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

• ClinicalTrials.gov Identifier: NCT01938625
• Recruitment Status: Completed
• First Posted: September 10, 2013
• Results First Posted: November 21, 2018
• Last Update Posted: November 21, 2018
• Sponsor: Janssen R&D Ireland
• Information provided by (Responsible Party): Janssen R&D Ireland

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Hepatitis C, Chronic	Drug: Simeprevir; Drug: Daclatasvir; Drug: Ribavirin; Drug: Cyclosporine; Drug: Tacrolimus	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Actual Study Start Date: December 12, 2013
• Actual Primary Completion Date: April 27, 2015
• Actual Study Completion Date: July 28, 2015

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Sustained Virologic Response 12 Weeks After the End of Treatment (SVR 12) [ Time Frame: Week 36 ]
   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.

Secondary Outcome Measures :

1. Percentage of Participants With Sustained Virologic Response 4 Weeks After the End of Treatment (SVR 4) [ Time Frame: Week 28 ]
   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.
2. Percentage of Participants With Sustained Virologic Response 24 Weeks After the End of Treatment (SVR 24) [ Time Frame: Week 48 ]
   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.
3. Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable [ Time Frame: Weeks 2, 4, 12, and 24 ]
   Percentage of participants with detectable and undetectable HCV RNA (<) 25 IU/mL during treatment at Weeks 2,4, 12, and 24 were reported.
4. Percentage of Participants With HCV RNA (<) 100 IU/mL at Week 4 [ Time Frame: Week 4 ]
   Percentage of participants with HCV RNA (<) 100 IU/mL at week 4 were reported.
5. Number of Participants With On-Treatment Failure [ Time Frame: Up to Week 24 after actual EOT (week 24) ]
   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).
6. Number of Participants With Viral Breakthrough [ Time Frame: Up to week 24 ]
   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.
7. Number of Participants With Viral Relapse [ Time Frame: Up to Week 24 after actual EOT (week 24) ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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 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

Contacts and Locations

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

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

Forns X, Berenguer M, Herzer K, Sterneck M, Donato MF, Andreone P, Fagiuoli S, Cieciura T, Durlik M, Calleja JL, Mariño 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.

• Responsible Party: Janssen R&D Ireland
• ClinicalTrials.gov Identifier: NCT01938625
• Other Study ID Numbers: CR102639; TMC435HPC3016 ( Other Identifier: Janssen R&D Ireland ); 2013-002726-23 ( EudraCT Number )
• First Posted: September 10, 2013
• Results First Posted: November 21, 2018
• Last Update Posted: November 21, 2018
• Last Verified: November 2018

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 A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic; Infections; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections; Cyclosporine; Ribavirin; Simeprevir; Tacrolimus; Cyclosporins; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents