| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019183 |
| E.1.2 | Term | HCV |
|
| 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 compare the parameter of HCV viral kinetics under therapy with the combination of Peginterferon alfa-2a, Ribavirin and All-trans Retinoic acid vs. the combination of Peginterferon alfa-2a and Ribavirin. |
|
| E.2.2 | Secondary objectives of the trial |
Comparison of the virological response rates and the immunological responses between treatment groups
Evaluation of safety and tolerability of combination therapy with Peginterferon alfa-2a, Ribavirin and All-trans Retinoic acid |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Serological evidence of chronic Hepatitis-C infection by positive anti-HCV testing and detectable HCV-RNA in serum (>100 IE/ml)
Non-responder to the previous anti-HCV combination therapy with pegylated Interferon and Ribavirin. Non-response is defined as a lack of at least a > 2 log drop in HCV-RNA at any time point during the previous therapy of at least 12 weeks, or a > 2 log drop at week 12, but HCV-RNA still detectable at week 24. During the previous course Peginterferon and Ribavirin had to be administered in standard dose, that is e.g. at least 1.0 µg/kg/body weight/week Peginterferon alfa-2b and 800 mg/d Ribavirin at the beginning or at least 135 µg/week Peginterferon alfa-2a and 800 mg/d Ribavirin at the beginning.
Evidence of HCV Genotype 1 by means of reverse hybridisation assay Inno LiPA from Bayer Versant (Innogenetics) within 24 months before randomisation
Histological evidence of inflammation and fibrosis (> F1) in the liver with or without evidence of compensated cirrhosis within 24 months before randomisation (Child-Pugh grade A)
The previous anti-HCV therapy course had to be finished at least 6 months before randomisation into this study
Men and women aged 18 to 65 years
Negative urine- or serum-pregnancy test for women with childbearing potential within 24 hours before administration of the first dose of medication (also for fertile female partners of male patients)
For female patients: During administration of the study medication and during 6 months of treatment free follow-up two highly effective methods of contraception have to be used, one of them with a barrier function, that is condom; (Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals, CPMP/ICH/286/95 mod); micro-dosed gestagenes („Minipille“) and oral contraceptives with a content of < 20 µg Ethinylestradiol as a method of contraception are not sufficient when All-trans Retinoic acid is used!
For male patients and their female partners: During administration of the study medication and during 7 months of treatment free follow-up two highly effective methods of contraception have to be used, one of them with a barrier function, that is condom; (Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals, CPMP/ICH/286/95 mod); micro-dosed gestagenes („Minipille“) and oral contraceptives with a content of < 20 µg Ethinylestradiol as a method of contraception are not sufficient when All-trans Retinoic acid is used!
Written informed consent concerning the participation in the study
An ophtalmological examination is recommended for all patients before randomisation
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|
| E.4 | Principal exclusion criteria |
Known hypersensitivity to the active substance of Peginterferon alfa-2a, to alfa-interferons or Ribavirin or one of the other ingredients
Known allergy to a substance of the class of retinoids or one of the other ingredients (e.g. allergy to soy beans or peanuts)
Persons under age or persons of age, that are not able to realize nature, meaning and significance of the clinical study and to adjust their will in that sense (according to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG)
Pregnancy or breastfeeding
Fertile women, not using highly effective methods of contraception
Male partners of pregnant women
Participation in another clinical study at the same time or within the last three months
Patients already included once into this study
Persons, that are eventually in dependence on the sponsor or investigator
Infection with HCV-Genotypes-2, -3, -4, -5 or -6
Evidence of HBsAg, HIV-antibodies during screening
Patients under immunosuppression
Treatment with systemic anti-neoplastic or immune modulatory medication (including supraphysiological oses of steroids or radiation) within the last 6 months before randomisation and throughout the whole study duration
Chronic hepatitis unrelated to Hepatitis-C-virus (e.g. Hemochromatosis, Autoimmunehepatitis, metabolic- or alcohol-related liver disease)
Decompensated cirrhosis or liver disease graded Child-Pugh grade B or C
Signs of a hepatocellular carcinoma before randomisation in case of a state of cirrhosis or transition to cirrhosis (_-Fetoprotein values > 100 ng/ml lead to exclusion of the patient from the study, with values of -Fetoproteins of > 50 ng/ml and < 100 ng/ml an HCC should be excluded by means of an established method)
Esophagael varices with bleeding in the medical history
Hemoglobin <12 g/dl for women and <13 g/dl for men during screening
Patients with an elevated risk for anemia (e.g. Thalassemia, Spherocytosis, etc.) or patients, for whom anemia would be a medical risk in particular
Neutropenia <1.500/ml or thrombocytopenia <70.000/ml during screening
Creatinine in serum >1,5 mg/dl during screening
Acute or known psychic illnesses or disturbances that negatively influence the ability of the patient to understand the requirements of this study
Severe depression in the medical history, defined as any sign on suicidal tendencies, or hospitalisation because of depression, or any exclusively antidepressive therapy of at least 3 months duration (an accompanying antidepressive treatment in the setting of a previous anti-HCV therapy with Interferons is allowed)
Severe psychotic or any other severe psychiatric disease in the medical history, defined as any antipsychotic or otherwise psychiatric treatment of at least 3 months duration in the medical history or any sign on suicidal tendencies or hospitalisation because of these illnesses
Patients with the state of excitation or irritation
Patients with delirant syndromes as well as exogenious psychosis in their medical history
Epilepsia
Autoimmune diseases (e.g. chronic inflammatory bowel disease, idiopathic thrombocytopenic Purpura, Lupus erythematodes, Sklerodermia, severe Psoriasis, rheumatoid Arthritis)
Disturbances in thyroid function, impossible to adjust euthyreod by medication
Insufficiently adjusted Diabetes mellitus (HbA1c > 7%) or insufficiently adjusted hypertriglyceridemia (> 350 mg/dl)
Clinically manifest gout
Chronic pulmonary disease with functional restriction
Severe cardiac disease (e.g. cardiac insufficiency NYHA class III or IV, myocardial infarction within the last 6 months, ventricular Tachy-arrhythmia in need of treatment, instable Angina pectoris, cerebrovascular circulation disturbance or any other significant cardiovascular disease)
Organ transplantation except cornea transplantation
Cancer within the last 5 years (with the exception of a adequately treated basaliom) or any other serious disease, that, in the investigators perspective, represents an exclusion criterion for the study
Information on clinically relevant retina changes (e.g. in the case of CMV-retinitis, makula degeneration or hypertensive or diabetic retinopathy)
Active drug abuse (including excessive alcohol consumption) within the last year before randomisation with the exception of a prescribed substitution medication
The following substances are not allowed in this study because of interacting potential with the study drugs or influence on the patients suitability for this study:
Vitamine A, Tetracycline, Antifibrinolytika such as Tranexam acid, Aminocapron acid, Aprotinin, Daunorubicin, Cytarabin
Unwillingness or inability to give written consent after being informed
Any other clinical condition, that, in the investigator perspective, questions enrollment of that patient.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
To compare the parameter M delta (corresponding to an increase in the elimination rate of infected hepatocytes during treatment) of HCV viral kinetics for therapy with the combination of Peginterferon alfa-2a, Ribavirin and All-trans Retinoic acid vs. the combination of Peginterferon alfa-2a and Ribavirin.
Based on viral load measurements at BL, days 1, 2, 3, weeks 1, 2, 3, 4, 6, 8 and 12 (treatment groups A and B) by means of the Roche COBAS Ampliprep /COBAS TaqMan Test (lower limit of detection <12 IU/ ml) M delta will be determined for each individual patient.
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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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
|
| Date of last visit (end of follow up) 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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