Ledipasvir/Sofosbuvir Fixed-Dose Combination + Ribavirin in Subjects With Chronic HCV With Advanced Liver Disease or Post-Liver Transplant

A Phase 2, Multicenter, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Ledipasvir Fixed-Dose Combination + Ribavirin Administered in Subjects Infected With Chronic HCV Who Have Advanced Liver Disease or Are Post-Liver Transplant

This study will evaluate ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) plus ribavirin (RBV) in participants with advanced liver disease or posttransplant and chronic genotype 1 or 4 hepatitis C virus (HCV) infection.

• Cohort A: decompensated cirrhosis (advanced liver disease), no prior liver transplant;
• Cohort B: post-liver transplant, with or without cirrhosis;
• Group assignment within cohorts is based on severity of liver impairment at screening (Child-Pugh-Turcotte (CPT) score for participants with cirrhosis; fibrosis; or presence of disease for fibrosing cholestatic hepatitis (FCH) groups)
• Randomization is 1:1 within groups to 12 or 24 weeks of LDV/SOF+RBV treatment.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 339
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
  • California
    • San Diego, California, United States, 92103
    • San Francisco, California, United States, 94143
  • Colorado
    • Aurora, Colorado, United States, 80045
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
  • Florida
    • Jacksonville, Florida, United States, 32224
    • Miami, Florida, United States, 33136
  • Illinois
    • Chicago, Illinois, United States, 60611
  • Indiana
    • Indianapolis, Indiana, United States, 46202
  • Kansas
    • Kansas City, Kansas, United States, 66160
  • Maryland
    • Lutherville, Maryland, United States, 21093
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
    • Detroit, Michigan, United States, 48202
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
    • Rochester, Minnesota, United States, 55905
  • Missouri
    • Saint Louis, Missouri, United States, 63110
  • New York
    • New York, New York, United States, 10016
    • New York, New York, United States, 10032
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
    • Durham, North Carolina, United States, 27710
  • Ohio
    • Cleveland, Ohio, United States, 44195
  • Oregon
    • Portland, Oregon, United States, 97239
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
    • Pittsburgh, Pennsylvania, United States, 15213
  • Texas
    • Dallas, Texas, United States, 75246
  • Utah
    • Murray, Utah, United States, 84107
  • Virginia
    • Richmond, Virginia, United States, 23219
  • Washington
    • Seattle, Washington, United States, 98104
    • Seattle, Washington, United States, 98101

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

Inclusion Criteria:

• Able to provide written informed consent
• Chronic genotype 1 or 4 HCV infection
• Normal ECG
• Negative serum pregnancy test for female subjects
• Male subjects and female subjects of childbearing potential must agree to use contraception
• Able to comply with the dosing instructions for study drug and able to complete the study schedule of assessments, including all required post treatment visits

Exclusion Criteria:

• Serious or active medical or psychiatric illness
• HIV or hepatitis B viral (HBV) infection
• Stomach disorder that could interfere with the absorption of the study drug
• Treated with an anti-HCV medication in the last 30 days
• Any prior exposure to an HCV nonstructural protein (NS)5a-specific inhibitor
• Use of human granulocyte-macrophage colony-stimulating factor (GM-CSF), epoetin alfa or other therapeutic hematopoietic agents within 2 weeks of screening
• History of clinically significant medical condition associated with other chronic liver disease
• Active spontaneous bacterial peritonitis at screening
• Females who are breastfeeding
• Infection requiring systemic antibiotics
• Participated in a clinical study with an investigational drug or biologic within the last 30 days
• Active or history (last 6 months) of drug or alcohol abuse
• History of organ transplant other than liver or kidney

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

14

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort A, Group 1 (12 wk): CPT Class B (7-9); LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 12 weeks in participants with CPT Class B (CPT score 7-9)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort A, Group 1 (24 wk): CPT Class B (7-9); LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 24 weeks in participants with CPT Class B (CPT score 7-9)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort A, Group 2 (12 wk): CPT Class C (10-12); LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 12 weeks in participants with CPT Class C (CPT score 10-12)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort A, Group 2 (24 wk): CPT Class C (10-12); LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 24 weeks in participants with CPT Class C (CPT score 10-12)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 3 (24 wk): F0-F3 Fibrosis; LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with Fibrosis Stage F0-F3	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 4 (12 wk): CPT Class A (5-6); LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with CPT Class A (CPT score 5-6)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 4 (24 wk): CPT Class A (5-6); LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with CPT Class A (CPT score 5-6)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 5 (12 wk): CPT Class B (7-9); LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 12 weeks in participants with CPT Class B (CPT score 7-9)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 5 (24 wk): CPT Class B (7-9); LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 24 weeks in participants with CPT Class B (CPT score 7-9)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 6 (12 wk): CPT Class C (10-12); LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 12 weeks in participants with CPT Class C (CPT score 10-12)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 6 (24 wk): CPT Class C (10-12); LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 24 weeks in participants with CPT Class C (CPT score 10-12)	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 7 (12 wk): FCH; LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with FCH	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 7 (24 wk): FCH; LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with FCH	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose
EXPERIMENTAL: Cohort B, Group 3 (12 wk): F0-F3 Fibrosis; LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with Fibrosis Stage F0-F3.	Drug: LDV/SOF; LDV/SOF FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: RBV; RBV tablets administered orally in a divided daily dose

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 Who Discontinued Study Drug Due to an Adverse Event		Up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HCV RNA < LLOQ at Week 2		Week 2
Percentage of Participants With HCV RNA < LLOQ at Week 4		Week 4
Percentage of Participants With HCV RNA < LLOQ at Week 8		Week 8
Percentage of Participants With HCV RNA < LLOQ at Week 12		Week 12
Percentage of Participants With SVR 2 Weeks After Discontinuation of Therapy (SVR2)	SVR2 was defined as HCV RNA < LLOQ at 2 weeks after stopping study treatment.	Posttreatment Week 2
Percentage of Participants With SVR 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 8 Weeks After Discontinuation of Therapy (SVR8)	SVR8 was defined as HCV RNA < LLOQ at 8 weeks after stopping study treatment.	Posttreatment Week 8
Percentage of Participants With SVR 24 Weeks After Discontinuation of Therapy (SVR24)	SVR24 was defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment.	Posttreatment Week 24
Percentage of Participants With Virologic Failure	Virologic failure was defined as: On-treatment virologic failure:Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ on 2 consecutive measurements while on treatment), orRebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on 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
Percentage of Participants With HCV RNA < LLOQ at Week 1		Week 1
Percentage of Participants With HCV RNA < LLOQ at Week 6		Week 6
Percentage of Participants With HCV RNA < LLOQ at Week 16		Week 16
Percentage of Participants With HCV RNA < LLOQ at Week 20		Week 20
Percentage of Participants With HCV RNA < LLOQ at Week 24		Week 24
Percentage of Participants With a Decrease, No Change, or Increase Between Baseline and Posttreatment Week 4 in MELD Score	Model for End-Stage Liver Disease (MELD) scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40; higher scores/increased scores indicate greater severity of disease.	Baseline to Posttreatment Week 4
Percentage of Participants With a Decrease, No Change, or Increase Between Baseline and Posttreatment Week 4 in CPT Score	CPT scores grade the severity of cirrhosis and are used to determine the need for liver transplantation. Scores can range from 5 to 15 (maximum score for entry into the study was 12); higher scores/increased scores indicate greater severity of disease. Groups are arranged by cohort, then by duration of treatment, then by CPT class at baseline.	Baseline to Posttreatment Week 4
Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12	pTVR was defined as HCV RNA < LLOQ at Week 12 after transplant.	Posttransplant Week 12
HCV RNA and Change From Baseline at Week 1		Baseline; Week 1
HCV RNA and Change From Baseline at Week 2		Baseline; Week 2
HCV RNA and Change From Baseline at Week 4		Baseline; Week 4
HCV RNA and Change From Baseline at Week 6		Baseline; Week 6
HCV RNA and Change From Baseline at Week 8		Baseline; Week 8
HCV RNA and Change From Baseline at Week 12		Baseline; Week 12

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Welzel TM, Reddy KR, Flamm SL, Denning J, Lin M, Hyland R, Pang PS, McHutchison JG, Charlton M, Everson GT, Zeuzem S, Afdhal N. On-treatment HCV RNA in patients with varying degrees of fibrosis and cirrhosis in the SOLAR-1 trial. Antivir Ther. 2016;21(6):541-546. doi: 10.3851/IMP3037. Epub 2016 Feb 18.
• Charlton M, Everson GT, Flamm SL, Kumar P, Landis C, Brown RS Jr, Fried MW, Terrault NA, O'Leary JG, Vargas HE, Kuo A, Schiff E, Sulkowski MS, Gilroy R, Watt KD, Brown K, Kwo P, Pungpapong S, Korenblat KM, Muir AJ, Teperman L, Fontana RJ, Denning J, Arterburn S, Dvory-Sobol H, Brandt-Sarif T, Pang PS, McHutchison JG, Reddy KR, Afdhal N; SOLAR-1 Investigators. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease. Gastroenterology. 2015 Sep;149(3):649-59. doi: 10.1053/j.gastro.2015.05.010. Epub 2015 May 15.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (ACTUAL): January 1, 2015
• Study Completion (ACTUAL): March 1, 2015

Study Registration Dates

• First Submitted: September 5, 2013
• First Submitted That Met QC Criteria: September 5, 2013
• First Posted (ESTIMATE): September 10, 2013

Study Record Updates

• Last Update Posted (ACTUAL): November 16, 2018
• Last Update Submitted That Met QC Criteria: October 19, 2018
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Hepatitis C; Anti-Infective Agents; Antiviral Agents; Sofosbuvir; Ledipasvir, sofosbuvir drug combination; Ledipasvir
• Other Study ID Numbers: GS-US-337-0123

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and-transparency.
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP