Efficacy and Safety of the Combination Vitamin D With Standard of Care in Egyptian Patients With Untreated Chronic Hepatitis C
Efficacy and Safety of the Combination Vitamin D With Standard of Care in Egyptian Patients With Untreated Chronic Hepatitis C
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).
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.