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

Primary Purpose

Hepatitis C Virus

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Daclatasvir
Simeprevir
Ribavirin
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C Virus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • San Francisco General Hospital
  • Kaiser Permanente Med Ctr
  • Indiana University
  • Johns Hopkins University
  • Nashville Medical Research Institute
  • Texas Clinical Research Institute, Llc
  • Metropolitan Research
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution
  • Local Institution

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort 1: (Genotype 1b) Daclatasvir + Simeprevir

Cohort 2: (Genotype 1b) Daclatasvir + Simeprevir + Ribavirin

Cohort 3: (Genotype 1a) Daclatasvir + Simeprevir + Ribavirin

Cohort 4: (Genotype 1a) Daclatasvir + Simeprevir + Ribavirin

Arm Description

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

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.

Full Information

First Posted
June 25, 2012
Last Updated
January 10, 2017
Sponsor
Bristol-Myers Squibb
Collaborators
Janssen Research & Development, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT01628692
Brief Title
Study of Daclatasvir (BMS-790052) and Simeprevir (TMC435) in Patients With Genotype 1 Chronic Hepatitis C Virus
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 Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
July 2012 (undefined)
Primary Completion Date
August 2013 (Actual)
Study Completion Date
November 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb
Collaborators
Janssen Research & Development, LLC

4. Oversight

Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C Virus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
230 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1: (Genotype 1b) Daclatasvir + Simeprevir
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 2: (Genotype 1b) Daclatasvir + Simeprevir + Ribavirin
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 3: (Genotype 1a) Daclatasvir + Simeprevir + Ribavirin
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 4: (Genotype 1a) Daclatasvir + Simeprevir + Ribavirin
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Daclatasvir
Other Intervention Name(s)
BMS-790052
Intervention Description
Tablets, oral, 30 mg, once daily
Intervention Type
Drug
Intervention Name(s)
Simeprevir
Other Intervention Name(s)
TMC435
Intervention Description
Capsule, oral, 150 mg, once daily
Intervention Type
Drug
Intervention Name(s)
Ribavirin
Intervention Description
Tablets, oral, 500-600 mg, twice daily
Primary Outcome Measure Information:
Title
Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)
Description
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.
Time Frame
Post Treatment Week 12 (Follow-up period)
Secondary Outcome Measure Information:
Title
Percentage of Participants With Rapid Virologic Response (RVR) at Week 4
Description
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.
Time Frame
Week 4
Title
Percentage of Participants With Complete Early Virologic Response (cEVR)
Description
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.
Time Frame
Week 12
Title
Percentage of Participants With Extended Rapid Virologic Response (eRVR)
Description
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.
Time Frame
Week 4 and Week 12
Title
Percentage of Participants With End of Treatment Response (EOTR)
Description
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.
Time Frame
End of treatment (Week 24)
Title
Percentage of Participants With Sustained Virologic Response at Week 12 (SVR12) by rs12979860 Single Nucleotide Polymorphisms in the IL-28B Gene Categories
Description
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.
Time Frame
Baseline, post-treatment Week 12 (Follow-up period)
Title
Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died
Description
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.
Time Frame
From start of treatment (Day 1) up to 7 days post last dose of study treatment (Week 24)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
San Francisco General Hospital
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
Kaiser Permanente Med Ctr
City
San Francisco
State/Province
California
ZIP/Postal Code
94118
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Johns Hopkins University
City
Lutherville
State/Province
Maryland
ZIP/Postal Code
21093
Country
United States
Facility Name
Nashville Medical Research Institute
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37205
Country
United States
Facility Name
Texas Clinical Research Institute, Llc
City
Arlington
State/Province
Texas
ZIP/Postal Code
76012
Country
United States
Facility Name
Metropolitan Research
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22031
Country
United States
Facility Name
Local Institution
City
Buenos Aires
ZIP/Postal Code
1119
Country
Argentina
Facility Name
Local Institution
City
Buenos Aires
ZIP/Postal Code
C1181ACH
Country
Argentina
Facility Name
Local Institution
City
Creteil Cedex
ZIP/Postal Code
94010
Country
France
Facility Name
Local Institution
City
Limoges
ZIP/Postal Code
87042
Country
France
Facility Name
Local Institution
City
Marseille Cedex 08
ZIP/Postal Code
13285
Country
France
Facility Name
Local Institution
City
Paris Cedex 13
ZIP/Postal Code
75651
Country
France
Facility Name
Local Institution
City
Paris Cedex 14
ZIP/Postal Code
75679
Country
France
Facility Name
Local Institution
City
Pessac
ZIP/Postal Code
33600
Country
France
Facility Name
Local Institution
City
Vandoeuvre Les Nancy
ZIP/Postal Code
54511
Country
France
Facility Name
Local Institution
City
Berlin
ZIP/Postal Code
10969
Country
Germany
Facility Name
Local Institution
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
Local Institution
City
Hamburg
ZIP/Postal Code
20099
Country
Germany
Facility Name
Local Institution
City
Koeln
ZIP/Postal Code
50937
Country
Germany
Facility Name
Local Institution
City
Budapest
ZIP/Postal Code
1097
Country
Hungary
Facility Name
Local Institution
City
Budapest
ZIP/Postal Code
1126
Country
Hungary
Facility Name
Local Institution
City
Gyula
ZIP/Postal Code
5700
Country
Hungary
Facility Name
Local Institution
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Local Institution
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Local Institution
City
Valencia
ZIP/Postal Code
46010
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
26453968
Citation
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.
Results Reference
derived
Links:
URL
http://www.bms.com/studyconnect/Pages/home.aspx
Description
BMS clinical trial educational resource

Learn more about this trial

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

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