Safety of Sofosbuvir in People With Advanced Kidney Failure

NCT03883698 | Completed Phase 3

• 2 other identifiers: 2018-167-IMP-107CTRI/2019/03/018011
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Infection with hepatitis C virus (HCV), a hepatotropic RNA virus, is often chronic, and causes liver cirrhosis and liver cancer. The virus is transmitted through parenteral exposure. This infection is particularly common in those on maintenance hemodialysis. Sofosbuvir, an inhibitor of HCV RNA-dependent RNA polymerase, forms the backbone of DAA-based anti-HCV treatment regimens. In pre-clinical pharmacokinetic studies, administration of the usual 400 mg daily dose to in presence of advanced kidney failure (estimated glomerular filtration rate \[eGFR\] of \<30 ml/min) showed that serum levels of the sofosbuvir and GS-331007, the primary metabolite of sofosbuvir, were elevated by several folds. Hence, sofosbuvir is not approved for use in people on maintenance hemodialysis. The newer DAAs (e.g. grazoprevir/elbasvir combination), which have been approved for use in people with eGFR \<30 ml/min, are very costly and are not available in Asian countries including India. Hence, as a rescue measures, several physicians, including our group, have tried half-daily dose (i.e, 200 mg daily or 400mg on alternate days) of sofosbuvir and 60 mg daclatasvir in dialysis-dependent people, with good results in terms of both safety and efficacy. In fact, the use of this empirical 200 mg daily dose schedule has become common in clinical practice. However, this use is not based on any pharmacokinetic data. Hence, it is proposed to study the pharmacokinetics of low-dose (200 mg daily or 400 mg alternate day) of sofosbuvir and GS-331007 metabolite in people with eGFR \<30/min and active HCV infection.

Conditions

Kidney Failure, Chronic; Hepatitis C

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetics study

  To study the Maximum Plasma Concentration \[Cmax\] of sofosbuvir and its metabolite (GS-331007) in participants with eGFR below 30 ml/min who are treated with low-dose of sofosbuvir and compare it with that in people with normal eGFR.

  At hour (from the time of drug administration) '0', 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24 on Day 1; hour 36 on Day 2; at hour 84 on Day 4; and at hour 156 on Day 7

• Pharmacokinetics study

  To study the Area Under the Curve \[AUC\] of sofosbuvir and its metabolite (GS-331007) in participants with eGFR below 30 ml/min who are treated with low-dose of sofosbuvir and compare it with that in people with normal eGFR.

  At hour (from the time of drug administration) '0', 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24 on Day 1; hour 36 on Day 2; at hour 84 on Day 4; and at hour 156 on Day 7

• Pharmacokinetics study

  To study the Terminal Half Life \[t1/2\] of sofosbuvir and its metabolite (GS-331007) in participants with eGFR below 30 ml/min who are treated with low-dose of sofosbuvir and compare it with that in people with normal eGFR.

  At hour (from the time of drug administration) '0', 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24 on Day 1; hour 36 on Day 2; at hour 84 on Day 4; and at hour 156 on Day 7

Secondary Outcomes (1)

• Clinical response

  12 weeks after stopping anti-HCV treatment

Study Arms (3)

ESRD, alternate day dose

EXPERIMENTAL

Participants with end stage renal disease (eGFR \<30 ml/min) and hepatitis C virus active infection and treated with sofosbuvir 400 mg on alternate days. Total duration of treatment will be 12 weeks

Drug: Sofosbuvir; Drug: Daclatasvir 60 mg

ESRD, daily dose

EXPERIMENTAL

Participants with end stage renal disease (eGFR \<30 ml/min) and hepatitis C virus active infection and treated with sofosbuvir 200 mg daily doses. The total duration of treatment will be 12 weeks

Drug: Sofosbuvir; Drug: Daclatasvir 60 mg

Control

ACTIVE COMPARATOR

Participants with normal eGFR and hepatitis C virus infection and treated with sofosbuvir 400 mg daily dose. The total duration of treatment will be 12 weeks

Drug: Sofosbuvir; Drug: Daclatasvir 60 mg

Interventions

Sofosbuvir DRUG

Sofosbuvir is the backbone of the most of the currently used anti-HCV treatment regimens

Control; ESRD, alternate day dose; ESRD, daily dose

Daclatasvir 60 mg DRUG

Daclatasvir, in combination with sofosbuvir, is approved for the treatment of hepatitis C virus infection in absence of liver cirrhosis

Control; ESRD, alternate day dose; ESRD, daily dose

Eligibility Criteria

• Age: 19 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Participants with:
• hepatitis C virus infection with detectable HCV RNA in blood
• naïve to direct acting antiviral drugs based anti-HCV treatment

You may not qualify if:

• Hepatitis B virus co-infection
• Human immunodeficiency virus co-infection
• Clinical evidence of cirrhosis or portal hypertension such as ascites, esophageal or gastric varices on esophago-gastro-duodenoscopy, liver stiffness more than 15 KPa as measured with transient elastography or history of hepatic encephalopathy.

Sponsors & Collaborators

• Sanjay Gandhi Postgraduate Institute of Medical Sciences: lead

Study Sites (1)

Sanjay Gandhi Postgraduate Institute of Medical Sciences

Lucknow, Uttar Pradesh, 226014, India

Location

Related Publications (4)

• Kirby BJ, Symonds WT, Kearney BP, Mathias AA. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir. Clin Pharmacokinet. 2015 Jul;54(7):677-90. doi: 10.1007/s40262-015-0261-7.

  PMID: 25822283 BACKGROUND

• 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.

  PMID: 29650333 BACKGROUND

• Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int Suppl (2011). 2018 Oct;8(3):91-165. doi: 10.1016/j.kisu.2018.06.001. Epub 2018 Sep 19. No abstract available.

  PMID: 30675443 BACKGROUND

• Goel A, Bhadauria DS, Kaul A, Verma P, Mehrotra M, Gupta A, Sharma RK, Rai P, Aggarwal R. Daclatasvir and reduced-dose sofosbuvir: An effective and pangenotypic treatment for hepatitis C in patients with estimated glomerular filtration rate <30 mL/min. Nephrology (Carlton). 2019 Mar;24(3):316-321. doi: 10.1111/nep.13222.

  PMID: 29327401 BACKGROUND

MeSH Terms

Conditions

Kidney Failure, Chronic; Hepatitis C

Interventions

Sofosbuvir; daclatasvir

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Uridine Monophosphate; Uracil Nucleotides; Pyrimidine Nucleotides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleotides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleotides

Study Officials

• Amit Goel, DM

  Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: This is a three arm, case control study aimed at studying the pharmacokinetics of sofosbuvir and its major metabolite (GS-331007) in people with estimated GFR (eGFR) \<30 ml/min. Two arms will include participants with advanced renal failure with eGFR below 30 ml/min and third arm will include participants with normal eGFR. Participants with eGFR \<30 ml/min will receive sofosbuvir in doses of either 400mg on alternate days or 200mg daily. The participants with normal eGFR will receive the standard of care, i.e, 400mg of sofosbuvir daily

Study Record Dates

• First Submitted: March 15, 2019
• First Posted: March 21, 2019
• Study Start: March 15, 2019
• Primary Completion: August 1, 2020
• Study Completion: August 1, 2020
• Last Updated: April 6, 2021

Record last verified: 2021-04

Locations

IN (1)