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

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Drug: Simeprevir; Drug: Daclatasvir; Drug: Ribavirin; Drug: Cyclosporine; Drug: Tacrolimus

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 9 participants were planned to receive cyclosporine as stable immunosuppressant therapy and a minimum of 9 participants were planned to receive tacrolimus as stable immunosuppressant therapy during Part 1. All participants will be receiving tacrolimus as stable immunosuppressant therapy during Part 2. 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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany
  • Hamburg, Germany
• Poland
  • Warszawa, Poland
• Spain
  • Barcelona, Spain
  • Madrid, Spain
  • Valencia, Spain

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

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 ribonucleic 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1; Participants with Metavir fibrosis score F1-F2 will receive treatment with combinational regimen of simeprevir, daclatasvir, and ribavirin along with cyclosporine or tacrolimus as stable immunosuppressant therapy.	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.; Drug: Cyclosporine; Participants will receive cyclosporine as one of the stable immunosuppressant therapy (no change in dose in the last month) for more than 3 months prior to the screening visit. Cyclosporine will be administered as per the manufacturer's prescribing information for 24 weeks.; Drug: Tacrolimus; Participants will receive tacrolimus as one of the stable immunosuppressant therapy (no change in dose in the last month) for more than 3 months prior to the screening visit. Tacrolimus will be administered as per the manufacturer's prescribing information for 24 weeks.
Experimental: Part 2; Participants with Metavir fibrosis score F1-F4 will receive treatment with combinational regimen of simeprevir, daclatasvir, and ribavirin along with tacrolimus as stable immunosuppressant therapy.	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.; Drug: Tacrolimus; Participants will receive tacrolimus as one of the stable immunosuppressant therapy (no change in dose in the last month) for more than 3 months prior to the screening visit. Tacrolimus will be administered as per the manufacturer's prescribing information for 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Sustained Virologic Response 12 Weeks After the End of Treatment (SVR 12)	Participants were considered to have achieved SVR12 if hepatitis C virus ribonucleic acid (HCV RNA) levels were less than (<) 25 international unit per milliliter (IU/mL) detectable or undetectable at 12 weeks after the end of treatment.	Week 36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Sustained Virologic Response 4 Weeks After the End of Treatment (SVR 4)	Participants were considered to have achieved SVR4 if HCV RNA levels were (<) 25 IU/mL detectable or undetectable at 4 weeks after the end of treatment.	Week 28
Percentage of Participants With Sustained Virologic Response 24 Weeks After the End of Treatment (SVR 24)	Participants were considered to have achieved SVR 24 if hepatitis C virus ribonucleic acid (HCV RNA) levels were (<) 25 IU/mL detectable or undetectable at 24 weeks after the end of treatment.	Week 48
Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable	Percentage of participants with detectable and undetectable HCV RNA (<) 25 IU/mL during treatment at Weeks 2,4, 12, and 24 were reported.	Weeks 2, 4, 12, and 24
Percentage of Participants With HCV RNA (<) 100 IU/mL at Week 4	Percentage of participants with HCV RNA (<) 100 IU/mL at week 4 were reported.	Week 4
Number of Participants With On-Treatment Failure	On-treatment failure is defined as participants who did not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of treatment. This was to include participants with: 1) Viral breakthrough, defined as a confirmed increase of greater than (>)1 log10 in HCV RNA from nadir, or confirmed HCV RNA of >100 IU/mL in participants whose HCV RNA had previously been <lower limit of quantification (LLOQ) while on treatment; 2) Other with confirmed detectable HCV RNA at the actual end of treatment (example, completed, discontinued due to adverse events (AEs), withdrawal of consent).	Up to Week 24 after actual EOT (week 24)
Number of Participants With Viral Breakthrough	Viral breakthrough is defined as a confirmed increase of >1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of >100 IU/mL in participants whose HCV RNA levels had previously been below the limit of quantification (<25 IU/mL detectable) or undetectable (<25 IU/mL undetectable) while on study treatment.	Up to week 24
Number of Participants With Viral Relapse	Participants who did not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (>=) LLOQ during follow-up.	Up to Week 24 after actual EOT (week 24)

Collaborators and Investigators

• Sponsor: Janssen R&D Ireland

Publications and helpful links

General Publications

• Forns X, Berenguer M, Herzer K, Sterneck M, Donato MF, Andreone P, Fagiuoli S, Cieciura T, Durlik M, Calleja JL, Marino Z, Shukla U, Verbinnen T, Lenz O, Ouwerkerk-Mahadevan S, Peeters M, Janssen K, Kalmeijer R, Jessner W. Efficacy, safety, and pharmacokinetics of simeprevir, daclatasvir, and ribavirin in patients with recurrent hepatitis C virus genotype 1b infection after orthotopic liver transplantation: The Phase II SATURN study. Transpl Infect Dis. 2017 Jun;19(3). doi: 10.1111/tid.12696. Epub 2017 May 4.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2013
• Primary Completion (Actual): April 27, 2015
• Study Completion (Actual): July 28, 2015

Study Registration Dates

• First Submitted: September 5, 2013
• First Submitted That Met QC Criteria: September 5, 2013
• First Posted (Estimate): September 10, 2013

Study Record Updates

• Last Update Posted (Actual): November 21, 2018
• Last Update Submitted That Met QC Criteria: November 20, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Simeprevir; Daclatasvir; Ribavirin; Hepatitis C, Chronic; TMC435; RBV; Recurrent Chronic Hepatitis C; Orthotopic Liver Transplantation; BMS-790052
• 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; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Immunosuppressive Agents; Immunologic Factors; Protease Inhibitors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Ribavirin; Tacrolimus; Cyclosporine; Cyclosporins; Simeprevir
• Other Study ID Numbers: CR102639; TMC435HPC3016 (Other Identifier: Janssen R&D Ireland); 2013-002726-23 (EudraCT Number)