Chronic Hepatitis C
Conditions
Keywords
Hepatitis C, Chronic
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.
Interventions
BIOLOGICALPeginterferon alfa-2a
Weekly injections of 180µg peginterferon alfa-2a for 48 weeks.
DRUGRibavirin
1000 mg (if \<75 kg body weight) or 1200 mg (if ≥75 kg body weight) ribavirin in divided daily doses for 48 weeks.
DRUGNitazoxanide
One oral 500 mg nitazoxanide tablet twice daily for 52 weeks.
DRUGPlacebo
One oral placebo tablet twice daily for 52 weeks.
Sponsors
Romark Laboratories L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virologic Response (HCV RNA Below Lower Limit of Detection) | 24 weeks after end of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| End of Treatment Response (HCV RNA Below Lower Limit of Detection) | At end of treatment | Hepatitis C Virus Ribonucleic Acid (HCV RNA) below lower limit of detection at the end of treatment. All others were considered non-responders. |
| Early Virologic Response (HCV RNA Below Lower Limit of Detection) | After 12 weeks combination treatment | Hepatitis C Virus Ribonucleic Acid (HCV RNA) below lower limit of detection after 12 weeks of combination therapy. |
| Rapid Virologic Response (HCV RNA Below Lower Limit of Detection) | After 4 weeks combination treatment | Hepatitis C Virus Ribonucleic Acid (HCV RNA) below lower limit of detection after 4 weeks of combination therapy. |
| Changes in ALT | From baseline to week 8 | 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. |
Countries
United States
Participant flow
Recruitment details
This study recruited patients from 10 study sites in the United States, including a Veterans Administrations hospital.
Participants by arm
| Arm | Count |
|---|---|
| NTZ+PR 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.
Ribavirin : 1000 mg (if \<75 kg body weight) or 1200 mg (if ≥75 kg body weight) ribavirin in divided daily doses for 48 weeks.
Nitazoxanide : One oral 500 mg nitazoxanide tablet twice daily for 52 weeks.
Peginterferon alfa-2a : Weekly injections of 180µg peginterferon alfa-2a for 48 weeks. | 42 |
| Placebo+PR 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.
Ribavirin : 1000 mg (if \<75 kg body weight) or 1200 mg (if ≥75 kg body weight) ribavirin in divided daily doses for 48 weeks.
Peginterferon alfa-2a : Weekly injections of 180µg peginterferon alfa-2a for 48 weeks.
Placebo : One oral placebo tablet twice daily for 52 weeks. | 22 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 34 | 18 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | NTZ+PR | Placebo+PR | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 21 Participants | 60 Participants |
| Age, Continuous | 54 years STANDARD_DEVIATION 8 | 53 years STANDARD_DEVIATION 6 | 53.5 years STANDARD_DEVIATION 6.9 |
| Region of Enrollment United States | 42 participants | 22 participants | 64 participants |
| Sex: Female, Male Female | 13 Participants | 8 Participants | 21 Participants |
| Sex: Female, Male Male | 29 Participants | 14 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 42 / 42 | 20 / 22 |
| serious Total, serious adverse events | 1 / 42 | 1 / 22 |
Outcome results
Primary
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.
Time frame: 24 weeks after end of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NTZ+PR | Sustained Virologic Response (HCV RNA Below Lower Limit of Detection) | Responders | 3 participants |
| NTZ+PR | Sustained Virologic Response (HCV RNA Below Lower Limit of Detection) | Non-responders | 39 participants |
| Placebo+PR | Sustained Virologic Response (HCV RNA Below Lower Limit of Detection) | Responders | 0 participants |
| Placebo+PR | Sustained Virologic Response (HCV RNA Below Lower Limit of Detection) | Non-responders | 22 participants |
Secondary
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.
Time frame: From baseline to end of follow up
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NTZ+PR | Changes in ALT | Remains Elevated | 0 participants |
| NTZ+PR | Changes in ALT | Elevated to Normal | 1 participants |
| NTZ+PR | Changes in ALT | Remains Normal | 4 participants |
| NTZ+PR | Changes in ALT | Normal to Elevated | 1 participants |
| Placebo+PR | Changes in ALT | Normal to Elevated | 0 participants |
| Placebo+PR | Changes in ALT | Remains Elevated | 0 participants |
| Placebo+PR | Changes in ALT | Remains Normal | 1 participants |
| Placebo+PR | Changes in ALT | Elevated to Normal | 0 participants |
Secondary
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.
Time frame: From baseline to week 8
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NTZ+PR | Changes in ALT | Remains Elevated | 14 participants |
| NTZ+PR | Changes in ALT | Elevated to Normal | 7 participants |
| NTZ+PR | Changes in ALT | Remains Normal | 9 participants |
| NTZ+PR | Changes in ALT | Normal to Elevated | 1 participants |
| Placebo+PR | Changes in ALT | Normal to Elevated | 1 participants |
| Placebo+PR | Changes in ALT | Remains Elevated | 8 participants |
| Placebo+PR | Changes in ALT | Remains Normal | 9 participants |
| Placebo+PR | Changes in ALT | Elevated to Normal | 2 participants |
Secondary
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.
Time frame: From baseline to week 16
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NTZ+PR | Changes in ALT | Remains Normal | 12 participants |
| NTZ+PR | Changes in ALT | Remains Elevated | 6 participants |
| NTZ+PR | Changes in ALT | Normal to Elevated | 0 participants |
| NTZ+PR | Changes in ALT | Elevated to Normal | 6 participants |
| Placebo+PR | Changes in ALT | Normal to Elevated | 1 participants |
| Placebo+PR | Changes in ALT | Elevated to Normal | 2 participants |
| Placebo+PR | Changes in ALT | Remains Normal | 6 participants |
| Placebo+PR | Changes in ALT | Remains Elevated | 2 participants |
Secondary
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.
Time frame: From baseline to end of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NTZ+PR | Changes in ALT | Remains Elevated | 0 participants |
| NTZ+PR | Changes in ALT | Elevated to Normal | 1 participants |
| NTZ+PR | Changes in ALT | Remains Normal | 5 participants |
| NTZ+PR | Changes in ALT | Normal to Elevated | 0 participants |
| Placebo+PR | Changes in ALT | Normal to Elevated | 0 participants |
| Placebo+PR | Changes in ALT | Remains Elevated | 0 participants |
| Placebo+PR | Changes in ALT | Remains Normal | 1 participants |
| Placebo+PR | Changes in ALT | Elevated to Normal | 0 participants |
Secondary
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.
Time frame: After 12 weeks combination treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NTZ+PR | Early Virologic Response (HCV RNA Below Lower Limit of Detection) | Responders | 3 participants |
| NTZ+PR | Early Virologic Response (HCV RNA Below Lower Limit of Detection) | Non-responders | 39 participants |
| Placebo+PR | Early Virologic Response (HCV RNA Below Lower Limit of Detection) | Responders | 0 participants |
| Placebo+PR | Early Virologic Response (HCV RNA Below Lower Limit of Detection) | Non-responders | 22 participants |
Secondary
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.
Time frame: At end of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NTZ+PR | End of Treatment Response (HCV RNA Below Lower Limit of Detection) | Responders | 6 participants |
| NTZ+PR | End of Treatment Response (HCV RNA Below Lower Limit of Detection) | Non-responders | 36 participants |
| Placebo+PR | End of Treatment Response (HCV RNA Below Lower Limit of Detection) | Responders | 1 participants |
| Placebo+PR | End of Treatment Response (HCV RNA Below Lower Limit of Detection) | Non-responders | 21 participants |
Secondary
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.
Time frame: After 4 weeks combination treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NTZ+PR | Rapid Virologic Response (HCV RNA Below Lower Limit of Detection) | Responders | 2 participants |
| NTZ+PR | Rapid Virologic Response (HCV RNA Below Lower Limit of Detection) | Non-responders | 40 participants |
| Placebo+PR | Rapid Virologic Response (HCV RNA Below Lower Limit of Detection) | Responders | 0 participants |
| Placebo+PR | Rapid Virologic Response (HCV RNA Below Lower Limit of Detection) | Non-responders | 22 participants |