Influence of Ribavirin on the Initial Virological Response in Treatment Naïve Patients With Hepatitis C Genotype 1 Infection

Study Overview
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Brief Summary
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This study examined the influence of ribavirin on the initial virological response in treatment-naïve participants with chronic hepatitis C, genotype 1. Participants were randomized to 1 of 3 treatment groups to receive placebo, ribavirin monotherapy 1000 milligrams (mg) to 1200 mg orally daily depending on body weight or pegylated interferon (PEG-IFN) alfa-2a (Pegasys®) 180 micrograms (mcg) subcutaneously (SC) weekly, for 6 weeks. Following the initial 6 weeks, all participants received combination therapy with PEG-IFN alfa-2a plus ribavirin (Copegus®) for 12 weeks. If there was an initial virological response after 12 weeks of combination therapy, treatment could be continued for a further 36 weeks outside of the study.

Official Title
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Randomized, Multicentric, Partially Double-Blinded Placebo-Controlled Phase II Study for Examining the Influence of Ribavirin on the Initial Virological Response With Treatment of Peginterferon Alfa-2a (40KD) and Ribavirin With a Six Week Pretreatment-Phase of Ribavirin/Placebo or PEG-Interferon Monotherapy in Treatment Naïve Patients With Chronic Hepatitis C Virus Genotype 1 Infection

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Pegylated Interferon (PEG-IFN) alfa-2a
* Drug: Placebo
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasians, male or female aged between 18 and 70 years Indication: serological proof of a chronic hepatitis C infection with positive result of anti-Hepatitis C virus (HCV) test and detectable HCV- Ribo Nucleic Acid (RNA) in serum Proven HCV genotype 1 by means of the reverse hybridization assays Proven histological infection activity within the liver with or without proven compensated cirrhosis within the last 24 months prior to start of the study (Child-Pugh degree A) Participants without previous anti-HCV therapy Exclusion Criteria: Known hypersensitivity to interferon or ribavirin or any of the other component parts Pregnant or nursing women, women with child bearing potential and without using a high effective method of contraception. The urine and serum pregnancy test at visit 0 in fertile participants or cohabitants of participants must show a negative result Male partners of pregnant women Infection with HCV genotype 2, 3, 4, 5, or 6 Pretreatment with interferon and/or ribavirin Immunocompromised participants Treatment of systemic anti-neoplastic or immunomodulatoric medication (including supraphysiological doses of steroids or radiation therapy) within the last 6 months prior to the start of treatment and during the complete time interval of study treatment Chronic hepatitis due to hepatitis C virus (e.g. haemochromatosis, autoimmunohepatitis, metabolic or alcohol-related liver disease) Decompensated liver cirrhosis or liver disease Child-Pugh degree B or C or condition after decompensation Signs of a hepatocellular carcinoma within 2 months prior to randomization in case of a cirrhosis or a transition to cirrhosis Ascites or esophagus varices with bleedings as documented in anamnesis Any medical condition that questions in the opinion of the investigator the participant's enrollment and participation in the trial Hemoglobin <13 grams/deciliter (g/dl) in females and <14 g/dl in males in screening phase Patients with an increased anemia risk (e.g. thalassemia, spherocytosis, etc.) or patients which would be at a particular medical risk in case of an anemia Diagnosed neutropenia <1.500/microliter (mcl) or thrombocytopenia <90.000/mcl in screening phase

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pegylated Interferon (PEG-IFN) alfa-2a<br>Participants with chronic hepatitis C, genotype 1, received pegylated interferon (PEG-IFN) alfa-2a monotherapy for 6 weeks. Thereafter, all participants received combination therapy with PEG-IFN alfa-2a plus ribavirin for 12 weeks. | Drug: Pegylated Interferon (PEG-IFN) alfa-2a<br>* Pegylated interferon (PEG-IFN) alfa-2a (40 kilodalton [KD]) 180 microgram (mcg) subcutaneously (SC) weekly, for 6 weeks during monotherapy and/or 12 weeks during combination therapy.<br>* Other names: Pegasys®;Drug: Ribavirin<br>* Ribavirin, 1000 mg orally (PO) (400 mg in the morning [=2 tablets] and 600 mg in the evening [=3 tablets]) in participants with a body weight less than 75 kilogram (kg) or 1200 mg PO (600 mg at each time =3 tablets, in the morning and evening, respectively) in participants with a body weight greater than or equal to 75 kg, PO daily for 6 weeks during monotherapy and/or 12 weeks during combination therapy.<br>* Other names: Copegus®;|
| Placebo Comparator: Placebo<br>Participants with chronic hepatitis C, genotype 1, received ribavirin matching placebo for 6 weeks. Thereafter, all participants received combination therapy with PEG-IFN alfa-2a plus ribavirin for 12 weeks. | Drug: Pegylated Interferon (PEG-IFN) alfa-2a<br>* Pegylated interferon (PEG-IFN) alfa-2a (40 kilodalton [KD]) 180 microgram (mcg) subcutaneously (SC) weekly, for 6 weeks during monotherapy and/or 12 weeks during combination therapy.<br>* Other names: Pegasys®;Drug: Placebo<br>* Ribavirin matching placebo orally (PO) twice daily for 6 weeks.<br>Drug: Ribavirin<br>* Ribavirin, 1000 mg orally (PO) (400 mg in the morning [=2 tablets] and 600 mg in the evening [=3 tablets]) in participants with a body weight less than 75 kilogram (kg) or 1200 mg PO (600 mg at each time =3 tablets, in the morning and evening, respectively) in participants with a body weight greater than or equal to 75 kg, PO daily for 6 weeks during monotherapy and/or 12 weeks during combination therapy.<br>* Other names: Copegus®;|
| Experimental: Ribavirin<br>Participants with chronic hepatitis C, genotype 1, received ribavirin monotherapy for 6 weeks. Thereafter, all participants received combination therapy with PEG-IFN alfa-2a plus ribavirin for 12 weeks. | Drug: Pegylated Interferon (PEG-IFN) alfa-2a<br>* Pegylated interferon (PEG-IFN) alfa-2a (40 kilodalton [KD]) 180 microgram (mcg) subcutaneously (SC) weekly, for 6 weeks during monotherapy and/or 12 weeks during combination therapy.<br>* Other names: Pegasys®;Drug: Ribavirin<br>* Ribavirin, 1000 mg orally (PO) (400 mg in the morning [=2 tablets] and 600 mg in the evening [=3 tablets]) in participants with a body weight less than 75 kilogram (kg) or 1200 mg PO (600 mg at each time =3 tablets, in the morning and evening, respectively) in participants with a body weight greater than or equal to 75 kg, PO daily for 6 weeks during monotherapy and/or 12 weeks during combination therapy.<br>* Other names: Copegus®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Log Likelihood Median Values of Hepatitis C-Virus (HCV) Kinetic Models for Quantitative HCV Ribonucleic Acid (RNA) Measurement With Various Assumptions of Ribavirin Mechanism of Action | To investigate possible action mechanisms, three different models were fitted to viruskinetic data and evaluated using related log-likelihood function values. These models were designed assuming individual effects with respect to infectiousness (model 1), virus production (model 2) or degradation of infected cells rate (model 3). The following viruskinetic parameters were fitted in each model: initial viral load, loss rate of infected cells (delta), effectivity of interferon with respect to a pharmacokinetic-pharmacodynamic model. A lower log likelihood function value indicates a lesser fit for the model. | Up to Day 126 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire | SF-36 is a psychometric scale to quantify health conditions. This psychometric scale has 8 dimensions of the subjective health status and consists of 36 individual items that have a varying number of related item scores (ranging from yes/no up to a 6-point scale). At first the raw scores were determined by summation over all items and weighted accordingly. Afterwards the raw scores were transformed to ranges of 0-100 with 100 being the highest level of health and compared to published reference scales. The following eight dimensions of subjective health conditions were considered: physical functioning index, role physical index, pain, general health perception, vitality, social functioning index, role emotional index and mental health index. The SF36 questionnaire had to be answered by the patients at screening before monotherapy, after monotherapy and at the end of the study (=end of combination therapy). | At screening (Days -56 to -1), at end of monotherapy (Week 6) and at end of combination therapy (Week 18) | 
| Percentage of Participants With Treatment Response | HCV-RNA level was measured at each visit by a central laboratory. Treatment response was estimated applying the following definitions of response/non-response: 1) Adequate first phase decline: HCV RNA decline ≥ 0.5 log10 International Units/milliliter (IU/mL) from time 0 to 48 hours of PEG-IFN treatment (PEG-IFN arm: day 0 - day 2; placebo and ribavirin arm: day 42-day 44), 2) Rapid virologic response: HCV RNA < 15 IU/mL (=detection limit) on day 70, 3) Complete early virologic response: HCV RNA < 15 IU/mL on day 126, 4) Partial early virologic response (log decrease): HCV RNA decrease ≥ 2 log10 IU/mL from day 0 to day 126, 5) Partial early virologic response (cut off): HCV RNA <30000 IU/mL on day 126, 6) Non-response: HCV RNA decrease <2 log10 IU/mL from day 0 to day 126, 7) Null-response: HCV RNA decrease <1 log10 IU/mL from day 0 to day 28 and from day 0 to day 70 for PEG-IFN arm and placebo / ribavirin arm, respectively. | Up to Day 126 | 
| Area Under the Concentration-Time Curve (AUC) of Ribavirin | Evaluation of ribavirin arm after Day 0. Evaluation of placebo and PEG-IFN arms after Day 42. | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | 
| Maximum Concentration (Cmax) of Ribavirin | Cmax was obtained directly from the concentration-time data. Evaluation of ribavirin arm after day 0. Evaluation of placebo and PEG-IFN arms after day 42. | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | 
| Time to Maximum Concentration (Tmax) of Ribavirin | Tmax was obtained directly from the concentration-time data. Evaluation of ribavirin arm after day 0. Evaluation of placebo and PEG-IFN arms after day 42. | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | 
| Area Under the Concentration-Time Curve (AUC) of PEG-IFN | Evaluation of PEG-IFN arm after Day 0. Evaluation of ribavirin and placebo arms after Day 42. | From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126 | 
| Maximum Concentration (Cmax) of PEG-IFN | Cmax was obtained directly from the concentration-time data. Evaluation of PEG-IFN arm after day 0. Evaluation of ribavirin and placebo arms after day 42. | From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126 | 
| Time to Maximum Concentration (Tmax) of PEG-IFN | Tmax was obtained directly from the concentration-time data. Evaluation of PEG-IFN arm after day 0. Evaluation of ribavirin and placebo arms after day 42. | From Day 0 at 0 hour (hr), 24 hr, 48 hr and 72 hr, Day 42 at 0 hr and 24 hr and at approximately every other visit up to Day 126 | 
| Area Under the Concentration-Time Curve (AUC) of Glutamate-Pyruvate Transaminase (GPT) |  | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | 
| Maximum Concentration (Cmax) of GPT | Cmax was obtained directly from the concentration-time data. | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. | 
| Time to Maximum Concentration (Tmax) of GPT | Tmax was obtained directly from the concentration-time data. | From Day 0 at 0 hour (hr), 12 hr, 24 hr, 36 hr, 48 hr, 60 hr and 72 hr, Day 42 at 0 hr, 12 hr, 24 hr and 36 hr and at each visit up to Day 126. |