A Study of Peginterferon Alfa-2a (Pegasys) When Administered in Combination With Ribavirin in Patients With Chronic Hepatitis C (CHC)

Study Overview
=================
Brief Summary
-----------------
This study will compare the efficacy and safety of 2 different treatment durations of peginterferon alfa-2a (Pegasys) plus ribavirin in patients with CHC. The anticipated time on study treatment is 1-2 years, and the target sample size is greater than (>) 500 individuals.

Official Title
-----------------
Randomized, Multicenter Study to Find Optimal Treatment Duration in Patients With Chronic Hepatitis C and Subtype 1 or 4 Depending on HCV RNA Level at Week 8 and Week 12

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female patients with chronic hepatitis C and genotype 1 (1a or 1b) or genotype 4 Age between 18 and 70 years Serologic evidence of chronic hepatitis C infection by an anti-HCV antibody test Present with at least one elevated serum alanine-aminotransferase (ALT) level higher than normal in the last 6 months before therapy start including the screening period Positive HCV-RNA level in serum Laboratory parameters (within 35 days prior to study start): -Hepatitis A anti - IgM negativity, HIV-Ab negativity, HBsAg negativity, Hemoglobin values > 12 g/dl in women or > 13 g/dl in men, Leukocyte count (WBC) > 3 000 /mcl, Platelets count > 100 000/mcl, Creatinine not 1.5 times higher than normal, normal TSH, normal uric acid with a maximum tolerance of 15 % in patients without history of gout Liver biopsy findings within 6 months prior to study therapy consistent with the diagnosis of chronic hepatitis C infection with or without compensated cirrhosis. Biopsies older than 1 year are eligible only after direct communication with the principal investigator Negative urine or blood pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of study drug. If there is no laboratory report existing, the physician should make an entry in the medical history that the pregnancy test was negative. All fertile females receiving ribavirin must be using two forms of effective contraception during treatment and during the 6 months after treatment end. All fertile men with female partners must be using two forms of effective contraception during treatment and during the 7 months after treatment end. Written informed consent obtained Exclusion Criteria: Any IFN and / or Pegylated IFN and ribavirin therapy at any previous time Class B or C cirrhosis as coded by Child Pugh classification Women with ongoing pregnancy or breast feeding Therapy with any systemic anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) 6 months prior to the first dose of study drug Any investigational drug 6 weeks prior to the first dose of study drug Drug addiction within 1 year prior to study start (patients participating in an official methadone program are eligible) Diabetes mellitus in patients receiving an insulin therapy Hemophiliac patients (due to the increased risk of requested liver biopsy) History or other evidence of a medical condition associated with chronic liver disease other than HCV (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures) History or other evidence of bleeding from esophageal varices or other conditions consistent with decompensated liver disease History of severe psychiatric disease, especially depression. Severe psychiatric disease is defined as treatment with an antidepressant medication or a major tranquilizer at therapeutic doses for major depression or psychosis, respectively, for at least 3 months at any previous time or any history of the following: a suicidal attempt, hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease. Exception: if there is a current psychiatric report which certifies there is no contraindication to interferon therapy, patient may be included History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis etc.) History or other evidence of chronic pulmonary disease associated with functional limitation History of a severe seizure disorder or current anticonvulsant use History of severe cardiac disease and severe coronary heart disease within the last 6 months (angina pectoris, congestive heart failure, recent myocardial infarction, severe hypertension or significant arrhythmia). If there is clinical suspicion of coronary heart disease cardiologic workup of the patient prior to study entry is recommended. History of thyroid disease poorly controlled on prescribed medications, elevated thyroid stimulating hormone (TSH) concentrations with elevation of antibodies to thyroid peroxidase and any clinical manifestations of thyroid disease History or other evidence of severe illness, malignancy or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study History of major organ transplantation with an existing functional graft Evidence of severe retinopathy (e.g. CMV retinitis, macula degeneration) Inability or unwillingness to provide informed consent or abide by the requirements of the study Additional exclusion criteria concerning ribavirin: Male partners of women who are pregnant Any patient with an increased baseline risk for anemia (e.g. thalassemia, spherocytosis, history of GI bleeding, etc) or for whom anemia would be medically problematic Patients with documented or presumed coronary artery disease or cerebrovascular disease should not be enrolled if, in the judgment of the investigator, an acute decrease in hemoglobin by up to 4 g/dL would not be well-tolerated

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PEG-IFN 24 weeks<br>Participants will receive PEG-IFN (180 microgram [mcg]), subcutaneously (sc), once weekly for 24 weeks and Ribavirin 1000-1200 milligram per day (mg/day) (<75 kilogram (kg); >75 kg) for 24 weeks. | Drug: Peginterferon alfa-2a<br>* PEG-IFN is available as 180 microgram (mcg) per 0.5 mL, prefilled syringe and pen for single dose sc. injection\n<br>* Other names: Pegasys;Drug: Ribavirin<br>* Ribavirin is available as 200 mg tablets<br>|
| Experimental: PEG-IFN 24/72 weeks<br>Participants will receive PEG-IFN (180 mcg), sc, once weekly and Ribavirin 1000-1200 mg/day (<75kg; >75 kg) till week 24; if patient is still HCV RNA positive. Treatment will be stopped if participant is HCV RNA negative at week 24 -treatment with PEG-IFN (180 mcg), sc, once weekly and Ribavirin 1000-1200 mg/day (<75kg; >75 kg) till week 72 | Drug: Peginterferon alfa-2a<br>* PEG-IFN is available as 180 microgram (mcg) per 0.5 mL, prefilled syringe and pen for single dose sc. injection\n<br>* Other names: Pegasys;Drug: Ribavirin<br>* Ribavirin is available as 200 mg tablets<br>|
| Experimental: PEG-IFN 48 weeks<br>Participants will receive PEG-IFN (180 mcg), sc, once weekly for 48 weeks and Ribavirin 1000-1200 mg/day (<75kg; >75 kg) for 48 weeks. | Drug: Peginterferon alfa-2a<br>* PEG-IFN is available as 180 microgram (mcg) per 0.5 mL, prefilled syringe and pen for single dose sc. injection\n<br>* Other names: Pegasys;Drug: Ribavirin<br>* Ribavirin is available as 200 mg tablets<br>|
| Experimental: PEG-IFN 72 weeks<br>Participants will receive PEG-IFN (180 mcg), sc, once weekly for 72 weeks and Ribavirin 1000-1200 mg/day (<75 kg; > 75 kg) for 72 weeks. | Drug: Peginterferon alfa-2a<br>* PEG-IFN is available as 180 microgram (mcg) per 0.5 mL, prefilled syringe and pen for single dose sc. injection\n<br>* Other names: Pegasys;Drug: Ribavirin<br>* Ribavirin is available as 200 mg tablets<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Relapse Rate in Groups A and B by Genotype at the End of Follow-up (Part 1) | Relapse rate (RR) was defined as the percentage of participants with non-detectable HCV RNA (< 100 copies/ml) at the end of treatment and detectable HCV RNA at the end of follow-up. End of treatment was defined as Week 48 for Group A and Week 72 for Group B, respectively. The end of follow-up was defined as Week 72 for Group A and Week 96 for Group B, respectively. Relapse rate for treatment Groups A and B, stratified for genotype (Genotype I and Genotype IV) and Week 4 response (< 600 units/milliliter [U/ml] and >= 600 U/ml) is presented. | Up to Week 96 | 
| Percentage of Participants Achieving Sustained Virological Response in Groups A1, B1, and E by Genotype at the End of Follow-up (Part 2) | The Sustained Virological Response (SVR) was defined as the percentage of participants in each group with non-detectable HCV RNA result at 24 weeks post completion of the treatment period (HCV RNA < 15 IU/ml at Week 72 of Groups A1 and E, and at Week 96 of Group B1). Participants without a HCV RNA results at this time point were considered as non-responders. The end of follow-up was defined as Week 72 for Groups A1 and E, and Week 96 for Group B1. The SVR for treatment Groups A1 + B1 and E, stratified for genotype (Genotype I and Genotype IV) is presented. | Up to Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Virological Response Rate in Groups A, B, C, and D at the End of Treatment Period (Part 1) | End of treatment response (ETR) rate was defined as the percentage of participants in each group with non-detectable HCV RNA at completion of the treatment period (HCV negative at Week 24 of Group D, Week 48 of Group A and at Week 72 of Groups B and C). Participants without a HCV RNA results at this time point were considered as non-responders. End of the treatment period was defined as Week 48 for Group A, Week 72 for Groups B and C, and Week 24 for Group D. | Up to Week 72 | 
| Percentage of Participants Achieving Sustained Virological Response in Groups A, B, C, and D at the End of Follow-up (Part 1) | The SVR was defined as the percentage of participants in each group with a non-detectable HCV RNA result at 24 weeks post-completion of the treatment period (HCV RNA < 15 IU/ml at Week 48 of Group D, at Week 72 of Group A, and at Week 96 of Groups B and C). Participants without a HCV RNA PCR at this time point were considered as non-responders in this calculation. The end of follow-up was defined as Week 72 for Group A, Week 96 for Groups B and C, and Week 48 for Group D. | Up to Week 96 | 
| Mean Short Form-36 Questionnaire Scores for Groups A and B Over Time (Part 1) | The Short Form-36 (SF-36) is a quality of life instrument consisting of a 36-item questionnaire. The SF-36 items were scored and transformed according to the SF-36 Health Survey Manual and Interpretation Guide. Summary scores for SF-36 dimensions (physical functioning, role functioning, bodily pain, general health, vitality, social functioning, mental health, health transition) as well as physical and mental summary measures were compiled after imputation of mean scores for missing items if more than 50% of dimension-related items were available. Scores for health transition ranged from 0 (worst) to 5 (best). Scores for all other dimensions ranged from 0 (worst) to 100 (best). The mean SF-36 scores are presented at Baseline (Day 1), Week 24, Week 48, Week 72 (for Groups A and B) and at Week 96 (for Group B). Lower score indicate worsening. | Baseline (Day 1), Week 24, Week 48, Week 72, and Week 96 | 
| Mean Fatigue Severity Scale Scores for Groups A and B Over Time (Part 1) | The Fatigue Severity Scale (FSS) is an instrument consisting of 10 self-administered questions. The FSS items were scored by calculating the average response to all answered items (including the 9 questions and the fatigue symptoms). Each of the 9 questions had answers within a score range of 1-7. A score of 1 for any question indicates less fatigue in everyday life and a score of 7 indicates a higher likelihood of fatigue in everyday life. The mean FSS scores are presented at Baseline (Day 1), Week 24, Week 48 and Week 72 (for Groups A and B) and at Week 96 (for Group B). | Baseline (Day 1), Week 24, Week 48 and Week 72, and Week 96 | 
| Number of Participants With Fibrosis Grades 0 to 4 at Baseline (Part 1) | Liver fibrosis stage was scored using the METAVIR system (Grade 0 to 4). Grade 0 indicates no fibrosis, Grade 1 indicates stellate enlargement of portal tract but without septa formation, Grade 2 indicates enlargement of portal tract with rare septa formation, Grade 3 indicates numerous septa without cirrhosis and grade 4 indicates cirrhosis. The number of participants with fibrosis grades ranging from 0 to 4 at Baseline is presented. | Baseline (Day 1) | 
| Number of Participants With Adverse Events and Serious Adverse Events (Part 1) | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. | Up to Week 96 | 
| Percentage of Participants With Relapse Rates in Groups A1 and B1 at the End of Follow-up (Part 2) | Virological relapse rate was defined as percentage of participants with non-detectable HCV RNA (< 15 IU/ml) at the EoT and detectable HCV RNA (≥ 15 IU/ml) at the end of FU. The end of treatment was defined as Week 48 in Group A1 and Week 72 in Group B1 and the end of follow-up was defined as Week 72 in Group A1 and Week 96 in Group B1. | Up to Week 96 | 
| Percentage of Participants With Virological Response Rates in Group A1, B1, C and D at the End of the Treatment Period (Part 2) | ETR virological response rate at the end of treatment period was defined as the percentage of participants in each group with non-detectable HCV RNA at completion of the treatment period (HCV RNA quantitative PCR result < 15 IU/ml at Week 24 for Group D, at Week 48 for Group A1, at Week 72 for Groups B1 and C). Participants without a HCV RNA PCR (missing values) at this time point were considered as non-responders in this calculation. The end of treatment period was defined as Week 48 for Group A1, Week 72 for Groups B1 and C1, and Week 24 for Group D. | Up to Week 72 | 
| Percentage of Participants Achieving Sustained Virological Response in Groups C and D by Genotype at the End of Follow-up (Part 2) | The SVR was defined as the percentage of participants in each group with non-detectable HCV RNA result at 24 weeks post completion of the treatment period (HCV RNA < 15 IU/ml at Week 48 of Group D and at Week 96 of Group C). Participants without a HCV RNA results at this time point were considered as non-responders. The end of follow-up was defined as Week 96 for Group C and Week 48 for Group D. | Up to Week 96 | 
| Mean Short Form-36 Questionnaire Scores for Groups A1, B1, and C Over Time (Part 2) | The SF-36 is a quality of life instrument consisting of a 36-item questionnaire. The SF-36 items were scored and transformed according to the SF-36 Health Survey Manual & Interpretation Guide. Summary scores for SF-36 dimensions (physical functioning, role functioning, bodily pain, general health, vitality, social functioning, mental health, health transition) as well as physical and mental summary measures were compiled after imputation of mean scores for missing items if more than 50% of dimension-related items were available. Scores for health transition ranged from 0 (worst) to 5 (best). Scores for all other dimensions ranged from 0 (worst) to 100 (best). The mean SF-36 scores were presented at Baseline (Day 1), Week 24, Week 48, Week 72 (for Groups A1, B1 and C) and at Week 96 (for Groups B1 and C). Lower score indicate worsening. | Baseline (Day 1), Week 24, Week 48, Week 72, and Week 96 | 
| Mean Fatigue Severity Scale Scores for Groups A1, B1 and C Over Time (Part 2) | The FSS is an instrument consisting of 10 self-administered questions. The FSS items were scored by calculating the average response to all answered items (including the 9 questions and the fatigue symptoms). Each of the 9 questions had answers within a score range of 1-7. A score of 1 for any question indicates less fatigue in everyday life and a score of 7 indicates a higher likelihood of fatigue in everyday life. The mean FSS scores are presented at Baseline (Day 1), Week 24, Week 48 and Week 72 (for Groups A1, B1 and C) and at Week 96 (for Groups B1 and C). | Baseline (Day 1), Week 24, Week 48 and Week 72, and Week 96 | 
| Number of Participants With Fibrosis Grades 0 to 4 at Baseline (Part 2) | Liver fibrosis stage was based upon biopsy and scored using the METAVIR system (Grade 0 to 4). Grade 0 indicates no fibrosis, Grade 1 indicates stellate enlargement of portal tract but without septa formation, Grade 2 indicates enlargement of portal tract with rare septa formation, Grade 3 indicates numerous septa without cirrhosis and grade 4 indicates cirrhosis. The number of participants with fibrosis grades ranging from 0 to 4 at Baseline (Day 1) is presented. | Baseline (Day 1) | 
| Number of Participants With Adverse Events and Serious Adverse Events (Part 2) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. | Up to Week 96 |