| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C, Genotype 1 |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate whether 72-weeks of treatment with peginteron alpha-2b plus ribavirin is more effective than 48-weeks of treatment in naive, genotype 1 hepatitis C patients with slow response (i.e., patients who are HCV-RNA-positive, with an equal or more than 2 log drop in viral load at week 12 as well as HCV-RNA negative at week 24) |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety of 72 weeks of treatment with peginterferon alpha 2b plus ribavirin, and to compare it with those patients who receive treatment for 48 weeks |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All previously untreated (naïve), genotype-1 chronic hepatitis C subjects are eligible for enrollment in this protocol.
1. Adult subjects aged 18 to 70 years, of either sex.
2. Genotype-1 HCV-RNA-positive subjects.
3. Subjects must be willing to give written informed consent and able to adhere to dosing and visit schedules.
4. 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.
5. Compensated liver disease with the following minimum hematological, biochemical, and serological criteria at the screen visit (WNL = within normal limits, ULN = Upper Limit Normal):
a) Hemoglobin values of equal or more than 12 gm/dL for females and 13 gm/dL for males.
b) WBC equal to or more than 3,000/mm3
c) Neutrophil count equal to or more than 1,500/mm3
d) Platelet count equal to or more than 80,000/mm3
e) Direct bilirubin up to 10% above ULN is acceptable
f) 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)
g) Albumin up to 10% above ULN is acceptable
h) Serum creatinine up to 10% above ULN is acceptable
i) ALT level above ULN at Screen
6. At the Screen Visit, glucose must be 70-140 mg/dL. Results between 116-140 mg/dL require repeat fasting glucose to be less than140 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).
Fasting specimens are not required, only preferred to reduce repeat lab testing. Results within protocol specifications from non-fasting specimens are acceptable
7. ANA must be less than or equal to 1:320
8. 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)
9. Confirmation by the principal investigator or a sub-investigator that sexually active females of childbearing potential are practicing adequate contraception.
10. 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 :
1) contraceptive pill or IUD or depot hormonal preparation (ring, injection implant) and
2) 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.
11. A serum pregnancy test obtained at Screen Visit prior to the initiation of treatment must be negative.
12. 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.
13. For subjects with a history of hypertension or diabetes, written clearance from an ophthalmologist has to be obtained prior to treatment start.
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| E.4 | Principal exclusion criteria |
1. Pregnant women, women who plan to become pregnant, male subjects whose partner wants to become pregnant, and breastfeeding women.
2. Previous treatment for chronic hepatitis C with an antiviral or immunomodulating agent or with some interferon or ribavirin product, whether alone or in combination.
3. Subjects weighing over 125 kg.
4. Suspected hypersensitivity to any interferon or ribavirin product.
5. Participation in other clinical trial within 30 days prior to screen into this study.
6. Coinfection with HBV, HIV, or both.
7. Any cause of liver disease other than chronic hepatitis C, including but not limited to:
a) Hemochromatosis
b) Alpha-1 antitrypsin deficiency
c) Wilson's disease
d) Autoimmune hepatitis
e) Alcoholic liver disease
f) Non-alcoholic steatohepatitis (NASH)
g) Drug-related liver disease
8. Active malignant disease or suspicion or history of malignant disease within five previous years (except for adequately treated basal cell carcinoma)
9. Known coagulation diseases such as hemophilia; hemoglobin diseases (e.g. thalassemia)
10. Known G6PD deficiency
11. Evidence of advanced liver disease such as history or presence of ascites, bleeding varices, or hepatic encephalopathy.
12. Subjects with organ transplants, except for corneal or hair transplant.
13. Any known preexisting medical condition that could interfere with the subject's participation in and completion of study, such as:
a) Preexisting psychiatric condition, especially moderate to severe depression, or a history of severe psychiatric disorder, such as psychosis, suicidal ideation, or suicide attempts. Severe depression includes the following:
hospitalization for depression
electroconvulsive therapy for depression, or
depression causing a prolonged absence from work or significantly altering daily functions.
Subjects with mild depression may be considered for entry into the study provided that a pre-treatment assessment demonstrates that the subject's emotional status is clinically stable, in which case a management plan must be formulated for the subject; this management plan will become a part of the subject's medical record.
b) Craniocerebral trauma which is not a concussion, or active seizure disorders requiring medication.
c) Clinically significant ECG abnormalities and/or cardiovascular dysfunction within 6 previous months (e.g., angina, congestive heart failure, recent myocardial infarction, or significant arrhythmia).
d) Chronic lung disease (e.g., chronic obstructive lung disease)
e) Poorly controlled diabetes mellitus
f) Immune-mediated disease (e.g., inflammatory bowel disease [Crohn's disease, ulcerative colitis], idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis)
g) Clinical gout
14. Subject is or was a substance abuser, such as alcohol (80 gm/day or more), methadone, IV, oral or inhaled drugs. To be considered for inclusion into the protocol, the subject must have abstained and agree to abstain from using any of the above for at least 6 months. Subjects treated with buprenorphine (Subutex) who have been stable for 6 months may be included
15. Cirrhotic subjects whose ultrasound confirms hepatocellular carcinoma
16. Any other condition that, in the investigator’s opinion, could determine that subject's participation in the study is not indicated or could interfere with the subject’s participation in and completion of the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The proportion of subjects with a sustained viral response at 24 weeks following the end of 48 weeks of treatment vs. 72 weeks of treatment
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Same IMPs- evaluating treatment duration |
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| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 78 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of trial: when last subject has completed 24-week follow up |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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