12 Weeks of Ledipasvir (LDV)/Sofosbuvir (SOF) With Weight-based Ribavirin vs. 24 Weeks of LDV/SOF

NCT02605304 | Terminated Phase 2 Results DMC

• 2 other identifiers: ACTG A5348UM1AI068636
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 2

Brief Summary

People who are infected with Hepatitis C Virus (HCV) have a great chance of being cured of the infection when they are treated with sofosbuvir. However, in some instances, treatment with sofosbuvir-containing therapy does not work. It is not known if people respond to retreatment with sofosbuvir, after it did not work the first time. There is an important need to understand retreatment options in those instances. This clinical trial was done to study the response to two different regimens, ledipasvir/sofosbuvir and ledipasvir/sofosbuvir with ribavirin, and to see if they are safe and well-tolerated in HCV-infected persons whose previous treatment with sofosbuvir had failed.

Conditions

HIV-1 Infection; Hepatitis C

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Sustained Virologic Response at 12 Weeks After Treatment Discontinuation (SVR12)

  SVR12 was defined as HCV RNA below the LLOQ of the assay (either target detected \[TD\] or target not detected \[TND\]) at 12 weeks after treatment discontinuation. The sample within the visit window, closest to the targeted time was used. If there was no HCV RNA sample within visit window, then the participant was considered not to have achieved SVR12, unless there were preceding and subsequent HCV RNA measurements that were both \<LLOQ (either TD or TND). HCV RNA testing was conducted at a central laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, version 2.0 (Roche Diagnostics, Rotkreuz, Switzerland). Wilson (score) method was used for confidence intervals.

  At 12 weeks after treatment discontinuation (i.e., at 24 weeks after study entry in Arm A and at 36 weeks after study entry in Arm B).

• Percentage of Participants With Grade 3 or Higher Adverse Event (AE), Serious AE (SAE), or AE Reported as the Reason for Permanent Discontinuation of Study Treatment

  Percentage of participants who experienced an AE (diagnosis, sign/symptom or laboratory abnormality) of ≥Grade 3, SAE according to International Conference on Harmonisation (ICH) criteria, or AE reported as the reason for permanent study treatment discontinuation, during study treatment and up to 30 days after study treatment. Events that were ongoing at the same grade from prior to study treatment initiation were excluded. AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (V2.0) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening. The percentage of participants who experienced any event (overall), and the percentage of participants who experienced each component of the outcome are provided in the data table below. The categories are not mutually exclusive. A participant may have experienced multiple events. Each participant is counted at most once within category, and in the overall summary line.

  From study treatment initiation to 30 days after study treatment discontinuation. Duration of treatment was 12 weeks in Arm A and 24 weeks in Arm B.

Secondary Outcomes (6)

• Percentage of Participants With Protocol-specified Renal Events

  From study entry to study completion (Week 36 in Arm A, Week 48 in Arm B)

• Percentage of Participants With Sustained Virologic Response at 4 Weeks After Treatment Discontinuation (SVR4)

  At 4 weeks after treatment discontinuation (i.e., at 16 weeks after study entry in Arm A and at 28 weeks after study entry in Arm B).

• Percentage of Participants With Sustained Virologic Response at 24 Weeks After Treatment Discontinuation (SVR24)

  At 24 weeks after treatment discontinuation (i.e., at 36 weeks after study entry in Arm A and at 48 weeks after study entry in Arm B).

• Number of Participants With Unquantifiable HCV RNA

  Entry (Week 0); at 1, 4, 8, 12 (and 16, 20, 24 in Arm B) weeks after study entry

• Number of Participants With HIV-1 RNA >50 Copies/mL

  Entry (Week 0); at 4, 12 (and 24 in Arm B) weeks after study entry, and at 4 weeks after treatment discontinuation

Study Arms (2)

Arm A: LDV/SOF + RBV

EXPERIMENTAL

Ledipasvir/sofosbuvir + ribavirin for 12 weeks, followed by 24 weeks of post-treatment follow-up.

Drug: Ledipasvir/sofosbuvir; Drug: Ribavirin

Arm B: LDV/SOF

EXPERIMENTAL

Ledipasvir/sofosbuvir for 24 weeks, followed by 24 weeks of post-treatment follow-up.

Drug: Ledipasvir/sofosbuvir

Interventions

Ledipasvir/sofosbuvir DRUG

Participants were prescribed one fixed dose tablet of LDV 90 mg/SOF 400 mg orally per day.

Also known as: LDV/SOF, Harvoni

Arm A: LDV/SOF + RBV; Arm B: LDV/SOF

Ribavirin DRUG

Based on weight at entry: For weight \<75 kg, participants were prescribed 1000 mg of RBV per day, divided into two doses to be taken orally. For weight ≥75 kg: participants were prescribed 1200 mg of RBV per day, divided into two doses to be taken orally.

Also known as: RBV

Arm A: LDV/SOF + RBV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent
• Documentation of non-cirrhotic or cirrhotic status
• HIV-1 infection
• HIV antiretroviral treatment status (ART), CD4+ T-cell (CD4) count and HIV-1 RNA as follows: (1) not on ART with CD4 count \>500 cells/mm\^3 within 42 days of study entry, (2) elite controller not on ART with CD4 \>200 cells/mm\^3 within 42 days of study entry and HIV-1 RNA \<500 copies/mL on all measurements within 48 weeks prior to study entry, (3) on a stable protocol-approved ART with CD4 count \>200 cells/mm\^3 and HIV-1 RNA \<50 copies/mL within 42 days of study entry
• HCV GT-1 within 12 months prior to study entry
• Prior virologic treatment failure with SOF-containing regimen (SOF/RBV, SOF/PEG/RBV, and SOF/SIM)
• Body mass index (BMI) ≥18 kg/m\^2 within 42 days prior to study entry
• Certain laboratory values obtained within 42 days prior to study entry
• Hemoglobin ≥12.0 g/dL for male, ≥11.0 g/dL for female participants
• Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGOT) \<10 x ULN
• For female participants of reproductive potential, a negative serum pregnancy test with a sensitivity of at least 25 mIU/mL performed at screening and within 48 hours prior to study entry
• Agreement to use at least two reliable forms of contraceptive simultaneously while receiving study treatment and for 6 months afterward
• Intention to comply with the dosing instructions and study schedule of assessments

You may not qualify if:

• Receipt of any investigational drug or device within 60 days prior to study entry
• Prior exposure to a DAA other than SOF and SIM
• Chronic liver disease of a non-HCV etiology
• Presence of active or acute AIDS-defining opportunistic infections within 42 days prior to study entry
• Active, serious infection (other than HIV-1 or HCV) requiring parenteral antibiotics, antivirals, or antifungals within 42 days prior to study entry
• Hepatitis B virus (HBV) infection (defined as HBsAg positive) within 42 days prior to study entry
• History of clinically significant hemoglobinopathy
• Chronic current use of systemically administered immunosuppressive agents
• History of solid organ transplantation
• Current or prior history of clinical hepatic decompensation
• History of a gastrointestinal disorder (or postoperative condition) that could interfere with the absorption of the study drug
• History of significant or symptomatic pulmonary disease, cardiac disease, or porphyria that in the opinion of the investigator would interfere with the study
• History of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy
• Active drug or alcohol use or dependence
• Use of any prohibited concomitant medications per the LDV/SOF product labeling, within 42 days prior to study entry

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

Ucsf Aids Crs (801)

San Francisco, California, 94110, United States

Location

7804 Weill Cornell Chelsea CRS

New York, New York, 10010, United States

Location

Related Publications (1)

• Tam E, Luetkemeyer AF, Mantry PS, Satapathy SK, Ghali P, Kang M, Haubrich R, Shen X, Ni L, Camus G, Copans A, Rossaro L, Guyer B, Brown RS Jr; RESCUE and ACTG A5348 study investigators. Ledipasvir/sofosbuvir for treatment of hepatitis C virus in sofosbuvir-experienced, NS5A treatment-naive patients: Findings from two randomized trials. Liver Int. 2018 Jun;38(6):1010-1021. doi: 10.1111/liv.13616. Epub 2017 Dec 5.

  PMID: 29091342 RESULT

Related Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

Hepatitis C

Interventions

ledipasvir, sofosbuvir drug combination; Ribavirin

Condition Hierarchy (Ancestors)

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)

Ribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Limitations and Caveats

The study accrual was terminated prematurely due to enrollment challenges. There was a small number of participants enrolled.

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Annie Luetkemeyer, MD

  University of California, San Francisco HIV/AIDS CRS

  STUDY CHAIR

• Jennifer J. Kiser, PharmD

  University of Colorado, Denver

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2015
• First Posted: November 16, 2015
• Study Start: February 17, 2016
• Primary Completion: January 20, 2017
• Study Completion: March 20, 2017
• Last Updated: May 2, 2018
• Results First Posted: February 15, 2018

Record last verified: 2018-04

Locations

US (2)