A Study of PEGASYS (Peginterferon Alfa-2a (40KD)) in Combination With Ribavirin in Patients With Chronic Hepatitis C (CHC) Previously Treated With PEG-Intron + Ribavirin

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety and tolerability of PEGASYS plus ribavirin in patients with CHC who could not tolerate or were not responsive to 12 weeks of therapy with PEG-Intron plus ribavirin. The anticipated time on study treatment is 1-2 years, and the target sample size is >100 individuals.

Official Title
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An Open-label, Multicenter, Efficacy and Safety Study of Pegasys® Plus Ribavirin in Patients With Chronic HCV Infection Who Are Unable to Tolerate or Who Do Not Respond to 12 Weeks of Therapy With PEGIntron ® Plus Ribavirin

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Ribavirin
* Drug: peginterferon alfa-2a [Pegasys]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients at least 18 years of age CHC infection, genotype 1 unable to tolerate or not responsive to PEG-Intron + ribavirin therapy after 12 weeks of treatment use of 2 forms of contraception during the study in both men and women Exclusion Criteria: women who are pregnant or breast-feeding medical condition associated with chronic liver disease (eg, hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposures) patients with decompensated cirrhosis patients receiving any systemic antiviral therapy or investigational drug, other than PEG-Intron + ribavirin, 24 weeks prior to the first dose of study drug

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-Responders<br>Participants will receive Pegasys 180 micro grams (µg or mcg) subcutaneously (SC) once a week and ribavirin 1000 or 1200 milligrams per day [(mg/day), < or >=75 kilogram (Kg) body weight, respectively], orally in divided doses for 60 weeks. | Drug: Ribavirin<br>* 1000/1200mg po bid for 36 or 60 weeks<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 micrograms weekly for 36 weeks (non-responders) or 60 weeks (non-tolerators)<br>|
| Experimental: Non-Tolerators<br>Participants will receive Pegasys 180 µg subcutaneously (SC) once a week and ribavirin 1000 or 1200 mg/day (< or >=75 kg body weight, respectively) orally in divided doses for 36 weeks. | Drug: Ribavirin<br>* 1000/1200mg po bid for 36 or 60 weeks<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 micrograms weekly for 36 weeks (non-responders) or 60 weeks (non-tolerators)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Pegasys and Ribavirin Therapy Completers | Therapy completers were defined as all participants who had demonstrable viremia after 12 weeks of Pegasys plus ribavirin therapy (who were to be discontinued for lack of efficacy), non-tolerators who completed 36 weeks of Pegasys plus ribavirin therapy, and non-responders who completed 60 weeks of Pegasys plus ribavirin therapy. Study completers included all participants who completed the planned treatment period (36 weeks for non-tolerators and 60 weeks for non-responders) and the 24-week treatment-free follow-up period and participants in either group who were prematurely discontinued per protocol due to insufficient therapeutic response at Week 12. | 36 weeks for Non-Tolerators and 60 weeks for Non-Responders | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With >=2-log10 Decrease or Undetectable (<60 International Units Per Milliliter) Hepatitis C Virus-ribonucleic Acid Over Time | Sustained virological response (SVR) is defined as undetectable Hepatitis C virus-ribonucleic acid (HCV RNA)(<60 International units per milliliter) or HCV RNA for >=2-log10 decrease in viral titre, 24 weeks after the end of treatment. A participant was classified as non-responder (SVR not achieved) if HCV RNA was detectable at the completion of antiviral treatment, at Week 24 post or at any time between Week 24 and completion of antiviral treatment. HCV RNA measured prior to or on the date of the first dose of Pegasys plus ribavirin was used as the baseline in all HCV RNA analyses. | Weeks 4, 12, 24, 36, 48, 60, and 84 | 
| Number of Participants With Normal Serum Alanine Transaminase Levels Over Time | The number of participants with serum alanine transaminase (ALT) concentration within the normal range at each time point assessed. Upper limit of normal serum ALT for men is 43 International units per liter (IU/L) and for women is 34 IU/L. | Baseline (Week 0), Weeks 4, 12, 24, 36, 48, 60, and 84 | 
| Number of Participants With Serious Adverse Events and Adverse Events | An adverse event (AE) was any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An adverse event could 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. Pre-existing conditions that worsened during the study were also to be reported as adverse events. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is medically significant or requires intervention to prevent one or other of the outcomes listed above. | Up to Week 84 | 
| Mean Score of Beck Depression Inventory Over Time | The Beck Depression Inventory (BDI-II) is a questionnaire with groups of statements in which the patient is asked to select the statement that most clearly describes the way he/she has felt in the past two weeks, including today. The score for each group is tallied and the ranges of scores are used as guidelines for measuring the degree of depression. For this study, scores are defined as follows: 0 to 15 as minimal, 16 to 21 as mild, 22 to 30 as moderate, and 31 to 63 as severe. The questionnaire was in two areas (changes in sleeping pattern and changes in appetite), selections 1, 2, and 3 contained options for both more and less with respect to the area of interest. Four statements (labelled 0, 1, 2, and 3) were offered that described the area of interest, with 0 indicating no effect and 3 indicating the worst effect. The individual area scores were summed to provide a total score. | Baseline (Week 0); Weeks 4, 12, 24, 36, 48, 60, and 84 | 
| Mean Score of Fatigue Severity Over Time | The Fatigue severity score (FSS) scale has a series of questions designed to assess tiredness, lack of energy, or total body give-out. Participants were to react to nine statements regarding fatigue over the previous 2 weeks, each on a scale (1 = completely agree, 7 = completely disagree). The FSS is the average of the scores on the 9 questions; ranging from 1-7, with lower scores indicating less fatigue. In addition, participants were to react to how much fatigue they had in the past 2 or 4 weeks by marking on a visual analogue scale labelled at one end with no fatigue ('0' being the best) and at the other end with greater fatigue ('100' being the worst). Longer distance on the scale from no fatigue indicated greater fatigue. FSS values are presented based on questionnaire and visual analog scale. | Baseline (Week 0); Weeks 4, 12, 24, 36, 48, 60, and 84 | 
| Number of Participants With Individual Flu-like Symptom | Participants were asked to complete a flu-like symptom questionnaire at screening, study baseline, and at all subsequent scheduled visits. The yes/no questionnaire evaluated the incidence of headache, fever, myalgia, and chills. If a participant answered yes to the question Has the patient experienced any flu-like symptoms since the last visit? all among headache, fever, muscle aches (myalgia), and chills that applied were to be marked. If any of the experienced symptoms was newly reported or had worsened, a corresponding adverse event was to be reported. | Baseline (Week 0); Weeks 12, 36, 60 and 84 | 
| Number of Participants With Marked Laboratory Abnormalities | Analysis was performed for hematology, clinical chemistry, thyroid function, and urinalysis. Normal ranges of the parameters were: Haematocrit (fraction): 0.37 - 0.49, Haemoglobin (g/L): 130 - 180 , Platelets (G/L): 150 - 350, White blood cell (G/L): 4.5 - 11.0, Lymphocytes (G/L): 1.00 - 4.80, Neutrophils (G/L): 1.80 - 7.70, Prothrombin Time in Seconds (sec): not defined, Prothrombin Time, normalized (ratio): 0.70 - 1.30, Partial thromboplastin Time (sec): 22.1 - 34.1, Aspartate transaminase (AST) or serum glutamate oxaloacetate transaminase (SGOT) in IU/L: 0 - 40, Alkaline Phosphatase (IU/L): 0 - 115, ALT or serum glutamate pyruvate transaminase (SGPT) in (IU/L): 0-55, Total Bilirubin (umol/L): 0 -17, Thyroxine (T4) (nmol/L): 58 -140, Thyroid-stimulating hormone (TSH, [U/mL]): 0.0 - 5.0, Triglycerides (mmol/L): 0.45 - 1.69, Phosphate (mmol/L): 0.84 - 1.45, Uric Acid (umol/L): 214 - 506 | Up to Week 84 | 
| Number of Participants With Abnormal Vital Signs | Abnormal vital signs were defined as Systolic blood pressure (BP) below 85 mm Hg or above 180 mm Hg with a change from baseline of > 20% Diastolic BP above 110 mm Hg with a change from baseline of > 20% where systolic and diastolic BP were pressure exerted by blood on the walls of blood vessels during left ventricular systole and diastole respectively. Pulse rate below 50 beats per minute and above 120 beats per minute, with a change from baseline of > 20%, where pulse represents the palpation of heartbeat | From screening (Day -21 to Day -1) to Week 84 | 
| Mean Score for Overall Local Injection Site Reaction | Local injection-site reactions were to be given an overall assessment based on pain or discomfort as Grade 0 for no pain or discomfort, Grade 1 for mild tenderness at the injection site, Grade 2 for moderate pain without limitation of usual activities, Grade 3 for severe pain requiring prescription non-topical analgesics or limiting usual activities, Grade 4 for a reaction that resulted in a new hospitalization, prolongation of hospitalization, death, or a persistent or significant disability/incapacity, or was life threatening or medically significant. Adverse events related to the injection site (injection site erythema, hematoma, pain, rash, or reaction) were reported. All of these events were reported as resolved without sequelae. | Baseline (Week 0), Week 4, 12, 24, 36, 48 and 60 |