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

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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:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Bristol-Myers Squibb

Tracking Information
First Submitted Date  ICMJE June 25, 2012
First Posted Date  ICMJE June 27, 2012
Results First Submitted Date  ICMJE August 13, 2015
Results First Posted Date  ICMJE November 30, 2015
Last Update Posted Date February 23, 2017
Study Start Date  ICMJE July 2012
Actual Primary Completion Date August 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 29, 2015)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 26, 2012)
Antiviral activity, as determined by the proportion of subjects with SVR12, defined as HCV RNA < LOQ at post-treatment Week 12, for each cohort defined by the previous response status, HCV genotype, initial treatment regimen and treatment duration [ Time Frame: Post treatment Week 12 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 29, 2015)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2012)
  • On-treatment safety, as measured by the frequency of Serious Adverse Events (SAEs) and discontinuations due to Adverse Events (AEs) [ Time Frame: Up to 24 weeks plus 7 days ]
  • Proportion of subjects with Sustained virologic response12 (SVR12) (HCV RNA < LOQ at post-treatment Week 12) by the rs12979860 single nucleotide polymorphisms (SNP) in the IL28B gene for each treatment arm [ Time Frame: Post treatment week 12 ]
  • Proportion of subjects with Hepatitis C virus (HCV) Ribonucleic acid (RNA) < Limit of quantitation (LOQ) [ Time Frame: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (End of treatment) (up to 24 weeks), post-treatment Week 24 (SVR24) for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms ]
  • Proportion of subjects with HCV RNA undetectable [ Time Frame: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 12 and post-treatment Week 24 for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Daclatasvir (BMS-790052) and Simeprevir (TMC435) in Patients With Genotype 1 Chronic Hepatitis C Virus
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hepatitis C Virus
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: Daclatasvir
    • Drug: Simeprevir
  • 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.
    Interventions:
    • Drug: Daclatasvir
    • Drug: Simeprevir
  • 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.
    Interventions:
    • Drug: Daclatasvir
    • Drug: Simeprevir
    • Drug: Ribavirin
  • 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.
    Interventions:
    • Drug: Daclatasvir
    • Drug: Simeprevir
    • Drug: Ribavirin
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 29, 2015)
230
Original Estimated Enrollment  ICMJE
 (submitted: June 26, 2012)
180
Actual Study Completion Date  ICMJE November 2013
Actual Primary Completion Date August 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   France,   Germany,   Hungary,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01628692
Other Study ID Numbers  ICMJE AI444-062
2012-000070-28 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bristol-Myers Squibb
Study Sponsor  ICMJE Bristol-Myers Squibb
Collaborators  ICMJE Janssen Research & Development, LLC
Investigators  ICMJE
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
PRS Account Bristol-Myers Squibb
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP