Study of Daclatasvir (BMS-790052) and Simeprevir (TMC435) in Patients With Genotype 1 Chronic Hepatitis C Virus

A Phase 2, Open-Label Study of Daclatasvir (BMS-790052) and TMC435 in Combination With or Without Ribavirin (RBV) For Treatment-Naive Subjects or Null Responders to Prior Peginterferon Alfa (PegIFN)/RBV Therapy With Genotype 1 Chronic Hepatitis C

The purpose of this study is to assess the safety and efficacy of daclatasvir and simeprevir with and without ribavirin for genotype 1 chronic hepatitis C virus infection in patients who are treatment-naive or null responders to previous pegylated interferon/ribavirin therapy.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 230
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1181ACH
    • Local Institution
  • Buenos Aires, Argentina, 1119
    • Local Institution
• France
  • Creteil Cedex, France, 94010
    • Local Institution
  • Limoges, France, 87042
    • Local Institution
  • Marseille Cedex 08, France, 13285
    • Local Institution
  • Paris Cedex 13, France, 75651
    • Local Institution
  • Paris Cedex 14, France, 75679
    • Local Institution
  • Pessac, France, 33600
    • Local Institution
  • Vandoeuvre Les Nancy, France, 54511
    • Local Institution
• Germany
  • Berlin, Germany, 10969
    • Local Institution
  • Frankfurt, Germany, 60590
    • Local Institution
  • Hamburg, Germany, 20099
    • Local Institution
  • Koeln, Germany, 50937
    • Local Institution
• Hungary
  • Budapest, Hungary, 1097
    • Local Institution
  • Budapest, Hungary, 1126
    • Local Institution
  • Gyula, Hungary, 5700
    • Local Institution
• Spain
  • Barcelona, Spain, 08035
    • Local Institution
  • Madrid, Spain, 28046
    • Local Institution
  • Valencia, Spain, 46010
    • Local Institution
• United States
  • California
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital
    • San Francisco, California, United States, 94118
      • Kaiser Permanente Med Ctr
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Maryland
    • Lutherville, Maryland, United States, 21093
      • Johns Hopkins University
  • Tennessee
    • Nashville, Tennessee, United States, 37205
      • Nashville Medical Research Institute
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clinical Research Institute, LLC
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Metropolitan Research

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

Key Inclusion Criteria:

• Hepatitis C virus (HCV) genotype 1a or 1b
• Males and females, ≥18 years of age
• HCV RNA ≥10,000 IU/mL

• Participants with compensated cirrhosis are permitted

  • Advanced fibrosis (F3/F4) is capped at approximately 35% of the total treated population with a minimum of 20% F4 patients
  • If no cirrhosis, a liver biopsy within 3 years prior to enrollment
  • If cirrhosis is present, any prior liver biopsy

Key Exclusion Criteria:

• Liver or any other transplant (other than cornea and hair)
• Evidence of a medical condition contributing to chronic liver disease other than HCV infection
• Current or known history of cancer, (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment
• Evidence of decompensated liver disease including, but not limited to, radiologic criteria, a history or presence of ascites, bleeding varices, or hepatic encephalopathy
• Patients infected with HIV or hepatitis B virus
• Gastrointestinal disease impacting absorption of study drug
• Uncontrolled diabetes or hypertension
• Prior exposure to an HCV direct-acting agent
• Any criteria that would exclude the patient from receiving ribavirin
• Absolute neutrophil count <1.5*1,000,000,000 cells/L (<1.2*1,000,000,000 cells/L for Black/African Americans)
• Platelets <90*1,000,000,000 cells/L
• Hemoglobin <12 g/dL for females, <13 g/dL for males
• Alanine aminotransferase ≥5*upper limit of normal
• In patients without cirrhosis, total bilirubin ≥2 mg/dL unless patient has a documented history of Gilbert's disease
• In patients with cirrhosis, total bilirubin o ≥1.5 mg/dL
• International normalized ratio ≥1.7
• QTcF or QTcB >500 mSec
• Creatinine clearance ≤50 mL/min
• Alpha fetoprotein (AFP) >100 ng/mL OR
• AFP ≥50 ng/mL and ≤100 ng/mL requiring liver ultrasound
• Albumin <3.5 g/dL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: (Genotype 1b) Daclatasvir + Simeprevir; Participants with hepatitis C virus genotype 1b received daclatasvir, 30 mg, once daily with or without food + simeprevir, 150 mg, once daily with a meal for 12 weeks	Drug: Daclatasvir; Tablets, oral, 30 mg, once daily; Other Names: BMS-790052; Drug: Simeprevir; Capsule, oral, 150 mg, once daily; Other Names: TMC435
Experimental: Cohort 2: (Genotype 1b) Daclatasvir + Simeprevir + Ribavirin; Participants with hepatitis C virus genotype 1b received daclatasvir, 30 mg, once daily with or without food + simeprivir, 150 mg, once daily with a meal + ribavirin, twice daily with food (patients weighing <75 kg received a total ribavirin dose of 1000 mg per day; those weighing >=75 kg received 1200 mg per day) for 12 weeks.	Drug: Daclatasvir; Tablets, oral, 30 mg, once daily; Other Names: BMS-790052; Drug: Simeprevir; Capsule, oral, 150 mg, once daily; Other Names: TMC435
Experimental: Cohort 3: (Genotype 1a) Daclatasvir + Simeprevir + Ribavirin; Participants with hepatitis C virus genotype 1a received daclatasvir, 30 mg, once daily with or without food + simeprevir, 150 mg, once daily with a meal + ribavirin, twice daily with food (patients weighing <75 kg received a total ribavirin dose of 1000 mg per day; those weighing >=75 kg received 1200 mg per day) for 12 weeks.	Drug: Daclatasvir; Tablets, oral, 30 mg, once daily; Other Names: BMS-790052; Drug: Simeprevir; Capsule, oral, 150 mg, once daily; Other Names: TMC435; Drug: Ribavirin; Tablets, oral, 500-600 mg, twice daily
Experimental: Cohort 4: (Genotype 1a) Daclatasvir + Simeprevir + Ribavirin; Participants with hepatitis C virus genotype 1a received daclatasvir, 30 mg, once daily with or without food + simeprivir, 150 mg, once daily with a meal + ribavirin, twice daily with food (patients weighing <75 kg received a total ribavirin dose of 1000 mg per day; those weighing >=75 kg received 1200 mg per day.	Drug: Daclatasvir; Tablets, oral, 30 mg, once daily; Other Names: BMS-790052; Drug: Simeprevir; Capsule, oral, 150 mg, once daily; Other Names: TMC435; Drug: Ribavirin; Tablets, oral, 500-600 mg, twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)	SVR12 rate was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, 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.	Post Treatment Week 12 (Follow-up period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Rapid Virologic Response (RVR) at Week 4	RVR was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at Week 4. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.	Week 4
Percentage of Participants With Complete Early Virologic Response (cEVR)	cEVR was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.	Week 12
Percentage of Participants With Extended Rapid Virologic Response (eRVR)	eRVR were defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at both Week 4 and Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.	Week 4 and Week 12
Percentage of Participants With End of Treatment Response (EOTR)	EOTR were defined as hepatitis C virus (HCV) RNA levels <lower limit of quantitation, target not detected at end of treatment. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory.	End of treatment (Week 24)
Percentage of Participants With Sustained Virologic Response at Week 12 (SVR12) by rs12979860 Single Nucleotide Polymorphisms in the IL-28B Gene Categories	Participants were categorized into 3 genotypes based on single nucleotide polymorphisms in the IL28B gene. SVR12 was defined as hepatitis C virus (HCV) RNA levels below lower limit of quantitation, 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.	Baseline, post-treatment Week 12 (Follow-up period)
Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died	AE was defined as any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily 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. Based on the severity, AEs were categorized as Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.	From start of treatment (Day 1) up to 7 days post last dose of study treatment (Week 24)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Janssen Research & Development, LLC

Publications and helpful links

General Publications

• Zeuzem S, Hezode C, Bronowicki JP, Loustaud-Ratti V, Gea F, Buti M, Olveira A, Banyai T, Al-Assi MT, Petersen J, Thabut D, Gadano A, Pruitt R, Makara M, Bourliere M, Pol S, Beumont-Mauviel M, Ouwerkerk-Mahadevan S, Picchio G, Bifano M, McPhee F, Boparai N, Cheung K, Hughes EA, Noviello S; LEAGUE-1 Study Team. Daclatasvir plus simeprevir with or without ribavirin for the treatment of chronic hepatitis C virus genotype 1 infection. J Hepatol. 2016 Feb;64(2):292-300. doi: 10.1016/j.jhep.2015.09.024. Epub 2015 Oct 8.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: June 25, 2012
• First Submitted That Met QC Criteria: June 26, 2012
• First Posted (Estimate): June 27, 2012

Study Record Updates

• Last Update Posted (Actual): February 23, 2017
• Last Update Submitted That Met QC Criteria: January 10, 2017
• Last Verified: January 1, 2017

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; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites; Protease Inhibitors; Ribavirin; Simeprevir
• Other Study ID Numbers: AI444-062; 2012-000070-28 (EudraCT Number)