Phase III Daclatasvir, Sofosbuvir, and Ribavirin in Cirrhotic Participants and Participants Post-liver Transplant (ALLY 1)

A Phase 3 Evaluation of Daclatasvir, Sofosbuvir, and Ribavirin in Genotype 1-6 Chronic Hepatitis C Infection Subjects With Cirrhosis Who May Require Future Liver Transplant and Subjects Post-Liver Transplant

This trial was open to participants who had received a liver transplant or had cirrhosis due to chronic HCV. All subjects were treated with daclatasvir+sofosbuvir+ribavirin and were followed for 24 weeks post treatment. Under certain conditions, the treatment duration could have been extended for cirrhotic participants. The study tested the efficacy and safety of this combination for treatment of HCV in cirrhotic and post transplant patients.

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: Sofosbuvir; Drug: Ribavirin; Drug: Daclatasvir

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Schiff Center for Liver Diseases
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor St. Luke's Medical Center
    • San Antonio, Texas, United States, 78215
      • American Research Corporation
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center

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

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Participants must be able to understand and agree to comply with the prescribed dosing regimens and procedures, report for regularly scheduled study visits, and reliably communicate with study personnel about adverse events and concomitant medications
• Participants chronically infected with hepatitis C virus (HCV) Genotype 1, 2, 3, 4, 5, or 6 with HCV RNA viral load of ≥10,000 IU/mL at screening
• Participants may be treatment-naïve or treatment-experienced
• Cirrhotic participants must have cirrhosis confirmed by biopsy, Fibroscan or fibrotest and Aspartate aminotransferase platelet ratio index (APRI) criteria as outlined in the protocol
• Post-transplant participants must be at least 3 months post-transplant with no evidence of moderate or severe rejection

Exclusion Criteria:

• History of multi-organ transplant, with the exception of dual transplantation of the liver/kidney, is prohibited
• Current or known history of cancer (with the following exceptions: In situ carcinoma of the cervix, adequately treated basal or squamous cell carcinoma of the skin, or hepatocellular carcinoma within Milan criteria for transplantation) within 5 years prior to screening
• Evidence of an ongoing medical condition contributing to chronic liver disease other than HCV (such as, but not limited to: hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, or toxin exposures)
• History of HIV infection or chronic hepatitis B virus (HBV) as documented by HBV serologies (e.g., HBsAg-seropositive). Participants with resolved HBV infection may participate (e.g., HBcAb-seropositive with concurrent HBsAg-seronegative)
• Active hospitalization for decompensated liver disease

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Post-liver Transplant Cohort; Participants with liver transplant received daclatasvir 60 mg, sofosbuvir 400 mg, and ribavirin (based on baseline hemoglobin and creatinine clearance and tolerated dose) tablets daily for 12 weeks and were followed for 24 weeks post treatment.	Drug: Sofosbuvir; Drug: Ribavirin; Drug: Daclatasvir; Other Names: BMS-790052
EXPERIMENTAL: Cirrhotic Cohort; Cirrhotic participants received daclatasvir 60 mg, sofosbuvir 400 mg, and ribavirin (based on baseline hemoglobin and creatinine clearance and tolerated dose) tablets orally for 12 weeks and were followed for 24 weeks post-treatment. Cirrhotic participants who received a liver transplant while on study treatment were eligible (>3 months post transplant) for a treatment extension of daclatasvir 60 mg, sofosbuvir 400 mg, and ribavirin (dose based on hemoglobin level) tablets orally for an additional 12 weeks	Drug: Sofosbuvir; Drug: Ribavirin; Drug: Daclatasvir; Other Names: BMS-790052

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of HCV Genotype-1 Infected Post-liver Transplanted Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12)	SVR12 was defined as hepatitis C Virus (HCV) RNA levels below the lower limit of quantitation (<LLOQ) i.e., 25 IU/mL target detected or target not detected, at post-treatment Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. For participants who missed the follow-up Week 12 visit, SVR12 was imputed using the next and closest available HCV RNA measurement after the follow-up Week 12 window.	Post-treatment follow-up Week 12
Percentage of Genotype-1 Infected Cirrhotic Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12)	SVR12 was defined as hepatitis C Virus (HCV) RNA levels below the lower limit of quantitation i.e., 25 IU/mL target detected or target not detected, at post-treatment Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. For participants who missed the follow-up Week 12 visit, SVR12 was imputed using the next and closest available HCV RNA measurement after the follow-up Week 12 window.	Post-treatment follow-up Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Sustained Virologic Response at Post-treatment Week 12 (SVR12) for All Genotypes and Genotypes 2, 3, 4, 6	SVR12 was defined as hepatitis C Virus (HCV) RNA levels below the lower limit of quantitation i.e., 25 IU/mL target detected or target not detected, at post-treatment Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. For participants who missed the follow-up Week 12 visit, SVR12 was imputed using the next and closest available HCV RNA measurement after the follow-up Week 12 window.	Post-treatment follow-up Week 12
Percentage of Participants Who Achieve Hepatitis C Virus RNA Levels Below the Lower Limit of Quantitation Target Detected or Target Not Detected at Each of the Following Weeks: 1, 2, 4, 6, 8, 12, End of Treatment; Follow Up Weeks 4, 8, and 24	Participants who responded to treatment were assessed using proportion of subjects with hepatitis C Virus RNA levels below the lower limit of quantitation i.e., 25 IU/mL target detected or target not detected, at each visit.	Week 1, 2, 4, 6, 8, 12, End of treatment, Follow-up Week 4, 8, and 24
Percentage of Participants Who Achieve Hepatitis C Virus RNA Levels Below the Lower Limit of Quantitation Target Not Detected at Each of the Following Weeks: 1, 2, 4, 6, 8, 12, End of Treatment	Participants who responded to treatment were assessed using proportion of subjects with hepatitis C Virus RNA levels below the lower limit of quantitation i.e., 25 IU/mL target not detected, at each on-treatment visit.	Week 1, 2, 4, 6, 8, 12, End of treatment
Percentage of Participants With CC or Non-CC Genotype Who Achieved Sustained Virologic Response at 12 Weeks After the Last Dose of Study Drug (SVR12)	Participants categorized into 2 genotypes (CC and non-CC) based on single nucleotide polymorphism in the IL28B gene were assessed for SVR12, defined as response in which hepatitis C virus RNA levels be <lower limit of quantitation ie, 25 IU/mL or below target detected or target not detected at follow-up Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. For participants who missed the follow-up Week 12 visit, SVR12 was imputed using the next and closest available HCV RNA measurement after the follow-up Week 12 window.	Post-treatment follow-up Week 12
Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), AEs Leading to Interruption, Treatment-related AEs/SAEs, Grade 3 to 4 AEs/SAEs, and Death	AE was defined as any new unfavorable symptom, sign, or disease or worsening of a pre-existing condition that does not have a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization.	From start of study treatment up to 7 days post last dose of study treatment (approximately 13 weeks)
Number of Participants With Treatment Emergent Grade 3-4 Laboratory Abnormalities	Grade 3-4 laboratory abnormalities were defined as: Hemoglobin as 6.50-7.4 g/dL for grade 3 and/or < 6.5 g/dL for grade 4, Platelet count as 25*10^9-50*10^9 /L for grade 3 and/or < 25.000*10^9 /L for grade 4, International normalized ratio as 2.1-3.0*upper limit of normal (ULN) > 3.0*ULN for grade 3 and/or > 3.0*ULN for grade 4, Leukocytes as 1.0*10^9-1.5*10^9/L for grade 3 and/or <1.0*10^9/L for grade 4, Lymphocytes (Absolute) as 0.350*109-0.499*10^9 /L for grade 3 and/or < 0.350*10^9 /L for grade 4, Alanine aminotransferase as 5.1-10.0*ULN for grade 3 and/or > 10.0*ULN for grade 4, Aspartate aminotransferase as 5.1-10.0*ULN for grade 3 and/or > 10.0*ULN for grade 4, Alkaline phosphatase as 5.1-10.0*ULN for grade 3 and/or > 10.0*ULN for grade 4, Bilirubin (Total) as 2.6-5.0*ULN for grade 3 and/or > 5.0*ULN for grade 4, Albumin as < 20 g/L, Lipase (Total) as 3.1-5.0*ULN for grade 3 and/or > 5.0*ULN for grade 4, and Creatinine as 1.9-3.4*ULN for grade 3 and/or ≥ 3.5*ULN for grade 4.	From start of study treatment up to 7 days post last dose of study treatment

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (ACTUAL): November 1, 2014
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: January 9, 2014
• First Submitted That Met QC Criteria: January 9, 2014
• First Posted (ESTIMATE): January 10, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2017
• Last Update Submitted That Met QC Criteria: December 15, 2016
• Last Verified: December 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; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Sofosbuvir; Ribavirin
• Other Study ID Numbers: AI444-215