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Completed

NCT Number: NCT02716779

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

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.

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Key information

Conditions

Hepatitis C, Chronic Blood-Borne Infections Chronic Disease Communicable Diseases Digestive System Diseases Disease Attributes Flaviviridae Infections Hepatitis Hepatitis C Hepatitis, Chronic Hepatitis, Viral, Human Infections Liver Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms RNA Virus Infections Virus Diseases

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Berlin, Germany

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

pegylated interferon (Peg-IFN) alfa-2a

Drug

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.

Other names: Pegasys®

Placebo

Drug

Ribavirin matching placebo orally (PO) twice daily for 6 weeks.

Ribavirin

Drug

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.

Other names: Copegus®

Primary outcomes

  1. 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

    Time frame: Up to Day 126

    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 outcomes

  1. Score in Quality of Life Assessed Using Short Form-36 (SF-36) Health Questionnaire

    Time frame: At screening (Days -56 to -1), at end of monotherapy (Week 6) and at end of combination therapy (Week 18)

    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).

  2. Percentage of Participants With Treatment Response

    Time frame: Up to Day 126

    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.

  3. Area Under the Concentration-Time Curve (AUC) of Ribavirin

    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.

    Evaluation of ribavirin arm after Day 0. Evaluation of placebo and PEG-IFN arms after Day 42.

  4. Maximum Concentration (Cmax) of Ribavirin

    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.

    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.

  5. Time to Maximum Concentration (Tmax) of Ribavirin

    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.

    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.

  6. Area Under the Concentration-Time Curve (AUC) of PEG-IFN

    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

    Evaluation of PEG-IFN arm after Day 0. Evaluation of ribavirin and placebo arms after Day 42.

  7. Maximum Concentration (Cmax) of PEG-IFN

    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

    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.

  8. Time to Maximum Concentration (Tmax) of PEG-IFN

    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

    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.

  9. 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.

  10. Maximum Concentration (Cmax) of 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.

    Cmax was obtained directly from the concentration-time data.

  11. Time to Maximum Concentration (Tmax) of 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.

    Tmax was obtained directly from the concentration-time data.

Sponsors and collaborators

Lead sponsor

Hoffmann-La Roche

Industry

Collaborators

  • Roche Pharma AG

Registry information

Official study 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

Important dates

Study start
2007
Primary completion
2010
Study completion
2010
First posted
Mar 23, 2016
Registry last updated
Aug 22, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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