A Study of Pharmacokinetics, Efficacy, Safety, Tolerability, of the Combination of Simeprevir (TMC435), Daclatasvir (BMS-790052), and Ribavirin (RBV) in Patients With Recurrent Chronic Hepatitis C Genotype 1b Infection After Orthotopic Liver Transplantation

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Janssen R&D Ireland
ClinicalTrials.gov Identifier:
NCT01938625
First received: September 5, 2013
Last updated: September 8, 2014
Last verified: September 2014
  Purpose

The purpose of the study is to evaluate effect of steady-state (when the amount of drug administered (in a given time period is equal to the amount of drug eliminated in that same period) of simeprevir and daclatasvir on the steady-state pharmacokinetics (what a medication does to the body) of cyclosporine (applicable to Part 1 only) and tacrolimus when administered as a combinational regimen in post-orthotopic liver transplantation (OLT) participants with recurrent hepatitis C virus (HCV) genotype 1b infection and effectiveness of a 24-week treatment regimen containing simeprevir, daclatasvir, and ribavirin (RBV) with respect to the proportion of HCV genotype 1b infected post-OLT participants achieving sustained virologic response 12 weeks after end of treatment.


Condition Intervention Phase
Hepatitis C, Chronic
Drug: Simeprevir
Drug: Daclatasvir
Drug: Ribavirin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 2, Open-Label Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Tolerability of the Combination of Simeprevir (TMC435), Daclatasvir (BMS-790052) and Ribavirin (RBV) in Subjects With Recurrent Chronic Hepatitis C Genotype 1b Infection After Orthotopic Liver Transplantation

Resource links provided by NLM:


Further study details as provided by Janssen R&D Ireland:

Primary Outcome Measures:
  • Number of participants with a sustained virologic response (SVR)12 Weeks after the end of treatment [ Time Frame: Week 36 ] [ Designated as safety issue: No ]
    SVR12 is defined as undetectable hepatitis C virus (HCV) ribonucleic acid (RNA) at the end of treatment and HCV RNA less than 25 IU/mL at 12 Weeks after the end of treatment.

  • Maximum Observed Plasma Concentration (Cmax) of cyclosporine and tacrolimus [ Time Frame: Pre-dose (within 15 minutes before the intake of study drug) and at 1, 2, 3, 4, 5, 6, 7, 9, 12, and 24 hours postdose on Baseline and Week 2 ] [ Designated as safety issue: No ]
    The Plasma Concentration (Cmax) is defined as maximum observed analyte concentration.

  • Area Under the Plasma Concentration-Time Curve From Time Zero to Time at Last Observed Quantifiable Concentration (AUC[last]) of cyclosporine and tacrolimus [ Time Frame: Pre-dose (within 15 minutes before the intake of study drug) and at 1, 2, 3, 4, 5, 6, 7, 9, 12, and 24 hours postdose on Baseline and Week 2 ] [ Designated as safety issue: No ]
    The Area Under the Plasma Concentration-Time Curve From Time Zero to Time at Last Observed Quantifiable Concentration (AUC[last]) is area under the plasma concentration-time curve from time zero to the last quantifiable concentration.


Secondary Outcome Measures:
  • Maximum Observed Plasma Concentration (Cmax) of simprevir and daclatasvir [ Time Frame: Pre-dose (within 15 minutes before the intake of study drug) and at 1, 2, 3, 4, 5, 6, 7, 9, 12, and 24 hours postdose on Week 2, 4, 8 and 12 ] [ Designated as safety issue: No ]
    The Plasma Concentration (Cmax) is defined as maximum observed analyte concentration.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of simprevir and daclatasvir [ Time Frame: Pre-dose (within 15 minutes before the intake of study drug) and at 1, 2, 3, 4, 5, 6, 7, 9, 12, and 24 hours postdose on Week 2, 4, 8 and 12 ] [ Designated as safety issue: No ]
    The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.

  • Predose (trough) concentration (C0h) of simprenavir and daclatasvir [ Time Frame: Pre-dose (within 15 minutes before the intake of study drug) on Week 2, 4, 8 and 12 ] [ Designated as safety issue: No ]
  • Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of simprevir and daclatasvir [ Time Frame: Pre-dose (within 15 minutes before the intake of study drug) on Week 2, 4, 8 and 12 ] [ Designated as safety issue: No ]
    The Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) is a measure of the plasma concentration of simprevir and daclatasvir from time zero to end of dosing interval.

  • Number of participants with dose adjustment of cyclosporine and tacrolimus during treatment with regimen simeprevir, daclatasvir and RBV [ Time Frame: Week 1 to 24 ] [ Designated as safety issue: No ]
  • Number of patients with a sustained virological response SVR4 after the end of treatment [ Time Frame: Week 28 ] [ Designated as safety issue: No ]
    SVR4 is defined as undetectable hepatitis C virus (HCV) ribonucleic acid (RNA) at the end of treatment and HCV RNA less than 25 IU/mL at 4 Weeks after the end of treatment.

  • Number of participants with a sustained virologic response SVR24 after the end of treatment [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    SVR24 is defined as undetectable hepatitis C virus (HCV) ribose nucleic acid (RNA) at the end of treatment and HCV RNA less than 25 IU/mL at 24 Weeks after the end of treatment.

  • Number of participants with adverse events [ Time Frame: Up to 48 Weeks ] [ Designated as safety issue: Yes ]
  • Number of participants with Undetectable HCV RNA (less than 25 IU/mL undetectable) and HCV RNA less than 25 IU/mL detectable [ Time Frame: Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
  • Number of participants with HCV RNA level less than 100 IU/mL [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  • Number of participants with on-treatment failure after treatment with regimen simeprevir, daclatasvir and RBV [ Time Frame: Screening, Baseline and Week 1 to 24 ] [ Designated as safety issue: No ]
    On-treatment failure is defined as HCV RNA level is greater than or equal to 25 IU/mL at end of treatment.

  • Number of participants with viral relapse after treatment with regimen simeprevir, daclatasvir and RBV [ Time Frame: Screening, Baseline, Week 1 to 24; 24 Weeks after end of treatment ] [ Designated as safety issue: No ]
    Viral relapse is defined as undetectable HCV RNA less than 25 IU/mL at end of treatment and greater than or equal to 25 IU/mL during the follow-up period.

  • Number of participants with HCV NS3/4A and NS5A sequences [ Time Frame: Screening, Baseline and Week 1 to 24 ] [ Designated as safety issue: No ]

Enrollment: 35
Study Start Date: December 2013
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1
Participants with Metavir fibrosis score F1-F2 will receive treatment with combinational regimen of simperevir, daclatasvir, and ribavirin.
Drug: Simeprevir
Participants will receive 150 milligram capsule of simeprevir orally (by mouth) once daily with food for 24 weeks. In Part 1, if simeprevir pre-dose plasma concentration is greater than 7,300 nanogram per milliliter (ng/mL), participants will receive simeprevir 150 milligram capsule orally every other day to complete 24 weeks of treatment.
Drug: Daclatasvir
Participants will receive 60 milligram tablet of daclatasvir orally once daily for 24 weeks.
Drug: Ribavirin
Participants will receive 5 or 6 tablets of 200 milligram of ribavirin orally twice a day with food for 24 weeks.
Experimental: Part 2
Participants with Metavir fibrosis score F1-F4 will receive treatment with combinational regimen of simeprevir, daclatasvir, and ribavirin.
Drug: Simeprevir
Participants will receive 150 milligram capsule of simeprevir orally (by mouth) once daily with food for 24 weeks. In Part 1, if simeprevir pre-dose plasma concentration is greater than 7,300 nanogram per milliliter (ng/mL), participants will receive simeprevir 150 milligram capsule orally every other day to complete 24 weeks of treatment.
Drug: Daclatasvir
Participants will receive 60 milligram tablet of daclatasvir orally once daily for 24 weeks.
Drug: Ribavirin
Participants will receive 5 or 6 tablets of 200 milligram of ribavirin orally twice a day with food for 24 weeks.

Detailed Description:

This is an open-label (all participants of this study know the identity of the intervention) and multicenter (study conducted at multiple sites) study. This study will be conducted in 2 parts. Both the parts of the study will consist of screening phase (4 weeks), treatment period (24 weeks), and a post-treatment follow-up (24 weeks). A total of 30 participants will be enrolled in Part 1 and Part 2 of the study. A minimum of 20 participants should be on cyclosporine as stable immunosuppressant therapy and a minimum of 10 participants should be on tacrolimus as stable immunosuppressant therapy. In Part 1 of the study, participants with Metavir score of F1-F2, will receive a combination of study drugs - simeprevir, daclatasvir, and ribavirin for 24 weeks. In Part 2 of the study, participants with Metavir score F1-F4 will receive a dosing regimen of study drugs based on the data from Part 1 of the study. Safety evaluations will include assessments of adverse events, clinical laboratory tests, urinalysis, electrocardiogram, vital signs, and physical examination. The total study duration for each participant will be approximately 52 weeks.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Liver transplant between 6 months and 10 years prior to the screening visit
  • Hepatitis C virus (HCV) genotype 1 subtype b infection confirmed at screening
  • Screening HCV ribose nucleic acid level greater than 10,000 IU/mL
  • HCV treatment-naïve participants must not have received post orthotopic liver transplant treatment with any approved or investigational drug for the treatment of HCV
  • Receiving stable immunosuppressant therapy (ie, no change in dose in the last month) with cyclosporine (only allowed in Part 1) or tacrolimus for more than 3 months prior to the screening visit

Exclusion Criteria:

  • Evidence of acute or chronic hepatic decompensation after the liver transplantation (including ascites, bleeding varices or hepatic encephalopathy)
  • Any liver disease of non-HCV etiology, including current evidence of graft rejection except the presence of liver steatosis
  • Any other clinically significant disease that in the opinion of the investigator would be exacerbated by the known effects of ribavirin
  • Coinfection with HCV of another genotype than genotype 1b, HIV type 1 or 2 (positive HIV-1 or HIV-2 antibodies test at screening), and hepatitis B virus (hepatitis B surface antigen positive)
  • Multi-organ transplant that included heart, lung, pancreas, or kidney
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01938625

Locations
Germany
Essen, Germany
Hamburg, Germany
Poland
Warszawa, Poland
Spain
Barcelona, Spain
Madrid, Spain
Valencia, Spain
Sponsors and Collaborators
Janssen R&D Ireland
Investigators
Study Director: Janssen R&D Ireland Clinical Trial Janssen R&D Ireland
  More Information

No publications provided

Responsible Party: Janssen R&D Ireland
ClinicalTrials.gov Identifier: NCT01938625     History of Changes
Other Study ID Numbers: CR102639, TMC435HPC3016, 2013-002726-23
Study First Received: September 5, 2013
Last Updated: September 8, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Spain: Spanish Agency of Medicines
Germany: Ethics Commission

Keywords provided by Janssen R&D Ireland:
Hepatitis C, Chronic
Recurrent Chronic Hepatitis C
Pharmacokinetics
Simeprevir
Daclatasvir
Ribavirin
Orthotopic Liver Transplantation
TMC435
BMS-790052
RBV

Additional relevant MeSH terms:
Hepatitis C, Chronic
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Ribavirin
Simeprevir
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Protease Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 01, 2014