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 (Vit D), With Pegylated Interferon Alpha-2b (PEG-IFN)/Ribavirin (RBV) in Egyptian Patients With Untreated Chronic Hepatitis C: A Phase III Randomized Open-label Clinical Trial

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.