Chronic Hepatitis C
Conditions
Keywords
Hepatitis C - Genotype 4, SVR (Sustained Virological Response), Vitamin D, Treatment Naïve
Brief summary
The purpose of this study is to show the superiority of a 4 weeks lead-in phase of Vitamin D followed by a 48 weeks combination of Vitamin D with PEG-IFN plus RBV in comparison with standard PEG-IFN + RBV in untreated Egyptian patients with chronic hepatitis C, on the sustained virological response (SVR) at 3 months after end of treatment (week 60).
Detailed description
\- Method: Phase III, randomized, open-label superiority clinical trial, among Egyptian patients with chronic hepatitis C. \- Treatment strategy: Vitamin D Arm: Vitamin D over a 4 weeks lead-in phase followed by Vitamin D in combination with PEG-INF plus RBV during 48 weeks. Standard of Care Arm: PEG-INF plus RBV during 48 weeks. \- Main outcome: Proportion of patients with Sustained Virological Response (SVR) as defined by HCV RNA below the detection limit based on quantitative PCR 12 weeks after stopping treatment. * Sample Size: 520 patients (260 per arm) * Enrollment period: 12 months * Patient's participation duration: 62 weeks (SOC Arm), 66 weeks (Vit-D Arm) * Statistical analysis: The superiority of the vitamin D arm will be tested against the standard PEG IFN + RBV combination. 260 patients in each arm will give 80% power to document a 12% difference in the SVR rates between the experimental (Vitamin D) and the control (standard treatment) arms.. A futility analysis is planned for this study, in order to be able to interrupt the trial prematurely in case preliminary results show a lack of efficacy of vitamin D. This analysis will be performed on half of the patients, thus 260 patients (130 patients per arm), on a week 12/14 week criterion (HCV RNA viral load at W12/W14).
Interventions
DRUGVitamin D + Pegylated Interferon Alpha 2b + Ribavirin
Vitamin D ARM: 28000UI/week during 4 weeks (lead in phase) then 28000 UI/week associated with PegIFN/RBV during 48 weeks
Sponsors
Institut Pasteur
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Common with National Program for Viral Hepatitis * Age: 18 years to 60 years * Positive HCV antibodies using a third generation test * Detectable HCV RNA by PCR * Liver biopsy showing chronic hepatitis with either a METAVIR score F1 with elevated liver enzymes or scores F2/F3 * Naïve to treatment with PEG-IFN and RBV * HBs antigen negative * Prothrombin time ≥60 %, normal bilirubin, alpha-foeto protein \< 3\*normal range of the laboratory, anti-nuclear antibodies\<1/160 Effective contraception during the treatment period; no breast-feeding Specific to the trial * Prior approval from the Ministry of Health to be treated as part of the National Program with allocation to Peg-IFN α2b treatment * Living \<100 km from Cairo and able to come to the centre every week for the treatment * Signed informed consent and willingness to participate in the trial * Naïve to treatment with vitamin D (received vitamin D less than 30 consecutive days in the 3 months preceding inclusion) * Biopsy slide validated by NHTMRI pathologist
Exclusion criteria
Common with National program for Viral Hepatitis * Serious co-morbid conditions such as severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes (HbA1C\>8%) , chronic obstructive pulmonary disease * Major uncontrolled depressive illness * Solid transplant organ (renal, heart, or lung) * Untreated thyroid disease * History of previous anti-HCV therapy * Body mass index (BMI) greater than 30 kg/m² * Known human immunodeficiency virus (HIV) coinfection: although HIV testing will not be proposed or done, patients with known HIV coinfection will not be included in the trial * Anti-HCV therapy contraindications: * hypersensitivity to one of the two drugs (PEG-IFN, RBV) * pregnancy or unwilling to comply with adequate contraception * breast-feeding * neutropenia (\<1500/mm3) * anaemia (\<11g/dL for women ; \<12g/dL for men) * thrombocytopenia (\<100,000/mm3) * elevated creatinin (\>1.5mg/dL) * concomitant liver disease other than hepatitis C (immuno-active chronic hepatitis B, autoimmune hepatitis, alcoholic liver disease, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson disease) * liver biopsy showing severe steatosis (\>66%) and steatohepatitis; decompensated cirrhosis (Child Pugh\>A); hepatocellular carcinoma, METAVIR score F4. * TSH\>5 mU/L Specific to the trial * Patients allocated to Peg-IFN alpha 2a treatment * Hypersensitivity to vitamin D * Vitamin D contraindications: * hypercalcaemia (fasting calcaemia \>105 mg/L or 2.62 mmol/L) * ratio calciuria / creatininuria (fasting ratio \>1 mmol Ca/mmol creatinin) * hyperphosphatemia (\>1.5 mmol/L) * calcium lithiasis * patients being treated with thiazide diuretics (risk of hypercalcaemia with vitamin D treatment) * patients being treated with glucocorticoïds (decrease in vitamin D efficacy) * postmenopausal women treated by vitamin D and calcium for osteoporosis * Treatment by vitamin D more than 30 consecutive days in the 3 months preceding inclusion in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with Sustained Virological Response (SVR). | 60 Weeks after peg-IFN/RBV initiation | Proportion of patients with Sustained Virological Response (SVR) as defined by HCV RNA below the detection limit based on quantitative PCR 12 weeks after stopping treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early Virological Response (EVR) | 12 Weeks after peg-IFN/RBV initiation | HCV RNA at 12 weeks post initiation of combination therapy |
| End of Treatment Response (ETR) | 48 Weeks after peg-IFN/RBV initiation | HCV RNA at end of treatment (week 48) |
| Rapid Virological Response (RVR) | 4 Weeks after peg-IFN/RBV initiation | HCV RNA at 4 weeks post initiation of combination therapy (PEG IFN + RBV) |
| Incidence of serious adverse events (SAE) grade 3 and 4 (ANRS scale) | From Lead-in phase (Week -4) to End of Follow-up (Week 60) | incidence of SAE leading to dosage reduction or treatment cessation, percentage of patients treated by EPO and G-CSF |
| Evolution of FibroScan values between pre-inclusion and week 60 | At Screening Visit 2 (S2) and at End of Follow-up (Week 60) | — |
| Normalization of ALT during treatment and 12 weeks after the end of treatment | From 2 Weeks after peg-IFN/RBV initiation to End of Follow-up (Week 60) | — |
Countries
Egypt
Outcome results
None listed