Sofosbuvir/Ledipasvir and Nitazoxanide for Treatment of COVID-19

NCT ID: NCT04498936

Last Updated: 2020-11-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-15
• Study Completion Date: 2020-10-30

Brief Summary

The efficacy of treating COVID-19 infection by using Sofosbuvir/Ledipasvir and Nitazoxanide will be examined. Included patients will be into 3 groups. The 1st group will receive Sofosbuvir/Ledipasvir plus the standard care treatment (SCT). The 2nd group will take Nitazoxanide and SCT, while the 3rd group will receive only SCT. Then the clinical improvement and the rate of PCR change from positive to negative will be evaluated in each group.

Detailed Description

This study is an open-label, randomized, controlled trial. A total of 240 patients who are recruited in 2 quarantine hospitals (15th of May hospital, Cairo, and Al Rajhi hospital, Assiut), will be randomly assigned in a 1:1:1 ratio (80 patient in each treatment arm), to receive either the fixed combination of Sofosbuvir/Ledipasvir (400 mg and 90 mg, orally) once daily for 14 days, plus the standard care treatment regimen (SCT) for COVID-19 patients according to the Egyptian Ministry of Health (MOH) protocol (Group 1), or nitazoxanide (500 mg, orally) four times per day for 14 days, plus STC (Group 2), or SCT alone (Group 3). All treatment groups will be followed up by laboratory investigations and PCR for SARS-CoV-2 virus at the time of enrollment, days 5, 8, 11, and 14. Supportive care comprised, as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation (ECMO). To ensure a balanced distribution of case severities in all study groups, randomization will be stratified based on the case severity index issued by WHO (https://www.who.int/docs/default-source/coronaviruse/clinical-management-of-novel-cov.pdf).

Written informed consent will be obtained from all patients or the patient's legal representative if the patient is too unwell to provide consent. The trial will be conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonisation. The authors are responsible for designing the trial and for compiling and analyzing the data. The authors vouch for data completeness and accuracy and adherence to the trial protocol.

Conditions

COVID

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Sofosbuvir/Ledipasvir

This group will receive a fixed combination of Sofosbuvir/Ledipasvir (400 mg and 90 mg, orally) once daily for 14 days, plus the standard care treatment regimen (SCT) for COVID-19 patients according to the Egyptian Ministry of Health (MOH) protocol.

Group Type: EXPERIMENTAL

Sofosbuvir and Ledipasvir

Intervention Type: DRUG

Evaluate the efficacy of Sofosbuvir/Ledipasvir in treatment of COVID-19

Nitazoxanide

This group will receive nitazoxanide (500 mg, orally) four times per day for 14 days, plus the standard care treatment regimen (SCT) for COVID-19 patients according to the Egyptian Ministry of Health (MOH) protocol.

Group Type: EXPERIMENTAL

Nitazoxanide

Intervention Type: DRUG

Evaluate the efficacy of Nitazoxanide in treatment of COVID-19

Standard care treatment

This group will receive only the standard care treatment regimen (SCT) for COVID-19 patients according to the Egyptian Ministry of Health (MOH) protocol.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Sofosbuvir and Ledipasvir

Evaluate the efficacy of Sofosbuvir/Ledipasvir in treatment of COVID-19

Intervention Type: DRUG

Nitazoxanide

Evaluate the efficacy of Nitazoxanide in treatment of COVID-19

Intervention Type: DRUG

Other Intervention Names

Treatment; Treatment

Eligibility Criteria

Inclusion Criteria

• This study will include patients with confirmed COVID-19 infection and admitted to COVID-19 quarantine hospitals. Included patients should be > 12 years old, with creatinine clearance > 30 mL/ml, and without any malignancy. Patients with COVID-19 infection are classified clinically into mild, moderate, severe, and critical cases according to the management guide for COVID-19 published by the Egyptian Ministry of Health and Population. Mild cases are defined as patients in whom clinical symptoms are mild, and no pneumonia manifestations can be found in imaging. Moderate cases are defined as patients having symptoms such as fever and respiratory tract symptoms, etc. and pneumonia manifestations can be seen in imaging. Severe cases are patients who meet any of the following criteria; (a) respiratory rate > 30 breaths/min, (b) oxygen saturations< 93% at a rest state, (c) arterial partial pressure of oxygen (PaO2)/ Fraction of inspired oxygen (FiO2)<300 mm Hg, or (d) patients with more than 50% lesions progression within 24 to 48 hours in lung imaging should be treated as severe cases. Finally, critical patients are those who are meeting any of the following criteria; (a) occurrence of respiratory failure requiring mechanical ventilation, or (b) the presence of shock; other organ failures that require monitoring and treatment in the ICU. All patients with an established diagnosis of COVID-19 in Egyptian quarantine hospitals at any clinical stage will be included in this study.

Exclusion Criteria

• Patients < 12 years old.
• Pregnant females.
• Patients with renal impairment with creatinine clearance < 30 mL/min.
• Patients with malignancies particularly Hepatocellular Carcinoma (HCC).
• Patients using Favipiravir or Lopinavir-Ritonavir, as the co-administration of these drugs with Sofosbuvir/Ledipasvir has not been studied.
• Patients with decompensated liver cirrhosis (Child-Pugh score B and C).

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Helwan University

OTHER

Sponsor Role: collaborator

Assiut University

OTHER

Sponsor Role: lead

Responsible Party

Mohammed Ahmed Medhat

Lecturer of Tropical Medicine and Gastroenterology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mohammed A Medhat, PhD

Role: PRINCIPAL_INVESTIGATOR

Assiut University

Mohamed El Kassas, PhD

Role: STUDY_CHAIR

Helwan University

Haidi K Ramadan, PhD

Role: PRINCIPAL_INVESTIGATOR

Assiut University

Locations

15th May Hospital

Helwan, Cairo Governorate, Egypt

Assiut University Hospital

Asyut, , Egypt

Countries

Egypt

References

Ju, J., et al., Nucleotide Analogues as Inhibitors of Viral Polymerases. bioRxiv, 2020: p. 2020.01.30.927574.

Reference Type: BACKGROUND

Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47. doi: 10.1038/nrd.2015.37. Epub 2016 Feb 12.

Reference Type: BACKGROUND

PMID: 26868298 (View on PubMed)

Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020 Jul 15;253:117592. doi: 10.1016/j.lfs.2020.117592. Epub 2020 Mar 25.

Reference Type: BACKGROUND

PMID: 32222463 (View on PubMed)

Chen YW, Yiu CB, Wong KY. Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. F1000Res. 2020 Feb 21;9:129. doi: 10.12688/f1000research.22457.2. eCollection 2020.

Reference Type: BACKGROUND

PMID: 32194944 (View on PubMed)

Mo Y, Fisher D. A review of treatment modalities for Middle East Respiratory Syndrome. J Antimicrob Chemother. 2016 Dec;71(12):3340-3350. doi: 10.1093/jac/dkw338. Epub 2016 Sep 1.

Reference Type: BACKGROUND

PMID: 27585965 (View on PubMed)

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.

Reference Type: BACKGROUND

PMID: 32187464 (View on PubMed)

European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol. 2018 Aug;69(2):461-511. doi: 10.1016/j.jhep.2018.03.026. Epub 2018 Apr 9. No abstract available.

Reference Type: BACKGROUND

PMID: 29650333 (View on PubMed)

Wu A, Peng Y, Huang B, Ding X, Wang X, Niu P, Meng J, Zhu Z, Zhang Z, Wang J, Sheng J, Quan L, Xia Z, Tan W, Cheng G, Jiang T. Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China. Cell Host Microbe. 2020 Mar 11;27(3):325-328. doi: 10.1016/j.chom.2020.02.001. Epub 2020 Feb 7.

Reference Type: BACKGROUND

PMID: 32035028 (View on PubMed)

Frieman M, Baric R. Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation. Microbiol Mol Biol Rev. 2008 Dec;72(4):672-85, Table of Contents. doi: 10.1128/MMBR.00015-08.

Reference Type: BACKGROUND

PMID: 19052324 (View on PubMed)

Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014 Oct;110:94-103. doi: 10.1016/j.antiviral.2014.07.014. Epub 2014 Aug 7.

Reference Type: BACKGROUND

PMID: 25108173 (View on PubMed)

Lam KK, Zheng X, Forestieri R, Balgi AD, Nodwell M, Vollett S, Anderson HJ, Andersen RJ, Av-Gay Y, Roberge M. Nitazoxanide stimulates autophagy and inhibits mTORC1 signaling and intracellular proliferation of Mycobacterium tuberculosis. PLoS Pathog. 2012;8(5):e1002691. doi: 10.1371/journal.ppat.1002691. Epub 2012 May 10.

Reference Type: BACKGROUND

PMID: 22589723 (View on PubMed)

Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016 May-Jun;9(3):227-30. doi: 10.1016/j.jiph.2016.04.001. Epub 2016 Apr 16.

Reference Type: BACKGROUND

PMID: 27095301 (View on PubMed)

Rossignol JF, La Frazia S, Chiappa L, Ciucci A, Santoro MG. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem. 2009 Oct 23;284(43):29798-808. doi: 10.1074/jbc.M109.029470. Epub 2009 Jul 28.

Reference Type: BACKGROUND

PMID: 19638339 (View on PubMed)

Cao J, Forrest JC, Zhang X. A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs. Antiviral Res. 2015 Feb;114:1-10. doi: 10.1016/j.antiviral.2014.11.010. Epub 2014 Nov 28.

Reference Type: BACKGROUND

PMID: 25451075 (View on PubMed)

Padmanabhan, S., Potential dual therapeutic approach against SARS-CoV-2/COVID-19 with Nitazoxanide and Hydroxychloroquine. 2020.

Reference Type: BACKGROUND

Ueda Y, Ikegami T, Akamatsu N, Soyama A, Shinoda M, Goto R, Okajima H, Yoshizumi T, Taketomi A, Kitagawa Y, Eguchi S, Kokudo N, Uemoto S, Maehara Y. Treatment with sofosbuvir and ledipasvir without ribavirin for 12 weeks is highly effective for recurrent hepatitis C virus genotype 1b infection after living donor liver transplantation: a Japanese multicenter experience. J Gastroenterol. 2017 Aug;52(8):986-991. doi: 10.1007/s00535-017-1310-9. Epub 2017 Jan 30.

Reference Type: BACKGROUND

PMID: 28138756 (View on PubMed)

Liu CJ, Chuang WL, Sheen IS, Wang HY, Chen CY, Tseng KC, Chang TT, Massetto B, Yang JC, Yun C, Knox SJ, Osinusi A, Camus G, Jiang D, Brainard DM, McHutchison JG, Hu TH, Hsu YC, Lo GH, Chu CJ, Chen JJ, Peng CY, Chien RN, Chen PJ. Efficacy of Ledipasvir and Sofosbuvir Treatment of HCV Infection in Patients Coinfected With HBV. Gastroenterology. 2018 Mar;154(4):989-997. doi: 10.1053/j.gastro.2017.11.011. Epub 2017 Nov 22.

Reference Type: BACKGROUND

PMID: 29174546 (View on PubMed)

Lim YS, Ahn SH, Lee KS, Paik SW, Lee YJ, Jeong SH, Kim JH, Yoon SK, Yim HJ, Tak WY, Han SY, Yang JC, Mo H, Garrison KL, Gao B, Knox SJ, Pang PS, Kim YJ, Byun KS, Kim YS, Heo J, Han KH. A phase IIIb study of ledipasvir/sofosbuvir fixed-dose combination tablet in treatment-naive and treatment-experienced Korean patients chronically infected with genotype 1 hepatitis C virus. Hepatol Int. 2016 Nov;10(6):947-955. doi: 10.1007/s12072-016-9726-5. Epub 2016 May 20.

Reference Type: BACKGROUND

PMID: 27198664 (View on PubMed)

Fox LM, Saravolatz LD. Nitazoxanide: a new thiazolide antiparasitic agent. Clin Infect Dis. 2005 Apr 15;40(8):1173-80. doi: 10.1086/428839. Epub 2005 Mar 14.

Reference Type: BACKGROUND

PMID: 15791519 (View on PubMed)

Stockis A, Deroubaix X, Lins R, Jeanbaptiste B, Calderon P, Rossignol JF. Pharmacokinetics of nitazoxanide after single oral dose administration in 6 healthy volunteers. Int J Clin Pharmacol Ther. 1996 Aug;34(8):349-51.

Reference Type: BACKGROUND

PMID: 8864798 (View on PubMed)

Related Links

https://google.com/covid19-map/?hl=en

Epidemiological data about Covid-19

Other Identifiers

COVID-19 treatment

Identifier Type: -

Identifier Source: org_study_id