamed Abdullatif) for their effective oversight throughout the project. 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