Study of Nitazoxanide, Peginterferon Alfa-2a and Ribavirin for the Treatment of Hepatitis C

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if nitazoxanide in combination with peginterferon alfa-2a and ribavirin is safe and effective in treating chronic hepatitis C in patients that have previously failed to respond to treatment with peginterferon and ribavirin.

Official Title
-----------------
Phase II, Randomized, Double-blind, Placebo-controlled Study of Nitazoxanide in Combination With Peginterferon Alfa-2a and Ribavirin in Patients With Hepatitis C Who Have Failed to Respond to a Prior Course of Peginterferon and Ribavirin

Conditions
-----------------
Chronic Hepatitis C

Intervention / Treatment
-----------------
* Drug: Nitazoxanide
* Drug: Placebo
* Biological: Peginterferon alfa-2a
* Drug: Ribavirin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Chronic hepatitis C genotype 1. Failed to respond to ≥12 weeks of peginterferon and ribavirin (<2 log10 drop in Hepatitis C Virus Ribonucleic Acid (HCV RNA) at week 12 or detectable Hepatitis C Virus Ribonucleic Acid (HCV RNA) at week 24). Exclusion Criteria: Females of child-bearing age who are either pregnant, breast-feeding or not using birth control and are sexually active. 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-Hepatitis A Virus Immunoglobulin M Antibody (anti-HAV IgM Ab), Hepatitis B's antigen (HBsAg), Anti-Hepatitis B core antigen Immunoglobulin M Antibody (anti-HBc IgM Ab) or Anti-Human Immunodeficiency Virus Antibody (anti-HIV Ab). Decompensated cirrhosis, history of variceal bleeding, ascites, hepatic encephalopathy, Child-Turcotte-Pugh (CTP) score >6 or Model for End-stage Liver Disease (MELD) score >8. Alcohol consumption of >40 grams per day or an alcohol use pattern that will interfere with the study. 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 Upper Limit of Normal (ULN). Hypothyroidism or hyperthyroidism not effectively treated with medication. Hemoglobin A1C (HgbA1c) >7.5 or history of diabetes mellitus. Body Mass Index (BMI) >28. 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). Ulcerative or hemorrhagic/ischemic colitis. Pancreatitis. 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. Requires concomitant theophylline or methadone. History of immunologically mediated disease requiring more than intermittent anti-inflammatory medications for management or that requires frequent or prolonged use of corticosteroids. History or other evidence of severe retinopathy or clinically relevant ophthalmological disorder due to diabetes mellitus or hypertension. Hemoglobinopathies. 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Oral 500 mg nitazoxanide twice daily for 4 weeks followed by oral 500 mg nitazoxanide twice daily plus weekly injections of peginterferon alfa-2a plus oral ribavirin (1000 mg if <75 kg body weight or 1200 mg if ≥75 kg body weight) in daily divided doses for 48 weeks. | Drug: Nitazoxanide<br>* One oral 500 mg nitazoxanide tablet twice daily for 52 weeks.<br>* Other names: Alinia;Biological: Peginterferon alfa-2a<br>* Weekly injections of 180µg peginterferon alfa-2a for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin<br>* 1000 mg (if <75 kg body weight) or 1200 mg (if ≥75 kg body weight) ribavirin in divided daily doses for 48 weeks.<br>* Other names: COPEGUS;|
| Placebo Comparator: 2<br>Oral placebo twice daily for 4 weeks followed by oral placebo twice daily plus weekly injections of peginterferon alfa-2a plus oral ribavirin (1000 mg if <75 kg body weight or 1200 mg if ≥75 kg body weight) in daily divided doses for 48 weeks. | Drug: Placebo<br>* One oral placebo tablet twice daily for 52 weeks.<br>Biological: Peginterferon alfa-2a<br>* Weekly injections of 180µg peginterferon alfa-2a for 48 weeks.<br>* Other names: PEGASYS;Drug: Ribavirin<br>* 1000 mg (if <75 kg body weight) or 1200 mg (if ≥75 kg body weight) ribavirin in divided daily doses for 48 weeks.<br>* Other names: COPEGUS;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response (HCV RNA Below Lower Limit of Detection) | Hepatitis C Virus Ribonucleic Acid (HCV RNA) below lower limit of detection 24 weeks after the end of treatment. All others were considered non-responders. | 24 weeks after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| End of Treatment Response (HCV RNA Below Lower Limit of Detection) | Hepatitis C Virus Ribonucleic Acid (HCV RNA) below lower limit of detection at the end of treatment. All others were considered non-responders. | At end of treatment | 
| Early Virologic Response (HCV RNA Below Lower Limit of Detection) | Hepatitis C Virus Ribonucleic Acid (HCV RNA) below lower limit of detection after 12 weeks of combination therapy. | After 12 weeks combination treatment | 
| Rapid Virologic Response (HCV RNA Below Lower Limit of Detection) | Hepatitis C Virus Ribonucleic Acid (HCV RNA) below lower limit of detection after 4 weeks of combination therapy. | After 4 weeks combination treatment | 
| Changes in ALT | This analysis was conducted using a comparison of changes in Alanine aminotransferase (ALT) from baseline through week 8, week 16, end of treatment and end of follow up. | From baseline to week 8 | 
| Changes in ALT | This analysis was conducted using a comparison of changes in Alanine aminotransferase (ALT) from baseline through week 8, week 16, end of treatment and end of follow up. | From baseline to week 16 | 
| Changes in ALT | This analysis was conducted using a comparison of changes in Alanine aminotransferase (ALT) from baseline through week 8, week 16, end of treatment and end of follow up. | From baseline to end of treatment | 
| Changes in ALT | This analysis was conducted using a comparison of changes in Alanine aminotransferase (ALT) from baseline through week 8, week 16, end of treatment and end of follow up. | From baseline to end of follow up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatitis C, Chronic