efficacy and safety of the combination vitamin d with standard of care in egyptian patients with untreated chronic hepatitis c

Conditions: Chronic Hepatitis C

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).

- 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).

Eligibility criteria:
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.

Keywords: hepatitis c - genotype 4 svr (sustained virological response) vitamin d treatment naïve