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

Primary Purpose

Hepatitis C, Chronic

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Pegylated Interferon (PEG-IFN) alfa-2a
Placebo
Ribavirin
Sponsored by
Hoffmann-La Roche
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C, Chronic

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Experimental

Arm Label

Pegylated Interferon (PEG-IFN) alfa-2a

Placebo

Ribavirin

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).
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.
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.
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.
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.
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.
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.
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.
Area Under the Concentration-Time Curve (AUC) of Glutamate-Pyruvate Transaminase (GPT)
Maximum Concentration (Cmax) of GPT
Cmax was obtained directly from the concentration-time data.
Time to Maximum Concentration (Tmax) of GPT
Tmax was obtained directly from the concentration-time data.

Full Information

First Posted
March 18, 2016
Last Updated
July 20, 2016
Sponsor
Hoffmann-La Roche
Collaborators
Roche Pharma AG
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1. Study Identification

Unique Protocol Identification Number
NCT02716779
Brief Title
Influence of Ribavirin on the Initial Virological Response in Treatment Naïve Patients With Hepatitis C Genotype 1 Infection
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2016
Overall Recruitment Status
Completed
Study Start Date
April 2007 (undefined)
Primary Completion Date
April 2010 (Actual)
Study Completion Date
April 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
Collaborators
Roche Pharma AG

4. Oversight

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C, Chronic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
68 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pegylated Interferon (PEG-IFN) alfa-2a
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Ribavirin
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Pegylated Interferon (PEG-IFN) alfa-2a
Other Intervention Name(s)
Pegasys®
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Ribavirin matching placebo orally (PO) twice daily for 6 weeks.
Intervention Type
Drug
Intervention Name(s)
Ribavirin
Other Intervention Name(s)
Copegus®
Intervention Description
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.
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Up to Day 126
Secondary Outcome Measure Information:
Title
Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire
Description
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).
Time Frame
At screening (Days -56 to -1), at end of monotherapy (Week 6) and at end of combination therapy (Week 18)
Title
Percentage of Participants With Treatment Response
Description
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.
Time Frame
Up to Day 126
Title
Area Under the Concentration-Time Curve (AUC) of Ribavirin
Description
Evaluation of ribavirin arm after Day 0. Evaluation of placebo and PEG-IFN arms after Day 42.
Time Frame
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.
Title
Maximum Concentration (Cmax) of Ribavirin
Description
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.
Time Frame
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.
Title
Time to Maximum Concentration (Tmax) of Ribavirin
Description
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.
Time Frame
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.
Title
Area Under the Concentration-Time Curve (AUC) of PEG-IFN
Description
Evaluation of PEG-IFN arm after Day 0. Evaluation of ribavirin and placebo arms after Day 42.
Time Frame
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
Title
Maximum Concentration (Cmax) of PEG-IFN
Description
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.
Time Frame
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
Title
Time to Maximum Concentration (Tmax) of PEG-IFN
Description
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.
Time Frame
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
Title
Area Under the Concentration-Time Curve (AUC) of Glutamate-Pyruvate Transaminase (GPT)
Time Frame
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.
Title
Maximum Concentration (Cmax) of GPT
Description
Cmax was obtained directly from the concentration-time data.
Time Frame
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.
Title
Time to Maximum Concentration (Tmax) of GPT
Description
Tmax was obtained directly from the concentration-time data.
Time Frame
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephan Zeuzem, Prof. Dr.
Organizational Affiliation
Roche Pharma AG, 79639 Grenazch Wyhlen, Germany
Official's Role
Principal Investigator
Facility Information:
City
Berlin
ZIP/Postal Code
13353
Country
Germany
City
Frankfurt Am Main
ZIP/Postal Code
60590
Country
Germany
City
Frankfurt Am Main
ZIP/Postal Code
60594
Country
Germany
City
Hannover
ZIP/Postal Code
30625
Country
Germany
City
Homburg/ Saar
ZIP/Postal Code
66424
Country
Germany

12. IPD Sharing Statement

Learn more about this trial

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

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