Hepatitis C, Chronic, Insulin Resistance
Conditions
Keywords
homeostasis model assessment of insulin resistance
Brief summary
This is a Phase 3b/4, prospective, open-label, randomized, multicenter study of peginterferon alfa-2b plus ribavirin in participants with chronic hepatitis C, genotype 1. The study consists of two parts: (1) a noninterventional arm (HOMA IR \<= 2) and (2) an interventional arm (HOMA IR \> 2), where HOMA IR is the insulin resistance index for the participants calculated by fasting insulin (uU/mL) x \[fasting glucose (mmol/L)/22.5\]. Participants in the noninterventional arm are treated according to the European labeling and response rates are evaluated at Month 1 (optional), 3, 6, 12, and follow up. Participants in the interventional arm are treated with PEG-Intron 1.5 ug/kg (subcutaneous) once weekly plus weight-based REBETOL 800-1400 mg (oral capsules) daily for a variable period depending on their response at Week 12: (1) HCV-RNA positive with \< 2-log drop in viral load, treatment will be discontinued; (2) HCV-RNA positive with \>= 2-log drop in viral load; participants will be randomized (1:1) to Group A (stop treatment at Week 48) or Group B (stop treatment at Week 72); and (3) HCV-RNA negative, treatment will be changed to be according to the European labeling and response rates will be evaluated at Month 6, 12, and follow up. All participants will go on with their treatment after Week 12 until the results of the HCV polymerase chain reaction (PCR) are available (maximum of 4 weeks).
Interventions
1. Powder for injection in Redipen (50, 80, 100, 120, and 150 microgram strengths), subcutaneous, dose of 1.5 micrograms/kg, weekly for 12 weeks, then up to 4 weeks until HCV PCR results are available, and then for another 36 weeks(Group A) or 60 weeks (Group B) postrandomization. 2. 200 mg capsules, oral, weight based dose of 800-1400 mg, daily for up to 12 weeks, then up to 4 weeks until HCV PCR results are available, and then for another 36 weeks (Group A) or 60 weeks (Group B) postrandomization
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 65 Years
Healthy volunteers
No
Inclusion criteria
* male and female participants with newly diagnosed chronic hepatitis C * age 18-65 * HCV-RNA positive in serum as measured by PCR * Genotype 1 * ALT levels according to European labeling * in women of child-bearing age, pregnancy must be excluded prior to entry into the study, and the use of a safe contraceptive device must be documented; sexually active male participants must practice a method of contraception considered acceptable (vasectomy, condom plus spermicide, plus relationship with a female partner who practices an acceptable method of contraception) * Lab parameters: * Hb: \>=12 g/dL (women) or \>= 13 g/dL (men) * leukocytes \>= 3,000/µL * thrombocytes \>= 100,000/µL * PT/PTT/coagulation must be within normal limits or clinically acceptable to the investigator/sponsor * Albumin must be within normal limits or clinically acceptable to the investigator/sponsor * creatinine must be within normal limits or clinically acceptable to the investigator/sponsor * uric acid must be within normal limits or clinically acceptable to the investigator/sponsor * antinuclear antibodies \<= 1:160 * signed informed consent
Exclusion criteria
* refusal by women of child-bearing age or by sexually active participants to use a safe contraceptive * breast-feeding women * cirrhosis stage B and C according to Child-Pugh * signs of decompensated liver disease * confirmed co-infection with HIV or HBV * existing psychiatric comorbidity * alcohol abuse * active malignant disease or suspicion or history of malignant disease within 5 previous years (except for adequately treated basal cell carcinoma) * existing psoriasis or other dermatological disorder * treatment with a study drug within the last 30 days * any uncontrolled underlying medical conditions * clinically significant ECG abnormalities and/or significant cardiovascular dysfunction within the last 6 months. In case of other suspected heart disease, a cardiological examination is required. * any liver disorder of other genesis than the study indication (with regard to elevated iron levels, only participants with manifest hemochromatosis are excluded) * autoimmune disorder (except LKM-positive participants).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Virological Response in Participants With and Without Insulin Resistance | At Week 12 (after start of therapy) | Early Virological Response (EVR) defined as HCV PCR at Week 12 either negative or at least 2 log units less than baseline in participants with and without insulin resistance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virological Response (PCR 24 Weeks After End of Treatment) | Up to 24 weeks following 48 or 72 weeks of therapy | Sustained virological response (SVR) was defined as undetectable HCV RNA in serum at the end of follow-up (24 weeks after end of therapy) according to a polymerase chain reaction (PCR) assay. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Total for Interventional Arm and Non Interventional Arm | 59 |
| Total | 59 |
Baseline characteristics
| Characteristic | Total for Interventional Arm and Non Interventional Arm |
|---|---|
| Age, Customized Between 18 and 65 years | 59 Participants |
| Sex/Gender, Customized Female | 24 Participants |
| Sex/Gender, Customized Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 17 | 37 / 42 |
| serious Total, serious adverse events | 3 / 17 | 4 / 42 |
Outcome results
Primary
Early Virological Response in Participants With and Without Insulin Resistance
Early Virological Response (EVR) defined as HCV PCR at Week 12 either negative or at least 2 log units less than baseline in participants with and without insulin resistance.
Time frame: At Week 12 (after start of therapy)
Population: Interventional arm: At baseline, PCR measurements for 38 out of 42 participants were available.~Non Interventional arm: At baseline, PCR measurements for 15 out of 17 participants were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non Interventional Arm HOMA IR <= 2 | Early Virological Response in Participants With and Without Insulin Resistance | 10 Participants |
| Interventional Arm HOMA IR > 2 | Early Virological Response in Participants With and Without Insulin Resistance | 24 Participants |
Secondary
Sustained Virological Response (PCR 24 Weeks After End of Treatment)
Sustained virological response (SVR) was defined as undetectable HCV RNA in serum at the end of follow-up (24 weeks after end of therapy) according to a polymerase chain reaction (PCR) assay.
Time frame: Up to 24 weeks following 48 or 72 weeks of therapy
Population: Information on PCR was available for 7 participants in the non interventional study arm and 11 participants in the interventional study arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non Interventional Arm HOMA IR <= 2 | Sustained Virological Response (PCR 24 Weeks After End of Treatment) | 1 Participants |
| Interventional Arm HOMA IR > 2 | Sustained Virological Response (PCR 24 Weeks After End of Treatment) | 3 Participants |