Efficacy of Nitazoxanide in the Treatment of Chronic Hepatitis C Virus (HCV)

Study Overview
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Brief Summary
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Chronic hepatitis C has become an endemic disease in Egypt with a rising prevalence (genotype 4), worldwide it also poses a significant health burden. To date standard of care treatment (pegylated interferon and ribavirin) give modest results with a sustained virological response (SVR) of about 50%. Several pharmaceutical and herbal agents have been used with an aim to improve current results. Recent reports have suggested an increased SVR with the addition of Nitazoxanide to standard of care. The results are preliminary and need to be confirmed. This is a randomized trial to assess the efficacy of nitazoxanide added to standard of care compared to standard of care alone.

Official Title
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Randomized Study for the Assessment of Nitazoxanide in the Treatment of Chronic Hepatitis C Genotype 4

Conditions
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Chronic Hepatitis c

Intervention / Treatment
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* Drug: Pegylated interferon alfa-2a
* Drug: Nitazoxanide
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (male or female), 18 to 65 years of age, with chronic HCV infection BMI < 35 Liver biopsy showing chronic hepatitis with significant fibrosis using Ishak scoring system Compensated liver disease; serum bilirubin < 1.5 mg/dl, INR (international normalized ratio) no more than 1.5, serum albumin > 3.4, platelet count > 75,000 mm, and no evidence of hepatic decompensation (hepatic encephalopathy or ascites) Acceptable hematological and biochemical indices (hemoglobin 13g/dl for men and 12 g/dl for women; neutrophil count 1500/mm3 or more and serum creatinine < 1.5 mg/dl Patients must be serum hepatitis B surface antigen (HBsAg) negative Negative Antinuclear Antibodies (ANA) or titer of < 1:160 Serum positive for anti-HCV antibodies and HCV-RNA Abdominal Ultrasound obtained within 3 months prior to entry in the study Electrocardiogram for men aged > 40 years and for women aged > 50 years Normal fundus examination Ensure strict measures to avoid conception for both male and female participants by using a proper contraception measure all throughout the course of treatment and six months later Female patients must not breast feed during therapy Exclusion Criteria: Patients who previously received interferon HgbA1c > 7.5 (glycoslylated haemoglobin)or history of diabetes mellitus BMI > 34 Women who are pregnant or breast-feeding Males whose female partners are either pregnant or of child-bearing potential or not using birth control and are sexually active Other causes of liver disease including autoimmune hepatitis Transplant recipients receiving immune suppression therapy Screening tests positive for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab or anti-HIV Ab Decompensated cirrhosis, history of variceal bleeding, ascites, hepatic encephalopathy, CTP score > 6 (Child-Turcot-Pugh) or MELD score > 8 Absolute neutrophil count < 1500 cells/mm3; platelet count < 135,000 cells/mm3; hemoglobin < 12 g/dL for women and < 13 g/dL for men; or serum creatinine concentration ≥ 1.5 times ULN (upper limit of normal) Hypothyroidism or hyperthyroidism not effectively treated with medication Alcohol consumption of > 40 grams per day or an alcohol use pattern that will interfere with the study History or other clinical evidence of significant or unstable cardiac disease History or other clinical evidence of chronic pulmonary disease associated with functional impairment Serious or severe bacterial infection(s) History of severe or uncontrolled psychiatric disease, including severe depression, history of suicidal ideation, suicidal attempts or psychosis requiring medication and/or hospitalization History of uncontrolled severe seizure disorder History of immunologically mediated disease requiring more than intermittent anti-inflammatory medications for management or that requires frequent or prolonged use of corticosteroids Patients with clinically significant retinal abnormalities History of hypersensitivity or intolerance to nitazoxanide or any of the excipients comprising the nitazoxanide tablets, peginterferon alfa-2a injectable solution or ribavirin tablets

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care<br>Group A: comprises 50 treatment-naive chronic hepatitis c patients who will receive the standard of care treatment: peginterferon Alfa 2a 160 ug once weekly and weight-based ribavirin 1000 or 1200 mg/day (based on body weight < 75 kg or ≥ 75 kg, respectively) in divided doses for 48 weeks. | Drug: Pegylated interferon alfa-2a<br>* Pegylated interferon 160ug once weekly 48 weeks<br>* Other names: Reiferon retard;Drug: Ribavirin<br>* Ribavirin (> 75kg:1200 mg, <75kg:1000mg daily)48 weeks<br>|
| Experimental: Triple therapy<br>Group B: comprises 50 treatment-naive chronic HCV patients who will receive oral Nitazoxanide 500 mg twice daily for 4 weeks (lead-in phase) followed by triple therapy, nitazoxanide 500 mg twice daily plus peginterferon alfa-2a (160ug once weekly) and weight-based ribavirin 1000-1200 mg daily (based on body weight < 75 kg or ≥ 75 kg, respectively) in divided doses for 48 weeks. | Drug: Pegylated interferon alfa-2a<br>* Pegylated interferon 160ug once weekly 48 weeks<br>* Other names: Reiferon retard;Drug: Nitazoxanide<br>* Nitazoxanide 500mg twice daily 4 weeks lead-in followed by triple therapy 48 weeks<br>* Other names: Xerovirin-C;Drug: Ribavirin<br>* Ribavirin (> 75kg:1200 mg, <75kg:1000mg daily)48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response | sustained virological response is defined as a negative HCV PCR at 180 days after the end of treatment (End of treatment being at 48 weeks for Group A, 52 weeks for Group B). For any patient who stopped treatment prematurely (e.g. due to adverse events) SVR was defined as a negative HCV PCR (polymerase chain reaction) at 180 days after the last dose of all medications (interferon, ribavirin and nitazoxanide) | 180 days (+- 7 days) after the end of treatment. (48 weeks for Group A, 52 weeks for Group B, or after the last dose of treatment for patients who stopped prematurely). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rapid Virological Response | A rapid virologic response is defined as a negative HCV PCR 4 weeks after treatment | 28 - 33 days after start of Pegylated interferon and ribavirin | 
| Early Virological Response | A complete early virologic response is defined as a negative HCV PCR 90 days after the start of pegylated interferon. A partial early virologic response is defined as a decrease of 2 or more log in HCV PCR at 90 days after the start of pegylated interferon | 90 ± 7 days from the start of pegylated interferon and ribavirin | 
| End-of-treatment Response | An end-of-treatment response is defined as a negative HCV PCR at 48 weeks after the start of pegylated interferon and ribavirin | 48 weeks +- 7 days after starting pegylated interferon and ribavirin | 
| Safety of Nitazoxanide (Number of Participants Experiencing Adverse Events) | The occurence of adverse events that could be linked temporally and reasonably to the administration of the tested drug. | throughout the period of treatment and up to 90 days after end of triple therapy |