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

Sponsor

ANRS, Emerging Infectious Diseases (Other)

Overall Status

Withdrawn

CT.gov ID

NCT02099604

Collaborator

Institut Pasteur (Industry)

Enrollment

Location

Arms

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis C	Drug: Vitamin D + Pegylated Interferon Alpha 2b + Ribavirin	Phase 3

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Apr 1, 2014

Actual Primary Completion Date :

Apr 1, 2014

Actual Study Completion Date :

Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vitamin D Vitamin D + Pegylated Interferon Alpha 2b + Ribavirin	Drug: Vitamin 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 Other Names: Vidrop PegIntron Rebetol
No Intervention: Standard of Care Pegylated Interferon Alpha 2b + Ribavirin

Arm

Intervention/Treatment

Experimental: Vitamin D

Vitamin D + Pegylated Interferon Alpha 2b + Ribavirin

Drug: Vitamin 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

Other Names:

Vidrop

PegIntron

Rebetol

No Intervention: Standard of Care

Pegylated Interferon Alpha 2b + Ribavirin

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

Rapid Virological Response (RVR) [4 Weeks after peg-IFN/RBV initiation]
HCV RNA at 4 weeks post initiation of combination therapy (PEG IFN + RBV)
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)
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) [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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.