Chronic Hepatitis c
Conditions
Brief summary
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.
Interventions
DRUGPegylated interferon alfa-2a
Pegylated interferon 160ug once weekly 48 weeks
DRUGNitazoxanide
Nitazoxanide 500mg twice daily 4 weeks lead-in followed by triple therapy 48 weeks
DRUGRibavirin
Ribavirin (\> 75kg:1200 mg, \<75kg:1000mg daily)48 weeks
Sponsors
Egyptian Railway Hospital
Cairo University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virologic Response | 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). | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rapid Virological Response | 28 - 33 days after start of Pegylated interferon and ribavirin | A rapid virologic response is defined as a negative HCV PCR 4 weeks after treatment |
| Early Virological Response | 90 ± 7 days from the start of pegylated interferon and ribavirin | 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 |
| End-of-treatment Response | 48 weeks +- 7 days after starting pegylated interferon and ribavirin | An end-of-treatment response is defined as a negative HCV PCR at 48 weeks after the start of pegylated interferon and ribavirin |
| Safety of Nitazoxanide (Number of Participants Experiencing Adverse Events) | throughout the period of treatment and up to 90 days after end of triple therapy | The occurence of adverse events that could be linked temporally and reasonably to the administration of the tested drug. |
Countries
Egypt
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care 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. | 50 |
| Triple Therapy 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. | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
Baseline characteristics
| Characteristic | Triple Therapy | Standard of Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants | 50 Participants | 100 Participants |
| Age Continuous | 45.42 years STANDARD_DEVIATION 8.36 | 45.46 years STANDARD_DEVIATION 6.88 | 45.44 years STANDARD_DEVIATION 7.61 |
| Region of Enrollment Egypt | 50 participants | 50 participants | 100 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 49 Participants | 48 Participants | 97 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 50 / 50 | 47 / 50 |
| serious Total, serious adverse events | 0 / 50 | 0 / 50 |
Outcome results
Primary
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)
Time frame: 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).
Population: All was intention-to-treat (ITT) analysis. Any patient who received at least one dose of interferon was included in the analyses.The only 2 dropouts (lost to follow-up) were calculated as failures.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Standard of Care | Sustained Virologic Response | 24 participants | 0.5 |
| Triple Therapy | Sustained Virologic Response | 25 participants | 0.5 |
Secondary
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
Time frame: 90 ± 7 days from the start of pegylated interferon and ribavirin
Population: ITT. Any patient who received at least one dose of interferon was included in the analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard of Care | Early Virological Response | Complete early virologic response | 35 participants |
| Standard of Care | Early Virological Response | Partial early virologic response | 5 participants |
| Standard of Care | Early Virological Response | No early virologic response response | 10 participants |
| Triple Therapy | Early Virological Response | Complete early virologic response | 36 participants |
| Triple Therapy | Early Virological Response | Partial early virologic response | 0 participants |
| Triple Therapy | Early Virological Response | No early virologic response response | 14 participants |
Secondary
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
Time frame: 48 weeks +- 7 days after starting pegylated interferon and ribavirin
Population: ITT. Any patient who received at least one dose of interferon was included in the analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care | End-of-treatment Response | 31 participants |
| Triple Therapy | End-of-treatment Response | 29 participants |
Secondary
Rapid Virological Response
A rapid virologic response is defined as a negative HCV PCR 4 weeks after treatment
Time frame: 28 - 33 days after start of Pegylated interferon and ribavirin
Population: Only 1 patient in standard of care arm and 3 patients in the triple therapy arm missed doing the PCR test at week 4. These patients were thus not included in this particular analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care | Rapid Virological Response | 30 participants |
| Triple Therapy | Rapid Virological Response | 25 participants |
Secondary
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.
Time frame: throughout the period of treatment and up to 90 days after end of triple therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care | Safety of Nitazoxanide (Number of Participants Experiencing Adverse Events) | 50 participants |
| Triple Therapy | Safety of Nitazoxanide (Number of Participants Experiencing Adverse Events) | 47 participants |