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Pegylated Interferon, Ribavirin, Telaprevir in Hepatitis C Virus Infection in Orthotopic Liver Transplant Recipients

This study has been terminated.
(Low accrual)
Sponsor:
Information provided by (Responsible Party):
University of Chicago
ClinicalTrials.gov Identifier:
NCT01592006
First received: April 27, 2012
Last updated: November 21, 2014
Last verified: November 2014
  Purpose

Patients are being asked to be part of this study because they are a liver transplant recipient and have the Hepatitis C Virus (HCV). Current routine treatment for HCV for liver transplant patients includes taking two medications called pegylated interferon alfa-2a (Pegasys®) and ribavirin. Patients Pegasys and ribavirin are FDA approved for the treatment of HCV.

This study will evaluate the safety and efficacy of adding a third drug called telaprevir for the experimental treatment of HCV in liver transplant patients. The combination of Pegasys, ribavirin and telaprevir is currently FDA approved for the treatment of HCV, but is specifically not FDA approved for HCV patients who have had a liver transplant. This is because more information is needed about possible drug interactions between telaprevir and cyclosporine, or telaprevir and tacrolimus-based immunosuppressive drugs, which are typically part of routine care for transplant patients.

Studies have shown that the addition of telaprevir greatly increases the efficacy of Pegasys and ribavirin for the treatment of HCV. However, these studies did not include adequate information on transplant patients due to the potential drug interactions.

The investigators hope to gather more information about the safety and efficacy of telaprevir given in combination with Pegasys and ribavirin in the liver transplant patients who have HCV that is not well controlled with Pegasys and ribavirin alone.


Condition Intervention Phase
Hepatitis C
Drug: Peginterferon alfa-2a
Drug: Ribavirin
Drug: telaprevir
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study on the Efficicay and Safety of Pegylated Interferon, Ribavirin and Telaprevir in Recurrent Hepatitis C Virus (HCV) Infection in Orthotopic Liver Transplant (OLT) Recipients.

Resource links provided by NLM:


Further study details as provided by University of Chicago:

Primary Outcome Measures:
  • evaluate the efficacy of triple antiviral therapy [ Time Frame: 3 years from start of study ] [ Designated as safety issue: No ]
    To evaluate the efficacy of triple antiviral therapy, consisting of pegylated interferon alfa-2a (Pegasys®), ribavirin, and telaprevir therapy in liver transplant recipients with hepatitis C. This will be measured and reported by sustained virologic response


Secondary Outcome Measures:
  • safety of triple antiviral therapy in HCV infected OLT recipients [ Time Frame: 6 years from the start of the study ] [ Designated as safety issue: Yes ]

    To evaluate the safety of triple antiviral therapy, consisting of pegylated interferon alfa-2a (Pegasys®), ribavirin, and telaprevir therapy in liver transplant recipients with hepatitis C

    To evaluate the pharmacokinetic effects of continuous use of telaprevir on serum cyclosporine or tacrolimus concentrations in this population

    Tolerability and Safety will be measured and reported by serious adverse events.



Enrollment: 3
Study Start Date: April 2012
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: HCV, LT, Pegasys, ribavirin, telaprevir
Patients are being asked to be part of this arm because they are orthotopic liver transplant recipients (OLT) and have the Hepatitis C Virus (HCV). They will be given the study drugs Pegasys, ribavirin and telaprevir
Drug: Peginterferon alfa-2a
Patients will be treated with pegylated interferon alfa-2a (Pegasys®) 180 mcg SQ per week for 12 weeks, followed by pegylated interferon alfa-2a (Pegasys®) and ribavirin for another 36 weeks. Patients will be assessed at periodic intervals for safety and adverse effects. Following completion of therapy, patients will be followed for another 24 weeks to determine sustained response.
Drug: Ribavirin
Patients will be given ribavirin 600-1200 mg PO per day for 12 weeks, followed by pegylated interferon alfa-2a (Pegasys®) and ribavirin for another 36 weeks. Patients will be assessed at periodic intervals for safety and adverse effects. Following completion of therapy, patients will be followed for another 24 weeks to determine sustained response.
Drug: telaprevir
Patients will be given telaprevir 750 mg tid (Incivek®) for 12 weeks, followed by pegylated interferon alfa-2a (Pegasys®) and ribavirin for another 36 weeks. Patients will be assessed at periodic intervals for safety and adverse effects. Following completion of therapy, patients will be followed for another 24 weeks to determine sustained response.

  Hide Detailed Description

Detailed Description:

BACKGROUND:

Cirrhosis from HCV is the most common indication for OLT. Unfortunately, disease recurrence in the allograft is virtually universal. The spectrum of disease recurrence ranges from minimal inflammation to severe cholestasis as well as cirrhosis, leading to allograft failure. Previous reports indicated a comparable survival rate between patients who received OLT for HCV and those who received OLT for other indications. More recent data, however, suggested that HCV-positive recipients have significantly impaired patient and allograft survival following OLT as compared to HCV-negative recipients. Approximately 20% of patients with recurrent HCV have cirrhosis at 5 years post-OLT.

Attempts to treat HCV recurrence in OLT recipients have had limited success. Sustained virologic responses (SVR) have only been seen in up to 30% of patients with genotype 1 infection, whereas SVR has been higher at 42-46% for non-transplant counterparts. Most recently, the addition of telaprevir to pegylated interferon and ribavirin to comprise the triple therapy in the nontransplant HCV-infected population has led to significantly higher sustained virologic response rate (SVR) of 75% when compared to 44% observed in the control arm which received pegylated interferon and ribavirin. Its side effect profile was acceptable to allow the FDA to approve the drug on May 23, 2011. However, there is no data on the efficacy and safety of telaprevir in OLT recipients. In fact, its use in this population is greatly hindered by a significant drug-drug interaction with the major immunosuppressive agents used in OLT, namely tacrolimus and cyclosporine. Telaprevir increases cyslosporine exposure by 4.6 fold and its half-life by 3.5 fold. It increases tacrolimus exposure to 70 fold and its half-life by 4.9 fold. Clearly, the doses of these immunosuppressive agents need to be adjusted at the start and end of telaprevir therapy.

The primary aim of our study is to determine the safety and efficacy of pegylated interferon alfa-2a (Pegasys®), ribavirin, and telaprevir therapy in liver transplant recipients with hepatitis C recurrence who are maintained on cyclosporine or tacrolimus-based immunosuppression. We hypothesize that triple therapy will have better sustained virologic response rates than the current standard of care, pegylated interferon and ribavirin, with an acceptable side-effect profile.

STUDY DESIGN:

Prospective, open-label, single center pilot study. All patients will receive the study drug along with the standard regimen of pegylated interferon and ribavirin.

DRUG DOSE AND TREATMENT DURATION:

Patients will be treated with pegylated interferon alfa-2a (Pegasys®) 180 mcg SQ per week, ribavirin 800-1200 mg PO per day (weight-based) for 48 weeks. Telaprevir 750 mg PO tid will be administered for the first 12 weeks. Following completion of therapy, patients will be followed for another 24 weeks to determine sustained response.

*Doses lower than 800 mg/day may be used by the investigator in patients with renal insufficiency (as ribavirin is renally excreted), at the investigator's discretion.

RESEARCH PROTOCOL:

This prospective study will include patients who have histologic evidence of recurrent HCV infection who are maintained on cyclosporine-based immunosuppression.

Patients who qualify for the study will be identified from the Liver Transplant Clinic. Patients will be treated with pegylated interferon alfa-2a (Pegasys®) 180 mcg SQ per week, ribavirin 600-1200 mg PO per day, and telaprevir 750 mg tid (Incivek®) for 12 weeks, followed by pegylated interferon alfa-2a (Pegasys®) and ribavirin for another 36 weeks. Patients will be assessed at periodic intervals for safety and adverse effects as delineated in the Schedule of Assessments (Appendix A). Growth factors such as erythropoietin and filgastrim will be allowed in the event that signficiant anemia and thrombocytopenia develops during therapy, at the discretion of the investigator.

The HCV RNA will be measured at baseline and weeks 2, 4, 8, 12, 24, 36 and 48 of therapy as well as during follow-up. Response to therapy is defined by HCV RNA <1000 IU/ml at weeks 4, 8, and 12 of therapy, which will allow continuation of treatment. Telaprevir will be discontinued if HCV RNA is >1000 IU/ml at weeks 4 or 8 of therapy, and pegylated interferon and ribavirin will be discontinued if HCV RNA is still detectable by week 24 of therapy.

Cyclosporine or tacrolimus trough levels will be drawn at baseline, days 1,2, 3, 4,5, 8, and to be continued every 2-3 days. The cyclosporine or tacrolimus dose will be cut by 50% at baseline and cyclosporine or tacrolimus dose adjustments will be made to maintain the level within the targeted therapeutic range. Once two consecutive levels within the targeted therapeutic range have been achieved, levels will be drawn weekly for the first month then biweekly until the end of telaprevir treatment. After the last dose of telaprevir, cyclosporine or tacrolimus levels will be drawn on days 1, 3, 5, 7 and to be continued every other day, and cyclosporine or tacrolimus dose adjustments will be made to maintain the level within the targeted therapeutic range. Once two consecutive levels within the targeted therapeutic range have been achieved, levels will be drawn in a week and then monthly for up to week 24 of therapy. Patients who complete therapy will continue to be followed for 24 weeks to determine their sustained virologic response.

STATISTICAL ANALYSIS:

This is a pilot, single arm study that evaluates the efficacy and safety of triple therapy in recurrent HCV. All clinical and laboratory data will be entered into a computer database. Categorical variables will be expressed as proportions and continuous variables will be expressed in mean values.

  Eligibility

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

Inclusion Criteria:

  • Male or female patients > 18 years of age.
  • Detectable plasma HCV-RNA by qualitative PCR assay.
  • HCV genotype 1 infection,
  • Documented recurrent hepatitis C by liver biopsy within the past year.
  • On cyclosporine or tacrolimus-based immunosuppression
  • Negative urine pregnancy test before initiating the treatment for women of childbearing potential.
  • Willingness of the patient and all potentially childbearing partners to use a reliable form of effective contraception during the study, unless the patient or partner is surgically sterile or post-menopausal.
  • Willingness to undergo provide informed consent and comply with study requirements.

Exclusion Criteria:

  • Genotype non-1 HCV infection.
  • Women who are pregnant or breast-feeding.
  • Male partners of women who are pregnant.
  • Evidence of co-infection with HIV or hepatitis B.
  • History of severe psychiatric disease.
  • History of immunologically mediated disease (e.g., inflammatory bowel disease, lupus erythematosus, rheumatoid arthritis, etc.)
  • History of clinically significant pulmonary disease.
  • History of severe cardiac disease.
  • History of malignancy where risk of recurrence is >20% within 2 years.
  • History of uncontrolled seizure disorder.
  • History of poorly controlled thyroid disease.
  • History of poorly controlled diabetes mellitus.
  • History of severe retinopathy.
  • Active gout.
  • History or evidence of severe medical illness that, in the opinion of the investigator, makes the patient unsuitable for pegylated interferon alfa-2a treatment (Pegasys®).
  • Inability or unwillingness to abstain from alcohol throughout the entire study period.
  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: NCT01592006

Locations
United States, Illinois
University of Chicago Medical Center
Chicago, Illinois, United States, 60637
Sponsors and Collaborators
University of Chicago
Investigators
Principal Investigator: Helen Te, MD University of Chicago
  More Information

No publications provided

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT01592006     History of Changes
Other Study ID Numbers: 12-0156
Study First Received: April 27, 2012
Last Updated: November 21, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Chicago:
hepatitis C virus
liver transplant recipient

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Digestive System Diseases
Enterovirus Infections
Flaviviridae Infections
Hepatitis, Viral, Human
Liver Diseases
Picornaviridae Infections
RNA Virus Infections
Virus Diseases
Interferons
Peginterferon alfa-2a
Ribavirin
Anti-Infective Agents
Antimetabolites
Antineoplastic Agents
Antiviral Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014