Sofosbuvir Plus Ribavirin, or Ledipasvir/Sofosbuvir in Adults With HCV Infection and Renal Insufficiency

A Phase 2b, Open-Label Study of 200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed Dose Combination (FDC) Tablet for 12 Weeks in Genotype 1 or 4 HCV Infected Subjects With Renal Insufficiency

The primary objectives of this study are to evaluate the safety and efficacy of sofosbuvir (SOF) plus ribavirin (RBV) for 24 weeks and ledipasvir/sofosbuvir (LDV/SOF) for 12 weeks, and to evaluate the steady state pharmacokinetics (PK) of SOF and its metabolites and LDV in participants with genotype (GT) 1, 3, or 4 hepatitis C virus (HCV) infection who have chronic renal insufficiency (impaired kidney function).

Study Overview

• Status: Completed
• Conditions: HCV Infection
• Intervention / Treatment: Drug: SOF; Drug: RBV; Drug: LDV/SOF

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• New Zealand
  • Christchurch, New Zealand, 8011
  • Auckland
    • Grafton, Auckland, New Zealand, 1142
• Puerto Rico
  • San Juan, Puerto Rico, 00927
• United States
  • California
    • San Francisco, California, United States, 94115
  • Florida
    • Miami, Florida, United States, 33134
  • Illinois
    • Chicago, Illinois, United States, 60611
  • Michigan
    • Detroit, Michigan, United States, 48202
  • New York
    • Rochester, New York, United States, 14642
  • Texas
    • San Antonio, Texas, United States, 78215
  • Washington
    • Seattle, Washington, United States, 98104

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Cohorts 1 and 2: chronic genotype 1 or 3 HCV infection
• Cohort 3: chronic genotype 1 or 4 HCV infection
• HCV RNA ≥ 10^4 IU/mL at screening
• Screening labs within defined thresholds
• Cirrhosis determination at screening

Key Exclusion Criteria:

• Females who are pregnant or nursing or males who have a pregnant partner
• Prior null response to pegylated interferon (Peg-IFN)+RBV therapy (Cohorts 1 and 2) or for individuals with cirrhosis, prior treatment failure with IFN-based therapy not resulting from treatment intolerance (Cohort 3)
• Current of prior history of hepatic decompensation
• Infection with hepatitis B virus (HBV) or HIV
• History of clinically significant illness (including psychiatric or cardiac) or any other medical disorder that may interfere with individual's treatment and/or adherence to the protocol

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: SOF 200 mg + RBV 200 mg (Cohort 1); Participants with genotype 1 or 3 HCV infection will receive SOF 200 mg (2 × 100 mg tablets) plus RBV once daily for 24 weeks.	Drug: SOF; Tablet(s) administered orally once daily; Other Names: Sovaldi®; GS-7977; Drug: RBV; 200 mg tablet administered orally once daily
EXPERIMENTAL: SOF 400 mg + RBV 200 mg (Cohort 2); Participants with genotype 1 or 3 HCV infection will receive SOF 400 mg (4 × 100 mg tablets or 1 × 400 mg tablet) plus RBV once daily for 24 weeks.	Drug: SOF; Tablet(s) administered orally once daily; Other Names: Sovaldi®; GS-7977; Drug: RBV; 200 mg tablet administered orally once daily
EXPERIMENTAL: LDV/SOF (Cohort 3); Participants with genotype 1 or 4 HCV infection will receive LDV/SOF once daily for 12 weeks.	Drug: LDV/SOF; 90/400 mg fixed-dose combination (FDC) tablet administered orally once daily; Other Names: Harvoni®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)	SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 12 weeks after stopping study treatment.	Posttreatment Week 12
Percentage of Participants Experiencing Treatment-Emergent Adverse Events		Up to 24 weeks plus 30 days
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities	Treatment-emergent laboratory abnormalities were defined as values that increased by at least 1 toxicity grade from baseline at any time postbaseline up to the date of last dose of study drug plus 30 days.	Up to 24 weeks plus 30 days
Percentage of Participants Experiencing Clinically Significant 12-lead Electrocardiogram (ECG) Abnormalities		Up to 24 weeks plus 30 days
Percentage of Participants Experiencing Treatment-Emergent Adverse Events Associated With Vital Sign Abnormalities		Up to 24 weeks plus 30 days
Pharmacokinetic (PK) Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	Cmax is defined as the maximum concentration of drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	Cmax is defined as the maximum concentration of drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	Cmax is defined as the maximum concentration of drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	Ctau is defined as the observed drug concentration at the end of the dosing interval.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	Ctau is defined as the observed drug concentration at the end of the dosing interval.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	Ctau is defined as the observed drug concentration at the end of the dosing interval.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4)	SVR4 was defined as HCV RNA < LLOQ at 4 weeks after stopping study treatment.	Posttreatment Week 4
Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24)	SVR4 was defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment.	Posttreatment Week 24
Percentage of Participants With Overall Virologic Failure	Virologic failure was defined as: On-treatment virologic failure:Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), orRebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), orNon-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment); Virologic relapse:Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit.	Up to Posttreatment Week 24
PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	AUClast is defined as the concentration of drug from time zero to the last observable concentration.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	AUClast is defined as the concentration of drug from time zero to the last observable concentration.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	AUClast is defined as the concentration of drug from time zero to the last observable concentration.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	Clast is defined as the last observable concentration of drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	Clast is defined as the last observable concentration of drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	Clast is defined as the last observable concentration of drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	Tmax is defined as the time (observed time point) of Cmax.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	Tmax is defined as the time (observed time point) of Cmax.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	Tmax is defined as the time (observed time point) of Cmax.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	Tlast is defined as the time (observed time point) of Clast.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	Tlast is defined as the time (observed time point) of Clast.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	Tlast is defined as the time (observed time point) of Clast.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)	t1/2 is defined as the estimate of the terminal elimination half-life of the drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)	t1/2 is defined as the estimate of the terminal elimination half-life of the drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)	t1/2 is defined as the estimate of the terminal elimination half-life of the drug.	Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Gane EJ, Robson RA, Bonacini M, Maliakkal B, Kirby B, Liu L, et al. Safety, Antiviral Efficacy, and Pharmacokinetics of Sofosbuvir in Patients With Severe Renal Impairment [Poster 966]. The 65th Annual meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD); 2014 November 07-11; Boston, MA.
• Martin P, Gane E, Ortiz-Lasanta G, Liu L, Sajwani K, Kirby B, et al. Safety and Efficacy of Treatment With Daily Sofosbuvir 400 mg + Ribavirin 200 mg for 24 Weeks in Genotype 1 or 3 HCV-Infected Patients With Severe Renal Impairment [Poster 1128]. American Association for the Study of Liver Diseases (AASLD); 2015 November 13-17; San Francisco, CA.
• Lawitz E, Landis CS, Maliakkal BJ, Bonacini M, Ortiz-Lasanta G, Zhang J, et al. Safety and Efficacy of Treatment with Once- Daily Ledipasvir/Sofosbuvir (90/400 mg) for 12 Weeks in Genotype 1 HCV-Infected Patients with Severe Renal Impairment [Abstract 1587]. The Liver Meeting® 2017 - The 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2017 20-24 October; Washington, D. C.
• Lawitz E, Landis CS, Flamm SL, Bonacini M, Ortiz-Lasanta G, Huang J, Zhang J, Kirby BJ, De-Oertel S, Hyland RH, Osinusi AO, Brainard DM, Robson R, Maliakkal BJ, Gordon SC, Gane EJ. Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study. Lancet Gastroenterol Hepatol. 2020 Oct;5(10):918-926. doi: 10.1016/S2468-1253(19)30417-0. Epub 2020 Jun 10.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 7, 2013
• Primary Completion (ACTUAL): July 18, 2017
• Study Completion (ACTUAL): October 19, 2017

Study Registration Dates

• First Submitted: October 6, 2013
• First Submitted That Met QC Criteria: October 6, 2013
• First Posted (ESTIMATE): October 9, 2013

Study Record Updates

• Last Update Posted (ACTUAL): August 8, 2018
• Last Update Submitted That Met QC Criteria: July 13, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Communicable Diseases; Kidney Diseases; Urologic Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Infections; Hepatitis C; Renal Insufficiency; Anti-Infective Agents; Antiviral Agents; Sofosbuvir; Ledipasvir, sofosbuvir drug combination
• Other Study ID Numbers: GS-US-334-0154; 2013-002897-30 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No