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

• ClinicalTrials.gov Identifier: NCT01628692
• Recruitment Status: Completed
• First Posted: June 27, 2012
• Results First Posted: November 30, 2015
• Last Update Posted: February 23, 2017
• Sponsor: Bristol-Myers Squibb
• Collaborator: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Bristol-Myers Squibb

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hepatitis C Virus	Drug: Daclatasvir; Drug: Simeprevir; Drug: Ribavirin	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 230 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: July 2012
• Actual Primary Completion Date: August 2013
• Actual Study Completion Date: November 2013

Arms and Interventions

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 Name: BMS-790052; Drug: Simeprevir; Capsule, oral, 150 mg, once daily; Other Name: 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 Name: BMS-790052; Drug: Simeprevir; Capsule, oral, 150 mg, once daily; Other Name: 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 Name: BMS-790052; Drug: Simeprevir; Capsule, oral, 150 mg, once daily; Other Name: 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 Name: BMS-790052; Drug: Simeprevir; Capsule, oral, 150 mg, once daily; Other Name: TMC435; Drug: Ribavirin; Tablets, oral, 500-600 mg, twice daily

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12) [ Time Frame: Post Treatment Week 12 (Follow-up period) ]
   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.

Secondary Outcome Measures :

1. Percentage of Participants With Rapid Virologic Response (RVR) at Week 4 [ Time Frame: 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.
2. Percentage of Participants With Complete Early Virologic Response (cEVR) [ Time Frame: Week 12 ]
   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.
3. Percentage of Participants With Extended Rapid Virologic Response (eRVR) [ Time Frame: Week 4 and Week 12 ]
   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.
4. Percentage of Participants With End of Treatment Response (EOTR) [ Time Frame: End of treatment (Week 24) ]
   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.
5. Percentage of Participants With Sustained Virologic Response at Week 12 (SVR12) by rs12979860 Single Nucleotide Polymorphisms in the IL-28B Gene Categories [ Time Frame: Baseline, post-treatment Week 12 (Follow-up period) ]
   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.
6. Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died [ Time Frame: From start of treatment (Day 1) up to 7 days post last dose of study treatment (Week 24) ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

San Francisco General Hospital

San Francisco, California, United States, 94110

Kaiser Permanente Med Ctr

San Francisco, California, United States, 94118

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202

United States, Maryland

Johns Hopkins University

Lutherville, Maryland, United States, 21093

United States, Tennessee

Nashville Medical Research Institute

Nashville, Tennessee, United States, 37205

United States, Texas

Texas Clinical Research Institute, Llc

Arlington, Texas, United States, 76012

United States, Virginia

Metropolitan Research

Fairfax, Virginia, United States, 22031

Argentina

Local Institution

Buenos Aires, Argentina, 1119

Local Institution

Buenos Aires, Argentina, C1181ACH

France

Local Institution

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

Germany

Local Institution

Berlin, Germany, 10969

Local Institution

Frankfurt, Germany, 60590

Local Institution

Hamburg, Germany, 20099

Local Institution

Koeln, Germany, 50937

Hungary

Local Institution

Budapest, Hungary, 1097

Local Institution

Budapest, Hungary, 1126

Local Institution

Gyula, Hungary, 5700

Spain

Local Institution

Barcelona, Spain, 08035

Local Institution

Madrid, Spain, 28046

Local Institution

Valencia, Spain, 46010

Sponsors and Collaborators

Bristol-Myers Squibb

Janssen Research & Development, LLC

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

More Information

Additional Information:

BMS clinical trial educational resource  Investigator Inquiry form 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zeuzem S, Hézode 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, Bourlière 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.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01628692
• Other Study ID Numbers: AI444-062; 2012-000070-28 ( EudraCT Number )
• First Posted: June 27, 2012
• Results First Posted: November 30, 2015
• Last Update Posted: February 23, 2017
• Last Verified: January 2017

Additional relevant MeSH terms:

Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Flaviviridae Infections; Hepatitis, Chronic; Ribavirin; Simeprevir; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Protease Inhibitors; Enzyme Inhibitors