Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination ± Ribavirin in Treatment-Experienced Subjects With Genotype 1 HCV Infection (ION-2)

• ClinicalTrials.gov Identifier: NCT01768286
• Recruitment Status: Completed
• First Posted: January 15, 2013
• Results First Posted: November 26, 2014
• Last Update Posted: November 16, 2018
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: January 10, 2013
• First Posted Date: January 15, 2013
• Results First Submitted Date: November 21, 2014
• Results First Posted Date: November 26, 2014
• Last Update Posted Date: November 16, 2018
• Study Start Date: January 2013
• Actual Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 21, 2014)

• Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) [ Time Frame: Posttreatment Week 12 ]
  SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 25 IU/mL) 12 weeks following the last dose of study drug.
• Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug [ Time Frame: Up to 24 weeks ]
  The percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug was summarized.

Original Primary Outcome Measures (submitted: January 11, 2013)

• Sustained virologic response after discontinuation of therapy [ Time Frame: 12 weeks after discontinuation of therapy ]
  Sustained virologic response (SVR) 12 weeks after the end of treatment (SVR12 defined as HCV RNA < lower limit of quantification [LLOQ] 12 weeks after last dose of study drug).
• Safety and tolerability of combination treatment with sofosbuvir (SOF)/GS-5885 fixed-dose combination (FDC) ± RBV as measured by review of the accumulated safety data [ Time Frame: Safety and tolerability on treatment and 30 days post last dose ]
  Frequency and severity of adverse events

Current Secondary Outcome Measures (submitted: November 21, 2014)

• Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) [ Time Frame: Posttreatment Weeks 4 and 24 ]
  SVR4 and SVR24 were defined as HCV RNA < LLOQ at 4 and 24 weeks following the last dose of study drug, respectively.
• Percentage of Participants With HCV RNA < LLOQ at Week 1 [ Time Frame: Week 1 ]
• Percentage of Participants With HCV RNA < LLOQ at Week 2 [ Time Frame: Week 2 ]
• Percentage of Participants With HCV RNA < LLOQ at Week 4 [ Time Frame: Week 4 ]
• Percentage of Participants With HCV RNA < LLOQ at Week 8 [ Time Frame: Week 8 ]
• Percentage of Participants With HCV RNA < LLOQ at Week 12 [ Time Frame: Week 12 ]
• Percentage of Participants With HCV RNA < LLOQ at Week 24 [ Time Frame: Week 24 ]
• Change From Baseline in HCV RNA at Week 1 [ Time Frame: Baseline; Week 1 ]
• Change From Baseline in HCV RNA at Week 2 [ Time Frame: Baseline; Week 2 ]
• Change From Baseline in HCV RNA at Week 4 [ Time Frame: Baseline; Week 4 ]
• Change From Baseline in HCV RNA at Week 8 [ Time Frame: Baseline; Week 8 ]
• Percentage of Participants With Virologic Failure [ Time Frame: Baseline to posttreatment Week 24 ]
  Virologic failure was defined as on-treatment virologic failure or virologic relapse.

  • On-Treatment Virologic Failure was defined as
    • Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), or
    • Rebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or
    • Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment)

  Virologic relapse was defined as confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit.

Original Secondary Outcome Measures (submitted: January 11, 2013)

• Sustained virologic response after discontinuation of therapy [ Time Frame: 4 and 24 weeks after discontinuation of therapy ]
  Sustained virologic response (SVR) at 4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24 defined as HCV RNA < lower limit of quantification [LLOQ] 12 weeks after last dose of study drug).
• Kinetics of circulating HCV RNA during and after treatment discontinuation [ Time Frame: 12 and 24 weeks ]
  On treatment and post treatment HCV RNA levels over time will be used to characterize the kinetics of circulating HCV RNA during and after treatment discontinuation.
• Viral resistance to sofosbuvir and GS-5885 combination therapy during and after treatment [ Time Frame: 12 and 24 weeks ]
  To evaluate the emergence of viral resistance to sofosbuvir and GS-5885 during treatment and after treatment discontinuation
• Characterization of steady state pharmacokinetics of sofosbuvir and GS-5885 [ Time Frame: 12 and 24 weeks ]
  To characterize steady state pharmacokinetics of sofosbuvir and GS-5885 during treatment and after treatment discontinuation

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination ± Ribavirin in Treatment-Experienced Subjects With Genotype 1 HCV Infection
• Official Title: A Phase 3, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/GS-5885 Fixed-Dose Combination ± Ribavirin for 12 and 24 Weeks in Treatment-Experienced Subjects With Chronic Genotype 1 HCV Infection
• Brief Summary: This study is to evaluate the safety, tolerability, and antiviral efficacy of ledipasvir/sofosbuvir fixed dose combination (FDC) with or without ribavirin (RBV) administered for 12 or 24 weeks in treatment-experienced subjects with chronic genotype 1 hepatitis C virus (HCV) infection.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Hepatitis C Virus

Intervention

• Drug: LDV/SOF
  Ledipasvir (LDV) 90 mg/sofosbuvir (SOF) 400 mg fixed-dose combination (FDC) tablet administered orally once daily
  Other Names:

  • Harvoni®
  • GS-5885/GS-7997
• Drug: RBV
  Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)

Study Arms

• Experimental: LDV/SOF 12 Weeks
  Participants will receive LDV/SOF FDC for 12 weeks.
  Intervention: Drug: LDV/SOF
• Experimental: LDV/SOF+RBV 12 Weeks
  Participants will receive LDV/SOF FDC plus RBV for 12 weeks.
  Interventions:

  • Drug: LDV/SOF
  • Drug: RBV
• Experimental: LDV/SOF 24 Weeks
  Participants will receive LDV/SOF FDC for 24 weeks.
  Intervention: Drug: LDV/SOF
• Experimental: LDV/SOF+RBV 24 Weeks
  Participants will receive LDV/SOF FDC plus RBV for 24 weeks.
  Interventions:

  • Drug: LDV/SOF
  • Drug: RBV

Publications *

• Grebely J, Mauss S, Brown A, Bronowicki JP, Puoti M, Wyles D, Natha M, Zhu Y, Yang J, Kreter B, Brainard DM, Yun C, Carr V, Dore GJ. Efficacy and Safety of Ledipasvir/Sofosbuvir With and Without Ribavirin in Patients With Chronic HCV Genotype 1 Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ION Trials. Clin Infect Dis. 2016 Dec 1;63(11):1405-1411. Epub 2016 Aug 23.
• Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, Nahass R, Ghalib R, Gitlin N, Herring R, Lalezari J, Younes ZH, Pockros PJ, Di Bisceglie AM, Arora S, Subramanian GM, Zhu Y, Dvory-Sobol H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Sulkowski M, Kwo P; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014 Apr 17;370(16):1483-93. doi: 10.1056/NEJMoa1316366. Epub 2014 Apr 11.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 27, 2014): 441
• Original Estimated Enrollment (submitted: January 11, 2013): 400
• Actual Study Completion Date: February 2014
• Actual Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age > 18, with chronic genotype 1 HCV infection
• HCV treatment-experienced, including patients who have previously failed a nonstructural protein (NS)3/4A protease inhibitor plus pegylated interferon (PEG)/RBV regimen
• HCV RNA > 10,000 IU/mL at screening
• Cirrhosis determination; a liver biopsy may be required
• Screening laboratory values within defined thresholds
• Use of two effective contraception methods if female of childbearing potential or sexually active male

Exclusion Criteria:

• Pregnant or nursing female or male with pregnant female partner
• Coinfection with HIV or hepatitis B virus
• Current or prior history of clinical hepatic decompensation
• Hepatocellular carcinoma or other malignancy (with exception of certain resolved skin cancers)
• Chronic use of systemic immunosuppressive agents
• History of clinically significant illness or any other medical disorder that may interfere with subject treatment, assessment or compliance with the protocol

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01768286
• Other Study ID Numbers: GS-US-337-0109
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.
• URL: http://www.gilead.com/research/disclosure-and-transparency

• Responsible Party: Gilead Sciences
• Study Sponsor: Gilead Sciences
• Collaborators: Not Provided

Investigators

• Study Director: Jenny Yang, PharmD; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: November 2014