Hepatitis C-Virus infection genotype 1 Infections and Infestations Hepatitis C
Conditions
Interventions
Study medication:
1. All-trans retinoic acid (Tretinoin): 45 mg/m^2 body surface area in 10 mg capsules (roughly corresponding to 8 capsules/day) administered orally (po) daily in spli
each 2 - 3 tablets bid with meals for 48 weeks (treatment arms A and B1) or for 60 weeks (treatment arm B2)
Sponsors
Johannes Gutenberg-University Mainz (Johannes Gutenberg-Universitat Mainz) (Germany)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Serological evidence of chronic Hepatitis C infection by positive anti-HCV testing and detectable HCV-Ribonucleic Acid (RNA) in serum (greater than 100 IE/ml) 2. 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 greater than two log drop in HCV-RNA at any time point during the previous therapy of at least 12 weeks, or a greater than two log drop at week 12, but HCV-RNA still detectable at week 24. During the previous course pegylated interferon and ribavirin had to be administered in standard dose, that is, for example, at least 1.0 µg/kg/body weight/week pegylated interferon alpha-2b and 800 mg/d ribavirin at the beginning or at least 135 µg/week peginterferon alpha-2a and 800 mg/d ribavirin at the beginning 3. Evidence of HCV genotype 1 by means of reverse hybridisation assay Inno LiPA from Bayer Versant (Innogenetics) within 24 months before randomisation 4. Histological evidence of inflammation and fibrosis (greater than F1) in the liver with or without evidence of compensated cirrhosis within 24 months before randomisation (Child-Pugh grade A) 5. The previous anti-HCV therapy course had to be finished at least 6 months before randomisation into this study 6. Men and women aged 18 to 65 years 7. 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) 8. 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 (accepted methods of contraception are: combined oral contraceptives, implants, injectables, some Intra-Uterine Devices [IUDs], vasectomised partner) (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 ("Minipill") and oral contraceptives with a content of less than 20 µg ethinylestradiol as a method of contraception are not sufficient when all-trans retinoic acid is used 9. 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 (accepted methods of contraception are: combined oral contraceptives, implants, injectables, some IUDs, vasectomised partner) (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 ("Minipill") and oral contraceptives with a content of less than 20 µg Ethinylestradiol as a method of contraception are not sufficient when all-trans retinoic acid is used 10. Written informed consent concerning the participation in the study 11. An ophtalmological examination is recommended for all patients before randomisation
Exclusion criteria
Exclusion criteria: 1. Known hypersensitivity to the active substance of pegylated interferon alpha-2a, to alpha-interferons or ribavirin or one of the other ingredients 2. Known allergy to a substance of the class of retinoids or one of the other ingredients (e.g. allergy to soy beans or peanuts) 3. Persons under age or persons of age, that are not able to realise nature, meaning and significance of the clinical study and to adjust their will in that sense (according to section [§] 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG [Arzneimittelgesetz] - the German law which regulates clinical trials) 4. Pregnancy or breastfeeding 5. Fertile women, not using highly effective methods of contraception 6. Male partners of pregnant women 7. Participation in another clinical study at the same time or within the last three months 8. Patients already included once into this study 9. Persons, that are eventually in dependence on the sponsor or investigator 10. Infection with HCV-Genotypes-2, -3, -4, -5 or -6 11. Evidence of Hepatitis B surface Antigen (HBsAg), Human Immunodeficiency Virus (HIV)-antibodies during screening 12. Patients under immunosuppression 13. Treatment with systemic anti-neoplastic or immune modulatory medication (including supraphysiological doses of steroids or radiation) within the last 6 months before randomisation and throughout the whole study duration 14. Chronic hepatitis unrelated to Hepatitis-C-virus (e.g. haemochromatosis, autoimmunehepatitis, metabolic- or alcohol-related liver disease) 15. Decompensated cirrhosis or liver disease graded Child-Pugh grade B or C 16. Signs of a Hepatocellular Carcinoma (HCC) before randomisation in case of a state of cirrhosis or transition to cirrhosis (alpha-fetoprotein values greater than 100 ng/ml lead to exclusion of the patient from the study, with values of alpha-fetoproteins of greater than 50 ng/ml and less than 100 ng/ml an HCC should be excluded by means of an established method) 17. Oesophagael varices with bleeding in the medical history 18. Haemoglobin less than 12 g/dl for women and less than 13 g/dl for men during screening 19. Patients with an elevated risk for anaemia (e.g. thalassemia, spherocytosis, etc.) or patients, for whom anaemia would be a medical risk in particular 20. Neutropenia less than 1,500/µl or thrombocytopenia less than 70,000/µl during screening 21. Creatinine in serum greater than 1.5 mg/dl during screening 22. Acute or known psychic illnesses or disturbances that negatively influence the ability of the patient to understand the requirements of this study 23. 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) 24. 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 te
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To compare the parameter Md (corresponding to an increase in the elimination rate of infected hepatocytes during treatment) of HCV viral kinetics for therapy with the combination of pegylated interferon alpha-2a, ribavirin and all-trans retinoic acid versus the combination of pegylated interferon alpha-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 less than 12 IU/ ml) Md will be determined for each individual patient. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Analysis of frequence and function of CD4+ and CD8+ T-cells, of dendritic cells, of NK-cells as well as of CD4+/CD25+ regulatory T-cells and additionally of interferon-induced plasma chemokines (CXCL9, CXCL10, CXCL11, CXCR3) for comparison of treatment groups A and B at BL, weeks 1, 2, 4, 8 and 12 2. Comparison of parameter e (corresponding to the antiviral efficiency) of HCV viral kinetics between treatment groups A and B on the basis of kinetic equations fitted for each individual patient 3. Comparison of early virological response rates (EVR, defined as at least a 2 log drop of HCV-RNA at treatment-week 12) between the combination of standard dose Peginterferon alfa-2a and Ribavirin (treatment group B), versus the same therapy combined with All-trans Retinoic acid (treatment group A) 4. Comparison of Sustained Virological Response rates (SVR) (defined as non-detectable HCV-RNA 24 weeks after the end of therapy), End Of Treatment virological response rates (EOT) (defined as non-detectable HCV-RNA at the end of therapy with at least 40 weeks of therapy) and week-24 virological response rates measured by Roche COBAS Ampliprep™/COBAS TaqMan™ Test (lower limit of detection less than 12 IU/ ml) between the combination of pegylated interferon alpha-2a, ribavirin and all-trans retinoic acid (treatment group A) and the combination of pegylated interferon alpha-2a and ribavirin (treatment group B1) (for this evaluation patients with a decrease in HCV-RNA of less than two log at week 12 will be classified as non-responders. This refers to all patients in group B2 and some patients in group A) 5. Comparison of the different virological response rates and the immunological responses between treatment groups A (combination with All-trans Retinoic acid from week 0 to week 12) and B2 (combination with All-trans Retinoic acid from week 12 to week 24) 6. Evaluation of safety and tolerability of com | — |
Countries
Germany
Outcome results
None listed