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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 294-316

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


1 Infectious Diseases Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Infectious Diseases, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
2 Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
3 Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Pharmacognosy and Biotechnology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
4 Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
5 Department of Infectious Diseases, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

Date of Submission08-Apr-2021
Date of Acceptance07-Aug-2021
Date of Web Publication17-Dec-2021

Correspondence Address:
Prof. Reza Khodarahmi
Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah.
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrptps.JRPTPS_46_21

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  Abstract 

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 (random-numbers 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.

Keywords: COVID-19, protocol, randomized controlled trial, sofosbuvir/velpatasvir, treatment


How to cite this article:
Sayad B, Mehrabi M, Khodarahmi R, Najafi F, Miladi R, Mohseni Afshar Z, Mansouri F, Shirvani M, Salimi M, Shadmani FK. 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. J Rep Pharma Sci 2021;10:294-316

How to cite this URL:
Sayad B, Mehrabi M, Khodarahmi R, Najafi F, Miladi R, Mohseni Afshar Z, Mansouri F, Shirvani M, Salimi M, Shadmani FK. 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. J Rep Pharma Sci [serial online] 2021 [cited 2022 Jan 17];10:294-316. Available from: https://www.jrpsjournal.com/text.asp?2021/10/2/294/332785




  Introduction Top


Since December 2019, COVID-19 (an international health problem around the world), developed by SARS-CoV-2, has caused a global outbreak of pulmonary disease.[1],[2] In contrast to this fact that the most infected patients appear mild, some patients have pulmonary complications with lethal lung injury.[3] More than 52 million individuals worldwide have been affected by COVID-19 and 1,284,690 have died as of November 11, 2020 (https://www.worldometers.info/coronavirus/). Although the most of participants experience a mild-to-moderate disease, some patients develop pulmonary distress with lung damage and multi-organ failure. To date, there are no known available effective antiviral drug for the treatment of severe COVID-19 patients.[4],[5] Hydroxychloroquine administration did not decrease the risk of mortality.[6] Remdesivir has not shown any statistically meaningful clinical advantages.[2] In hospitalized individuals with severe COVID-19, lopinavir–ritonavir treatment had no benefit over the existing standard of care (SOC).[7] Tocilizumab, mavrilimumab, anakinra, and interferon beta-1b may be effective, but confirmation of effectiveness requires more controlled trials; therefore, referring patients to clinical trials is very important.[8],[9],[10],[11],[12] Sofosbuvir, the FDA-approved drug for the treatment of hepatitis C virus (HCV), also is able to inhibit other members of positive-sense RNA viruses (Togaviridae and Flaviviridae). The available data reported the theoretical efficacy of ribavirin and sofosbuvir in the treatment of COVID-19 patients.[13],[14],[15],[16] Coronaviruses are a family of RNA viruses with conserved RNA-dependent polymerase (RdRp), so that SARS-CoV-2 RdRp is most probably to be successfully inhibited by this safe and well-tolerated antiviral drug and it is suggested that sofosbuvir could be used as treatment against SARS-CoV-2 infection.[15] Also, velpatasvir is a potent inhibitor of the NS5A protein of HCV. According to the recent studies, velpatasvir can inhibit the biological activity of 3C-like protease (3CLpro) of coronavirus.[14] Therefore, sofosbuvir in combination with velpatasvir may be good candidates as inhibitor of two coronavirus enzymes, and this combined therapy may reduce the emergence of virus resistance. Direct-acting antiviral agents have fewer associated side effects and also they are simply administered orally.[17] The goal of the current trial is to determine the usefulness of “SOC plus hydroxychloroquine and lopinavir/ritonavir” vs. “SOC plus a combination of hydroxychloroquine and lopinavir/ritonavir and sofosbuvir/velpatasvir” in hospitalized individuals with laboratory-confirmed COVID-19 disease.

Methods/design

In this randomized controlled trial, individuals over 18 years of age who have been diagnosed with COVID-19 by positive reverse transcriptase–polymerase chain reaction (RT–PCR) for SARS-CoV-2 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 and reducing hospital stays. Adverse events were handled and reported in accordance with the Good Clinical Practice (GCP) guidelines.

Perspective

If COVID-19 treatment with sofosbuvir/velpatasvir-containing regimen can reduce mortality, reduce time to clinical improvement, or reduce hospital stay, it may be introduced as one of the effective treatments for this disease.

Trial registration

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).

Objectives

The goal of this survey is to determine the safety and efficacy of “SOC plus hydroxychloroquine and lopinavir/ritonavir” vs. “SOC plus a combination of hydroxychloroquine and lopinavir/ritonavir and sofosbuvir/velpatasvir” in hospitalized individuals with SARS-CoV-2-related disease, i.e., COVID-19. In other words, the primary goal of this clinical trial is to assess (1) all-cause mortality in hospital and up to 28 days after randomization and (2) the efficacy of the employed regimens with respect to clinical status (clinical improvement, time to clinical improvement, duration of hospitalization). Clinical improvement was assessed by a six-stage saturation status on days 3, 5, and 7. Clinical improvement was defined as follows: reduce the two points (from the status at randomization) on a six-stage saturation status or live discharge from the hospital, whichever comes first, i.e., the point at which the individual/recovered patient was deemed eligible for discharge from hospital as per the study-specific criteria. Also we set out to determine whether the employed sofosbuvir–velpatasvir-based regimen could shorten the duration of hospitalization and modify ICU admissions and/or requirement for invasive mechanical ventilation.


  Materials and Methods Top


Design

This project was a single center, prospective, randomized controlled trial, with two arms (ratio 1:1) parallel groups design. One arm of the patients received treatment with SOC plus hydroxychloroquine and lopinavir/ritonavir (dual therapy) and the other arm received treatment with SOC plus a combination of hydroxychloroquine and lopinavir/ritonavir and sofosbuvir/velpatasvir (triple therapy). The study followed the principles of GCP. SOVECOD stands for sofosbuvir/velpatasvir for possible COVID-19 treatment.

Patients

Patients who were hospitalized with COVID-19 (according to positive RT–PCR and/or compatible chest CT scan) were screened for eligibility at Farabi Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Inclusion and exclusion criteria

Patients showing signs and symptoms of COVID-19 were screened for eligibility using a flowchart. This flowchart is already in use at Farabi Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran (see Supplementary File). The screening was carried out by an infectious diseases’ resident or a trained General Practitioner. The individuals who meet eligibility criteria were adequately given information about the SOVECOD study. If they wanted to participate, they would be given a consent form which should be signed by the participant and the principle investigator. The Kermanshah University of Medical Sciences (KUMS) and the National Research Ethics Committee in Iran confirmed the consent form.

Inclusion criteria

Inclusion criteria are as follows:

  • - Confirmed COVID-19 diagnosis (positive RT–PCR and/or compatible chest CT scan);


  • - Patients over 18 years;


  • - Absolute lymphocyte count <1100/μL or SaO2≤ 93.


Exclusion criteria

Exclusion criteria are selected according to the doctor’s decision, and patients who have any of the following criteria will be excluded to participate in the survey:

  • - Pregnancy and breast-feeding;


  • - The doctor’s decision that enrollment in the study was not a good option for patients;


  • - Presence of conditions that do not allow the protocol to be completed;


  • - Known hypersensitivity or allergy to hydroxychloroquine, sofosbuvir–velpatasvir, or lopinavir–ritonavir;


  • - Known severe liver disease (e.g., cirrhosis, with an alanine aminotransferase or an aspartate aminotransferase level >5× the upper limit of the normal range);


  • - Use of drugs that are contraindicated include hydroxychloroquine, sofosbuvir–velpatasvir, or lopinavir–ritonavir;


  • - Known human immunodeficiency virus (HIV) or HCV infection.


If the patient is having difficulty swallowing, oral drugs are administered through NG tube.

Data collection and management

Nasopharyngeal swab

Nasopharyngeal swab specimens were collected on day 1 (before drug administration) and at the time of discharge for qualitative SARS-CoV-2 RT–PCR.

Six-stage saturation status, drugs safety, and laboratory findings

Patients were visited every day by trained nurses using daily record cards and flow-sheets that captured data on a six-stage saturation status and on safety from day 1 to hospital discharge or death. Safety was checked in accordance with the GCP guidelines (see Supplementary File).

Outcomes

Primary outcome measures

  • - All-cause mortality in hospital and up to 28 days after randomization.


Secondary outcome measures

  • - Clinical improvement: Reduce the two points (from the status at randomization) on a six-stage saturation status (see Supplementary File) or live discharge from the hospital, whichever comes first;


  • - Clinical recovery time: The time from randomization to clinical recovery;


  • - Length of hospital stay;


  • - Need for mechanical ventilation;


  • - Duration for mechanical ventilation;


  • - The number of days from randomization to death;


  • - PCR conversion from positive to negative at the time of randomization to discharge from hospital.


The size of sample

Although there were several outcomes that the investigators were interested in, as previous studies have not compared these two types of treatment regimens, we decided to determine the size of sample according to the “duration of stay in hospital.” By consulting with the infectious disease specialists who were all involved in the management of COVID-19 cases, we assumed that the significant difference between the two groups is only 1 day with a standard deviation of 1.5 days. Therefore, such study needs 36 experimental individuals and 36 control individuals to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with probability (power) of 0.8. The Type I error probability associated with this test of null hypothesis is 0.05.

Blinding and randomization

For the purpose of allocation sequence generation, using a random-numbers table (as Excel file) and simple random allocation, 80 included patients entered to the study, 40 patients in each group. 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 an open label, randomized trial in which all the physicians and nurses plus all patients were aware of the type of treatment.

Intervention

Day 1

After the consent form was signed by the patient and physician, the epidemiological and clinical information questionnaire was completed by an infectious diseases’ resident. Also, the status of the patients on a six-stage saturation status and laboratory findings upon enrollment records were registered in cards and flow-sheets. Specimens of nasopharyngeal swab were collected on day 1 (before drug administration). The patients were randomized into two arms: 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 non-invasive and invasive ventilation, supplemental oxygen, vasopressor support, antibiotic agents, renal-replacement therapy, and corticosteroids.

Days 1–10 or day of hospital discharge or death

Patients were regularly visited every day by an infectious disease doctor and their treatment process was thoroughly checked. Also, they were assessed daily by trained nurses using daily record cards and flow-sheets that captured data on a six-stage saturation status and on safety from day 1 to hospital discharge, or death. Safety was monitored according to the GCP guidelines. Specimens of nasopharyngeal swab were collected on day 1 (before drug administration) and at the time of discharge (see Supplementary File).

Day 28

The health status of patients who have been discharged from the hospital prior to 28 days after enrollment to the study was questioned/followed over the phone and recorded in their respective files.

Safety

Criteria for termination of the study

For the individual patient:

  • - Serious adverse effect to the study drugs;


  • - Decided to leave the survey.


For the study itself:

  • - When an enough number of individual cases are included in the study;


  • - If more than 10% of cases in each study arm stop taking the drugs for any reason.


Adverse effects

We expected gastrointestinal intolerance for both study arms. During the daily visit of patients, the occurrence of drug side effects was considered by the infectious disease specialist and patients were asked about them and are openly recorded in the patients’ files. In case of severe adverse effects, it was reported according to the principles of GCP and treatment was stopped.

Potential drug interactions

Sofosbuvir/velpatasvir has no interaction with hydroxychloroquine. In contrast, sofosbuvir/velpatasvir has interaction with ritonavir and their interactions can lead to an increase in the amount of sofosbuvir/velpatasvir in the patient’s body, but as the amount of ritonavir in lopinavir/ritonavir is very low (its amount in our daily regimen is 100 mg), it is not used therapeutically, so this combination therapy has shown good safety with minimal drug interactions. In other words, ritonavir is a protease inhibitor, an anti-HIV drug, that decreases the amount of virus in the body and its effective dose for the treatment of HIV infection is 300 mg twice daily which is a very high dose. However, ritonavir is currently exclusively used as a pharmacokinetic enhancer of other protease inhibitors with the standard adult dose of 100 mg twice daily which is a very low dose compared with 300 mg twice daily (for the treatment of HIV infection). So in this trial, combination of ritonavir with sofosbuvir/velpatasvir has demonstrated minimal drug interactions. More importantly, sofosbuvir is safe and well tolerated at 400 mg (and even 1200 mg) daily in a 24-week therapeutic regimen; therefore, its interaction was not serious.

Registering and handling of data

Data registration was done during the study. For this purpose, a file had been prepared for each patient and data handling followed the principles of GCP. Subject requests for access to the trial database will be considered in discussion with the local Research Ethics Committee.

Statistical analyses

Data analyses were conducted according to the intention-to-treat basis and employed to cover all the patients included in the randomization process. The median [inter-quartile range (IQR)] and number (percent) were considered for the quantitative and qualitative variables, respectively. The independent sample T-test and the Mann–Whitney test were used to compare the groups in terms of quantitative variables. Also, using the χ2 test, qualitative variables in the groups were compared. In addition, Fisher’s exact test was applied in case of data sparsity. Employing version 14 of Stata software, the statistical analysis was performed. In the course of analysis, impossible range data and outlier were taken into consideration and finally, P < 0.05 was considered significant.

Monitoring

A person has been appointed by the University Ethics Committee to oversee all stages of the project. This trial was managed in consistent with the rules of the GCP, ethical principles of the Helsinki Declaration, and national laws and regulations.

Ethical considerations

Unfortunately, there is not any effective antiviral treatment for COVID-19 patients[5],[6]; therefore, referring patients to clinical trials is crucial.[11],[12] In the current trial, half of the cases received hydroxychloroquine 400 mg single dose and lopinavir–ritonavir (400 and 100 mg) twice daily orally, plus SOC for 10 days, and the other half was administered with hydroxychloroquine 400 mg single dose and lopinavir–ritonavir (400 and 100 mg) twice daily plus sofosbuvir–velpatasvir (400 and 100 mg) once daily. Developing serious adverse effect was low because of acceptable safety profile of sofosbuvir/velpatasvir in the intervention arm. If the patient was diagnosed as eligible to enter the study, he/she would be provided by the required information orally and in writing. It is noteworthy that participation was entirely voluntary and leaving the study had no effect on the type/quality of assistance or treatment. It was clear that a participant can leave the research study at any moment. If the participants had any questions about the clinical trial, they could call a research nurse or a research physician at the study site. It is emphasized that if the participants worsened during the survey or experienced serious side effects, they informed the infectious disease specialist or the nurses of the hospital, and the trial was discontinued if anyone displayed an unusual or unknown reaction.

Ethical approval for this study was received from the Research Ethics Committee at Kermanshah University of Medical Sciences, Kermanshah, Iran on March 3, 2020 (this trial is sponsored by the Kermanshah University of Medical Sciences, reference IR.KUMS.REC.1399.044). All the information about intervention details plus SOC for 10 days were in the informed consent. All of the research participants were given the SOC as well as the drugs recommended in the international guidelines for the treatment of COVID-19.


  Preliminary Results and Discussion Top


There is no known established treatment recommended for SARS-CoV-2 infection. Patients who had moderate-to-acute illness are usually admitted at the hospital. Although some medications have been suggested to treat COVID-19, their results are not sufficient to apply these experimental treatments outside of clinical research. Well-organized randomized controlled studies are essential for the treatment of Covid-19. Sofosbuvir, the clinically approved drug against HCV, is also able to inhibit other members of positive-sense RNA viruses (Togaviridae and Flaviviridae) and may have inhibitory activity against SARS-CoV-2 RdRp. Notably, sofosbuvir is safe and well tolerated at 400 mg (and even 1200 mg) a day in a 24-week therapeutic regimen.[15] Sofosbuvir active metabolite, however, indicates very high intracellular stability; therefore, it is predicted that SARS-CoV-2 infection in vivo could also be susceptible to sofosbuvir,[15] whereas velpatasvir can inhibit the biological activity of 3C-like protease (3CLpro) of coronavirus, so we conducted an open label randomized controlled trial to assess safety, efficacy, and effectiveness of sofosbuvir–velpatasvir as add-on treatment to national SOC in hospitalized adults with Covid-19. If we demonstrate that all-cause mortality in hospital and up to 28 days after randomization is significantly lower in the sofosbuvir–velpatasvir arm, we can suggest the use of this drug in future “large-scale trials” in patients with severe illness to determine the benefits of treatment. Shortening clinical improvement time, reducing hospital stay, the need for mechanical ventilation, duration for mechanical ventilation, the number of days from randomization to death, and also PCR conversion from positive to negative at the time of randomization to discharge from hospital in the intervention arm can be due to the possible effectiveness of sofosbuvir/velpatasvir.

As a primary outcome, the 28-day mortality rate was numerically greater in the sofosbuvir/velpatasvir arm (n = 3, 13%) in comparison to the control arm (n = 1, 3.7%); but the difference was statistically non-significant. In addition, it is to be noted that after randomization, one patient in the sofosbuvir/velpatasvir arm died within the first 24 h of admission and did not administer sofosbuvir/velpatasvir.

As a secondary outcome, the median time to clinical recovery within 28 days in the sofosbuvir/velpatasvir [6 days (IQR 5–8)] and control arms [6 days (IQR 4–12)] was the same. Other secondary outcome was the length of stay in hospital. The median length of hospitalization in the control group and intervention group was also the same (6 days). Moreover, conversion of RT–PCR result was statistically non-significant between the two arms; P=0.17 [Table 1].
Table 1: Interim analysis on the 13th day of the study

Click here to view


In addition, need for mechanical ventilation and duration of mechanical ventilation were not significantly different between arms (data not shown). More common adverse reactions in both arms (the intervention and control arms) were nausea, vomiting, diarrhea, and headache, respectively. Diarrhea incidence in the intervention arm was significantly higher than that in the control group. No significant difference existed in the incidence of other adverse events between the arms. Furthermore, there were no apparent differences in biochemistry laboratory abnormalities between the arms (data not shown).

As a summary, the antiviral drug, sofosbuvir, displayed encouraging results for the inhibition of SARS-CoV-2 RdRp activity in vitro (see citing references of Sayad et al.[15]). But, interestingly, clinical recovery within specified days of trial, duration of hospital stays, and the pooled risk of all-cause mortality in the sofosbuvir/velpatasvir arm (in the clinical trial) showed no statistically significant change when compared with those of the control arm [Table 1]. So, it can be inspired from the evidence that the sofosbuvir/velpatasvir regimen does not improve recovery and the dead rate in hospitalized COVID-19 patients with moderate-to-severe illness. However, we should wait for the final results of the research and re-analyze the whole data. The preliminary result of this well-designed trial is of great importance because Simmons et al.[18] in a recently published report have concluded that sofosbuvir/daclatasvir improves recovery and survival in hospitalized COVID-19 patients with moderate-to-severe illness. However, it is noteworthy that (contrary to our well-designed clinical trial) in the mentioned study: (a) the size of the sample for clinical trial was approximately small, (b) one of the analyses was not randomized, and (c) the designs were not standardized and the results should be confirmed in greater randomized clinical trials. Change in the drug administration (for instance, sofosbuvir as rectal formulation), increase of duration of the intervention, or increase of drug dosage (e.g., 800 mg daily of sofosbuvir) should be considered in upcoming clinical trials.

Acknowledgements

The authors gratefully acknowledge the help provided by the nursing staff in all departments of Farabi University Hospital. We would also like to thank the Radiology Department and the Clinical Laboratory Department of Farabi University Hospital for their cooperation. The authors wish to thank the Research Council of Kermanshah University of Medical Sciences for the financial support (Grant No. 990097).

Financial support and sponsorship

The clinical study was sponsored by the KUMS Research Council (Grant No. 990097) as funding body. It is also declared that the funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript but it monitors/assesses the study.

Conflicts of interest

The authors declare that they have no competing interests. Ethics approval and consent to participate were given.

Authors’ contributions

BS and RK conceived and designed the study, FN and FKS contributed to randomization and statistical analysis, RM, ZMA, FM, MSH, and MS contributed to study design. RK led the drafting of the manuscript and BS and MM edited the manuscript. The authors wrote, read, and approved the final manuscript.

Ethical approval and consent form to participate

This trial has received ethical approval from the Research Ethics Committee at Kermanshah University of Medical Sciences (KUMS), Kermanshah, Iran on March 3, 2020 (reference IR.KUMS.REC.1399.044). We also certify that this trial has received ethical approval from the appropriate ethical committee as described above. Written informed consent was obtained from all patients or their legal representative if they were unable to provide consent.

Consent for publication

Not applicable.

Data and materials availability

The data (in details) will be available from the corresponding author (on reasonable request). This needs agreement of KUMS Research Council.

Trial registration

This clinical trial has been registered on March 30, 2020 under IRCT number 46790, as: “Comparative assessment of the efficacy and safety of add-on treatment with ‘sofosbuvir plus velpatasvir’ to ‘standard of care therapeutic regimen’ in patients with COVID-19” in Iranian Registry of Clinical Trials (https://www.irct.ir/trial/46790).



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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