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

Study Overview
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Brief Summary
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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
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- 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).

Official Title
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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

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: Vitamin D + Pegylated Interferon Alpha 2b + Ribavirin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D<br>Vitamin D + Pegylated Interferon Alpha 2b + Ribavirin | Drug: Vitamin D + Pegylated Interferon Alpha 2b + Ribavirin<br>* Vitamin D ARM: 28000UI/week during 4 weeks (lead in phase) then 28000 UI/week associated with PegIFN/RBV during 48 weeks<br>* Other names: Rebetol;|
| No Intervention: Standard of Care<br>Pegylated Interferon Alpha 2b + Ribavirin | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with Sustained Virological Response (SVR). | 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. | 60 Weeks after peg-IFN/RBV initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rapid Virological Response (RVR) | HCV RNA at 4 weeks post initiation of combination therapy (PEG IFN + RBV) | 4 Weeks after peg-IFN/RBV initiation | 
| Early Virological Response (EVR) | HCV RNA at 12 weeks post initiation of combination therapy | 12 Weeks after peg-IFN/RBV initiation | 
| End of Treatment Response (ETR) | HCV RNA at end of treatment (week 48) | 48 Weeks after peg-IFN/RBV initiation | 
| 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) | 
| Incidence of serious adverse events (SAE) grade 3 and 4 (ANRS scale) | incidence of SAE leading to dosage reduction or treatment cessation, percentage of patients treated by EPO and G-CSF | From Lead-in phase (Week -4) to End of Follow-up (Week 60) | 
| Evolution of FibroScan values between pre-inclusion and week 60 |  | At Screening Visit 2 (S2) and at End of Follow-up (Week 60) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SVR (Sustained Virological Response), Treatment Naïve, Hepatitis C - Genotype 4, Vitamin D