Hepatitis C, Chronic
Conditions
Brief summary
This is a controlled, randomized, parallel-groups, open-label, multinational study designed to evaluate the efficacy and safety of PEG-Intron® (pegylated interferon alfa-2b) plus Rebetol® (ribavirin) in subjects with chronic hepatitis C. It is designed to evaluate whether 72 weeks of treatment with PEG-Intron plus Rebetol is more effective than 48 weeks of treatment in subjects with Genotype 1 chronic hepatitis C who exhibit a slow response to treatment.
Interventions
DRUGCombination of pegylated interferon alfa-2b (PEG-Intron®) and ribavirin (Rebetol®)
1. Powder for injection in vial or Redipen (50, 80, 100, 120, and 150 microgram strengths), subcutaneous, dose of 1.5 micrograms/kg, weekly for 48 weeks 2. 200 mg capsules, oral, weight based dose of 800-1400 mg, daily for 48 weeks
1. Powder for injection in vial or Redipen (50, 80, 100, 120, and 150 microgram strength), subcutaneous, dose of 1.5 micrograms/kg, weekly for 72 weeks. 2. 200 mg capsules, oral, weight based dose of 800-1400 mg, daily for 72 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Adult subjects aged 18 to 70 years, of either sex. * Genotype-1 hepatitis C virus (HCV)-ribonucleic acid (RNA)-positive subjects. * Subjects must be willing to give written informed consent and able to adhere to dosing and visit schedules. * Confirmation of liver biopsy availability: Availability of a liver biopsy performed within 18 months prior to the Screen visit, with a pathology report confirming the histological diagnosis of chronic hepatitis or liver cirrhosis. * Compensated liver disease with the following minimum hematological, biochemical, and serological criteria at the screen visit (WNL = within normal limits, ULN = Upper Limit Normal): * Hemoglobin values of equal or more than 12 g/dL for females and 13 g/dL for males. * White blood cells (WBCs) equal to or more than 3,000/mm\^3 * Neutrophil count equal to or more than 1,500/mm\^3 * Platelet count equal to or more than 80,000/mm\^3 * Direct bilirubin up to 10% above ULN is acceptable. * Indirect bilirubin up to 10% above ULN is acceptable (unless non-hepatitis related factors such as Gilbert's disease explain an indirect bilirubin rise). In such cases indirect bilirubin should be less than or equal to 3.0 mg/dL (less than or equal to 51.3 µmol/L) * Albumin up to 10% above ULN is acceptable. * Serum creatinine up to 10% above ULN is acceptable. * Alanine aminotransferase (ALT) level above ULN at Screen. * At the Screen Visit, fasting glucose must be 70-140 mg/dL. Results between 116-140 mg/dL require repeat fasting glucose to be less than 140 mg/dL and HbA1C less than or equal to 8.5%. HbA1C must be less than or equal to 8.5% in diabetic subjects (whether on medication or diet controlled). * Antinuclear antibodies (ANA) must be less than or equal to 1:320. * Thyroid Stimulating Hormone (TSH) WNL whether in euthyroid subjects or subjects requiring medical treatment. (subjects requiring medication to maintain TSH levels within normal limits are eligible if all other inclusion/
Exclusion criteria
are met). * Confirmation by the principal investigator or a sub-investigator that sexually active females of childbearing potential are practicing adequate contraception. * Female subjects cannot be pregnant or breastfeeding and must be either postmenopausal, surgically sterile or using 2 methods of birth control. While abstinence from sexual activity is the only certain method to prevent pregnancy, female patients of childbearing potential who are or who anticipate the possibility of becoming sexually active with a male partner must use a combination of the following 2 methods : * Contraceptive pill or intrauterine device (IUD) or depot hormonal preparation (ring, injection implant) and * A barrier method of contraception such as diaphragm, sponge with spermicide, condom, or a method of birth control considered acceptable by the study physician. 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. * A serum pregnancy test obtained at Screen Visit prior to the initiation of treatment must be negative. * Confirmation by the principal investigator or a sub-investigator that sexually active male subjects are practicing a method of contraception considered acceptable (vasectomy, condom plus spermicide, plus relationship with a female partner who practices an acceptable method of contraception). Contraception must be used during the treatment period and for seven months (or 6 months, according to local label) after the completion of therapy, including condom use by male subjects with pregnant partners. * For subjects with a history of hypertension or diabetes, written clearance from an ophthalmologist has to be obtained prior to treatment start.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virologic Response, Defined as a Plasma HCV-RNA (Hepatitis C Ribonucleic Acid) Level Below the LLQ (Lower Level of Quantitation) at 24 Weeks Post-treatment. | 48 or 72 weeks of treatment plus 24 weeks of follow-up. | LLQ = 30 IU/mL by reverse transcription polymerase chain reaction (RT-PCR) (Taqman Roche) |
Participant flow
Pre-assignment details
1428 patients enrolled; 159 patients qualified as slow responders per treatment week 12 and 24 protocol-specified eligibility criteria; 159 patients were randomized
Participants by arm
| Arm | Count |
|---|---|
| Standard Therapy (48-week Treatment) Slow responders (defined as being polymerase chain reaction \[PCR\] positive at Week 12 with at least 2 log reduction in viral load and PCR negative at Week 24) who are randomized at Week 48 to stop treatment at Week 48. | 86 |
| Extended Therapy (72-week Treatment) Slow responders (defined as being PCR positive at Week 12 with at least 2 log reduction in viral load and PCR negative at Week 24) who are randomized at Week 48 to continue treatment to Week 72. | 73 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative | 0 | 1 |
| Overall Study | Adverse Event | 3 | 6 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 6 |
Baseline characteristics
| Characteristic | Standard Therapy (48-week Treatment) | Extended Therapy (72-week Treatment) | Total |
|---|---|---|---|
| Age, Continuous | 44.5 years STANDARD_DEVIATION 9.9 | 46.5 years STANDARD_DEVIATION 11.6 | 45.35 years STANDARD_DEVIATION 10.79 |
| Sex: Female, Male Female | 34 Participants | 27 Participants | 61 Participants |
| Sex: Female, Male Male | 52 Participants | 46 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1,337 / 1,427 |
| serious Total, serious adverse events | 93 / 1,427 |
Outcome results
Primary
Sustained Virologic Response, Defined as a Plasma HCV-RNA (Hepatitis C Ribonucleic Acid) Level Below the LLQ (Lower Level of Quantitation) at 24 Weeks Post-treatment.
LLQ = 30 IU/mL by reverse transcription polymerase chain reaction (RT-PCR) (Taqman Roche)
Time frame: 48 or 72 weeks of treatment plus 24 weeks of follow-up.
Population: According to the protocol, the efficacy analysis was carried out on all slow responders (ie, patients who had at least 2 log drop in HCV-RNA level at treatment week 12, and undetectable HCV-RNA at treatment week 24).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Therapy (48-week Treatment) | Sustained Virologic Response, Defined as a Plasma HCV-RNA (Hepatitis C Ribonucleic Acid) Level Below the LLQ (Lower Level of Quantitation) at 24 Weeks Post-treatment. | 37 Participants |
| Extended Therapy (72-week Treatment) | Sustained Virologic Response, Defined as a Plasma HCV-RNA (Hepatitis C Ribonucleic Acid) Level Below the LLQ (Lower Level of Quantitation) at 24 Weeks Post-treatment. | 35 Participants |
p-value: 0.644595% CI: [-20.4, 10.6]Asymptotic Z-test