| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| treatment of patients with Chronic Hepatitis C who are Non-responders to a course with approved doses of PEGinterferon alpha + Ribavirin |
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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 |
Efficacy Objectives
The primary efficacy endpoint is:
• proportion of patients who are HCV RNA negative at the end of observation period
(Week 72 – sustained virological response)
Safety Objectives
This study will evaluate safety data, including vital signs, ECG, haematological measures and measures of liver and kidney function as well as the frequency of adverse events, during the treatment period, and for 24 weeks following the last administration of the study drugs.
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| E.2.2 | Secondary objectives of the trial |
Efficacy Objectives
The secondary efficacy endpoints are:
• the proportion of patients with normal ALT at the end of observation period
(Week 72 – sustained biochemical response)
• the proportion of patients with normal ALT at the end of treatment period
(Week 48 – end of treatment biochemical response)
• the proportion of patients who are HCV RNA negative at the end of treatment period
(Week 48 – end of treatment virological response)
• improvement in Histological Activity Index (Knodell Score) by at least 2 points from pre-treatment biopsy, evaluated as described in Section 7.2.3 and 7.2.4 (Histological Response) of Protocol ST1472-DM-03-004 (Final Version 1.0)
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent.
2. Age > 18 or less than/equal to 70.
3. Presence of HCV RNA measured by quantitative PCR.
4. Non responder to previous approved doses of therapy with PEGinterferon alpha plus ribavirin. Patients must have been treated for at least 12 weeks with documented HCV RNA quantitative not showing greater than/equal to 2 log ^10 HCV RNA reduction or patients treated for at least 24 weeks with documented HCV RNA qualitative not showing a virological response (i.e. viral RNA clearance).
5. Liver biopsy consistent with a diagnosis of chronic hepatitis C or histological cirrhosis. Biopsy will not be required if: The NON-CIRRHOTIC patient can produce a biopsy performed within the year preceding the randomization day and was performed at least 6 months after the end of the latter course of therapy; THE CIRRHOTIC PATIENT CAN PRODUCE A BIOPSY PERFORMED WITHIN THIRTY MONTHS PRECEDING THE RANDOMIZATION DAY.
6. Wash-out period of at least 6 months from previous therapy with PEGinterferon alpha plus ribavirin.
7. Compensated liver disease (if cirrhotic, Child-Pugh A only) with prothrombin time prolonged less than 0.3 INR (INR normal range between 0,9 and 1,25) over control, serum albumin stable and within normal limits, total bilirubin less than/equal to 2 mg/dl, and no history of hepatic encephalopathy, bleeding oesophageal varices or ascites.
8. An ultrasound of the liver within 3 months of entry negative for HCC.
9. Haematocrit greater than/equal to 30%, platelet count greater than/equal to 75 x 10^3/mm^3, WBC greater than/equal to 2.5 x 10^3/mm^3, total neutrophil granulocytes count greater than/equal to 1.5 x 10^3/mm^3, and haemoglobin greater than/equal to 12 g/dl for women and greater than/equal to 13 g/dl for men.
10. Adequate renal function as demonstrated by serum creatinine level within the normal range.
11. Normal TSH or evidence of proper thyroid hormone replacement.
12. All women of childbearing potential, either participating in the study as a patient or partners of male patients participating in the study, must agree to practice abstinence from sexual intercourses or to use two reliable forms of effective contraception (combined) during the treatment period and follow-up. These may include, but are not limited to, birth control pills, IUDs, condoms, diaphragms, implants, surgical sterilization. Because ribavirin may be transmitted in semen, it is recommended that one method of contraception be a barrier type.
13. Negative pregnancy test prior (no more than 24 hours) to first study medication dose.
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| E.4 | Principal exclusion criteria |
1. Use of systemic corticosteroids within 6 months of entry.
2. Use of any drug known to be hepatotoxic, any drug (other than the study drugs) known to have or suspected of having therapeutic activity in hepatitis C, or of any immunosupressive drug (including corticosteroids).
3. α-fetoprotein > 200 ng/mL.
4. Any other liver disease including hepatitis B, hepatitis delta, alcoholic liver disease, drug-induced liver injury, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, haemochromatosis, alpha 1-antitrypsin deficiency, or Wilson’s disease. (Except for hepatitis B and haemochromatosis, clinical judgment should be adequate to rule out the co-existence of other liver diseases and laboratory testing should ordinarily not be required.)
5. Decompensated liver disease based on a history of hepatic encephalopathy, bleeding oesophageal varices, or ascites.
6. Decompensate or advanced liver cirrhosis (Child-Pugh B or C).
7. Stage of oesophageal varices grade F2 or more (evaluated by endoscopy exam).
8. HIV infection diagnosed by HIV seropositivity and confirmed by Western blot.
9. Concomitant or prior history of malignancy other than surgically cured in situ carcinoma of the cervix.
10. Active infectious process other than HCV that is not of a self-limiting nature. TB and AIDS are examples of infectious processes that are not of a self-limiting nature.
11. Serum ANA >1:320; rheumatoid arthritis or other clinical indications of autoimmune disease.
12. Insulin-dependent Diabetes Mellitus.
13. Clinical evidence of retinopathy.
14. Severe haemoglobinopathy.
15. Positive liver and kidney microsomal auto antibodies.
16. Positive anti-thyroid antibodies.
17. Lactation; Pregnancy as documented by a urine pregnancy test. The patient and female partners of male patients must agree to practice an adequate method of birth control (as well described in the inclusion criteria) for the duration of the study, including the follow-up period.
18. Alcohol or intravenous drug abuse within the previous 1 year.
19. Patients who are in poor medical or psychiatric conditions, or who have any non-malignant systemic disease that, in the opinion of the Investigator, would make it unlikely that the patient could complete the study protocol.
20. Any indication that the patient would not comply with the conditions of the study protocol.
21. Previous treatment with thymosin alpha 1.
22. Patients with known hypersensitivity to any PEGinterferon and/or ribavirin.
23. Patients with a history of severe depression that required either hospitalization or electroshock therapy; or depression associated with suicide attempt.
24. Simultaneous participation in another investigational drug study or participation in any clinical trial involving investigational drugs within 3 months before study entry.
25. Presence of serious pulmonary or cardiovascular disorders. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Objectives
The primary efficacy endpoint is:
• proportion of patients who are HCV RNA negative at the end of observation period
(Week 72 – sustained virological response)
Safety Objectives
This study will evaluate safety data, including vital signs, ECG, haematological measures and measures of liver and kidney function as well as the frequency of adverse events, during the treatment period, and for 24 weeks following the last administration of the study drugs.
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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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
| |
| 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 | 1 |
| 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 | 1 |
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