Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects With Chronic Genotype 1 or 4 HCV and HIV-1 Co-infection

• ClinicalTrials.gov Identifier: NCT02073656
• Recruitment Status: Completed
• First Posted: February 27, 2014
• Results First Posted: October 21, 2016
• Last Update Posted: November 16, 2018
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: February 25, 2014
• First Posted Date: February 27, 2014
• Results First Submitted Date: August 30, 2016
• Results First Posted Date: October 21, 2016
• Last Update Posted Date: November 16, 2018
• Study Start Date: February 2014
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 30, 2016)

• 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) at 12 weeks after stopping study treatment.
• Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event [ Time Frame: Up to 12 weeks ]

Original Primary Outcome Measures (submitted: February 25, 2014)

• Proportion of participants with sustained virologic response 12 weeks after discontinuation of therapy (SVR12) [ Time Frame: Posttreatment Week 12 ]
  SVR12 is defined as HCV RNA < the lower limit of quantitation (LLOQ) 12 weeks following the last dose of study drug.
• Incidence of adverse events leading to permanent discontinuation of study drug(s) [ Time Frame: Baseline to Week 12 ]

Current Secondary Outcome Measures (submitted: August 30, 2016)

• 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 SVR 24 were defined as HCV RNA < LLOQ at 4 and 24 weeks after stopping study treatment, respectively.
• Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 [ Time Frame: Weeks 1, 2, 4, 6, 8, 10, and 12 ]
• Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, and 8 [ Time Frame: Baseline; Weeks 1, 2, 4, 6, and 8 ]
• Percentage of Participants With Virologic Failure [ Time Frame: Up to Posttreatment Week 24 ]
  Virologic failure was defined as:

  • On-treatment virologic failure:
    • 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:
    • Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit.
• Percentage of Participants That Maintain HIV-1 RNA < 50 Copies/mL While on HCV Treatment [ Time Frame: Weeks 4, 8, and 12 ]
• Change From Baseline in Serum Creatinine at the End of Treatment (Week 12) and at Posttreatment Weeks 12 and 24 [ Time Frame: Baseline; Week 12, Posttreatment Weeks 12 and 24 ]
• For Participants in the Retreatment Substudy, Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24) [ Time Frame: Posttreatment Weeks 4, 12, and 24 of Retreatment Substudy ]
  SVR4, SVR12, and SVR 24 were defined as HCV RNA < LLOQ at 4, 12, and 24 weeks after stopping study treatment, respectively.
• For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, and 24 of the Retreatment Substudy ]
• For Participants in the Retreatment Substudy, Change From Baseline in HCV RNA at Retreatment Weeks 2, 4, and 8 [ Time Frame: Baseline; Weeks 2, 4, and 8 of Retreatment Substudy ]
• For Participants in the Retreatment Substudy, Percentage of Participants With Virologic Failure [ Time Frame: Up to Posttreatment Week 24 of Retreatment Substudy ]
  Virologic failure was defined as:

  • On-treatment virologic failure:
    • 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:
    • Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit.

Original Secondary Outcome Measures (submitted: February 25, 2014)

• Proportion of participants with sustained virologic response at 4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24) [ Time Frame: Posttreatment Weeks 4 and 24 ]
  SVR4 and SVR24 is defined as HCV RNA < LLOQ at 4 and 24 weeks following the last dose of study drug, respectively.
• Proportion of participants with HCV RNA < LLOQ on treatment [ Time Frame: Up to 12 weeks ]
• Change in HCV RNA from Baseline [ Time Frame: Baseline to posttreatment Week 24 ]
• Proportion of participants with virologic failure [ Time Frame: Baseline to posttreatment Week 24 ]
  Virologic failure is defined as virologic breakthrough (participant achieved undetectable HCV RNA levels during treatment but subsequently had detectable HCV RNA while continuing treatment), nonresponse (HCV RNA ≥ LLOQ through 12 weeks of treatment), or relapse (participant achieved undetectable HCV RNA levels during treatment maintained undetectable HCV RNA for the duration of treatment or achieved undetectable HCV RNA within 4 weeks of the end of treatment but did not achieve SVR at 4, 12, or 24 weeks posttreatment).
• For retreatment group only: Proportion of participants with sustained virologic response at 4, 12 and 24 weeks after discontinuation of therapy (SVR4, SVR12, and SVR24) [ Time Frame: Posttreatment Weeks 4, 12, and 24 ]
• Proportion of participants that maintain HIV-1 RNA < 50 copies/mL while on treatment [ Time Frame: Baseline to Week 12 ]
• Change from baseline of serum creatinine at end of treatment, posttreatment weeks 12 and 24 [ Time Frame: Week 12 and posttreatment weeks 12 and 24 ]

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

Descriptive Information

• Brief Title: Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects With Chronic Genotype 1 or 4 HCV and HIV-1 Co-infection
• Official Title: A Phase 3, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination for 12 Weeks in Subjects With Chronic Genotype 1 or 4 Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV)-1 Co-infection

Brief Summary

This study will evaluate the antiviral efficacy, safety, and tolerability of ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) administered for 12 weeks in hepatitis C virus (HCV) treatment-naive and treatment-experienced (including treatment intolerant) participants with chronic genotype 1 or 4 HCV infection who are co-infected with HIV-1.

Participants who experience confirmed post-treatment virologic failure (relapse) at or before Posttreatment Week 24 may be eligible to be enrolled in the Retreatment Substudy to receive LDV/SOF plus ribavirin (RBV) for 24 weeks.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hepatitis C Virus
• HIV

Intervention

• Drug: LDV/SOF
  90/400 mg FDC tablet administered orally once daily
  Other Names:

  • Harvoni®
  • GS-5885/GS-7977
• Drug: 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
  LDV/SOF for 12 weeks
  Intervention: Drug: LDV/SOF
• Experimental: Retreatment Substudy
  LDV/SOF plus RBV for 24 weeks
  Interventions:

  • Drug: LDV/SOF
  • Drug: RBV

Publications *

• Cooper C, Naggie S, Saag M, Yang JC, Stamm LM, Dvory-Sobol H, et al. Retreatment of Patients Who Failed 12 Weeks of Ledipasvir/Sofosbuvir-Based Regimens with Ledipasvir/Sofosbuvir with Ribavirin for 24 Weeks [Poster Presentation]. 23nd Conference on Retroviruses and Opportunistic Infections (CROI); 2016 February 22-25; Boston, MA.
• Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, Marks K, Luetkemeyer A, Baden RP, Sax PE, Gane E, Santana-Bagur J, Stamm LM, Yang JC, German P, Dvory-Sobol H, Ni L, Pang PS, McHutchison JG, Stedman CA, Morales-Ramirez JO, Brau N, Jayaweera D, Colson AE, Tebas P, Wong DK, Dieterich D, Sulkowski M; ION-4 Investigators. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015 Aug 20;373(8):705-13. doi: 10.1056/NEJMoa1501315. Epub 2015 Jul 21.
• Naggie S, Cooper C, Saag M, Stamm LM, Yang JC, Pang PS, et al. Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected With HCV and HIV-1 [Oral Presentation]. 22nd Conference on Retroviruses and Opportunistic Infections (CROI); 2015 February 23-26; Seattle, WA.
• Cooper C, Naggie S, Saag M, Yang JC, Stamm LM, Dvory-Sobol H, Han L, Pang PS, McHutchison JG, Dieterich D, Sulkowski M. Successful Re-treatment of Hepatitis C Virus in Patients Coinfected With HIV Who Relapsed After 12 Weeks of Ledipasvir/Sofosbuvir. Clin Infect Dis. 2016 Aug 15;63(4):528-31. doi: 10.1093/cid/ciw349. Epub 2016 May 25.
• Saeed S, Strumpf EC, Walmsley SL, Rollet-Kurhajec K, Pick N, Martel-Laferriere V, Hull M, Gill MJ, Cox J, Cooper C, Klein MB; Canadian Co-Infection Cohort Study; Cohen J, Conway B, Cooper C, Cote P, Cox J, Gill J, Haider S, Harris M, Haase D, Hull M, Montaner J, Moodie E, Pick N, Rachlis A, Rouleau D, Sandre R, Tyndall JM, Vachon ML, Walmsley S, Wong D. How Generalizable Are the Results From Trials of Direct Antiviral Agents to People Coinfected With HIV/HCV in the Real World? Clin Infect Dis. 2016 Apr 1;62(7):919-926. doi: 10.1093/cid/civ1222. Epub 2016 Jan 6.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 1, 2015): 335
• Original Estimated Enrollment (submitted: February 25, 2014): 300
• Actual Study Completion Date: December 2015
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• HCV RNA ≥ 10,000 IU/mL at screening
• HCV genotype 1 or 4
• HIV-1 infection
• Cirrhosis determination, a fibroscan or liver biopsy may be required
• Screening laboratory values within defined thresholds
• Use of protocol specified method(s) of contraception if female of childbearing potential or sexually active male

Exclusion Criteria:

• Clinically-significant illness (other than HCV or HIV) or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol
• Current or prior history of clinical hepatic decompensation, hepatocellular carcinoma (HCC), or other malignancy (with the exception of certain resolved skin cancers)
• Hepatitis B virus (HBV) infection
• Pregnant or nursing female
• Chronic use of systemically administered immunosuppressive agents

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: Canada, New Zealand, Puerto Rico, United States

Administrative Information

• NCT Number: NCT02073656
• Other Study ID Numbers: GS-US-337-0115
• 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

• Current Responsible Party: Gilead Sciences
• Original Responsible Party: Same as current
• Current Study Sponsor: Gilead Sciences
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Jenny Yang, PharmD; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: August 2016