Hepatitis C, Chronic, Liver Cirrhosis, Liver Transplantation
Conditions
Brief summary
This is an exploratory study and is a Phase 3, single-arm, multi-center, open-label study of pegylated interferon alfa-2b, PEG-IFN alpha-2b (PEG-Intron) and ribavirin (RBV) to determine the sustained virologic response (SVR) at 24-week follow-up to 48 week in subjects after orthotopic liver transplantation (OLT) with chronic hepatitis C (HCV) recurrence.
Interventions
DRUGCombination of (a) pegylated interferon alfa-2b and (b) rebetol
1. Powder for injection in vials and Redipen (50, 80, 120, and 150 microgram strengths), subcutaneous, dose of 1.5 micrograms/kg, weekly for up to 48 weeks 2. 200 mg capsules, oral, weight based dose of 400-1200 mg, daily for up to 48 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Subjects must confirm that all prior medication washout times have been observed. * Subject must be 18 - 70 years of age of either gender and of any race. * Subject must be transplanted for end-stage hepatitis C or fulminant hepatitis C. * Subject must have documented: * persistent HCV viremia after OLT as defined by plasma positive for HCV RNA by quantitative reverse transcription-polymerase chain reaction (RT-PCR), * A liver transplant performed at least 3 months prior to screening but not more than 3 years prior to screening. * Subject must be on stable doses of immunosuppression for at least 1 month. * Compensated liver disease with minimum hematologic, biochemical, and serologic criteria at the (Day 1) baseline visit. * Alpha-fetoprotein value (AFP) less than or equal to 250ng/mL. If AFP greater than 100 ng/mL, patient will need evidence of normal liver (magnetic resonance imaging) MRI and normal chest computerized tomography (CT) scan within the last 3 months or during the screening period. * For subjects with a history of diabetes or hypertension, clearance from an ophthalmologist has to be obtained prior to treatment start (Day 1/Visit 2). * Subjects with a history of mild depression may be considered for entry into this study. * Female subjects cannot be pregnant or breastfeeding and must be either postmenopausal, surgically sterile or using 2 methods of birth control. * Sexually active male subjects are practicing an acceptable, method of contraception. * Contraceptive measures will be reviewed with female subjects at each visit. Dual methods of contraception must be used for 1 month prior to the start of treatment and 6 months after treatment discontinuation. * Pregnancy tests obtained at Screen Visit and Day 1 Visit prior to the initiation of treatment must be negative.
Exclusion criteria
* Pregnant women, women who plan to become pregnant, male subjects whose partner wants to become pregnant, and breastfeeding women (during study and up to 6 months after study completion). * Subject has used any investigational product within 30 days prior to Screening or is participating in any other clinical study. * Prior treatment for chronic hepatitis C post-liver transplant, including but not limited to antiviral or immunomodulatory product, any interferon product, or RBV, either as monotherapy or in combination. * Subjects with other organ transplants. * Any subject who received a positive hepatitis C core antibody (HBcAb) or HCV positive donor liver graft. * Retransplantation of the liver for rejection or graft failure. * Evidence of decompensated liver disease. * Known coagulopathies including hemophilia. * Known hemoglobinopathies. * Known glucose-6-phosphate dehydrogenase (G6PD) deficiency. * Hypersensitivity to alpha interferon and/or RBV. * Co-infection with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV). * Evidence of active or suspected malignancy or a history of malignancy within the last 5 years (with the exception of pre-transplant hepatocellular carcinoma histologically within the Milan criteria, and adequately treated basal or squamous cell carcinoma of the skin). * Any known pre-existing medical condition that could interfere with the subject's participation in and completion of the study. * Subject is or was a substance abuser. Subjects treated with buprenorphine (Subutex) who have been stable for 6 months may be included. * Patients weighing over 135 kg; Is participating in any other clinical study(ies); Is allergic to or has sensitivity to the study drug or its excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| A Sustained Virologic Response (SVR), Defined as a Plasma HCV RNA Level Below the Lower Level of Quantitation (LLQ) at 24 Weeks Post-treatment | 24 weeks after completion of up to 48 weeks of therapy | Number of participants with SVR at 24-week follow up after treatment with PEG-Intron and Ribavirin in post-orthotopic liver transplant recipients with recurrent HCV. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PEG-Intron Plus Ribavirin PEG-Intron plus ribavirin treatment for up to 48 weeks with 24-week follow up | 125 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 38 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Treatment failure | 7 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | PEG-Intron Plus Ribavirin |
|---|---|
| Age, Continuous | 54.2 years STANDARD_DEVIATION 5.7 |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 125 / 125 |
| serious Total, serious adverse events | 32 / 125 |
Outcome results
Primary
A Sustained Virologic Response (SVR), Defined as a Plasma HCV RNA Level Below the Lower Level of Quantitation (LLQ) at 24 Weeks Post-treatment
Number of participants with SVR at 24-week follow up after treatment with PEG-Intron and Ribavirin in post-orthotopic liver transplant recipients with recurrent HCV.
Time frame: 24 weeks after completion of up to 48 weeks of therapy
Population: Intent to Treat (ITT) Data Set: All enrolled subjects who received at least one dose of any study medication (PEG-Intron or Rebetol (RBV)). Analysis of all primary and secondary efficacy endpoints and safety variables was based on the ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEG-Intron Plus Ribavirin | A Sustained Virologic Response (SVR), Defined as a Plasma HCV RNA Level Below the Lower Level of Quantitation (LLQ) at 24 Weeks Post-treatment | 36 Participants |
95% CI: [0.21, 0.38]