Taribavirin Phase 2 Dose Finding Study for the Treatment of Hepatitis C Virus (HCV)

Study Overview
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Brief Summary
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The objective of the study is to select an optimal dose of taribavirin by comparing the efficacy and safety of 3 taribavirin dose levels, 20, 25, and 30 mg/kg/day, versus ribavirin 800 to 1400 mg/day based on body weight, both administered in combination with peginterferon alfa-2b to therapy-naive patients with chronic Hepatitis C Virus (HCV) genotype 1 infection.

Detailed Description
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The objective of the study is to select an optimal dose of taribavirin by comparing the efficacy and safety of 3 taribavirin dose levels, 20, 25, and 30 mg/kg/day, versus ribavirin 800 mg/day to 1400 mg/day based on subject body weight, with both drugs administered in combination with peginterferon alfa-2b to therapy-naive patients with chronic Hepatitis C Virus genotype 1 infection.

Official Title
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Phase 2 Comparison of Weight-based Doses of Taribavirin Combined With Peginterferon Alfa-2b Versus Ribavirin Combined With Peginterferon Alfa-2b in Therapy-naïve Patients With Chronic Hepatitis C Virus Genotype 1 Infection

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: Taribavirin
* Drug: Taribavirin
* Drug: Taribavirin
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Subject Inclusion Criteria To be eligible for enrollment, patients must meet all of the following criteria: At least 18 years of age Diagnosed with compensated chronic HCV genotype 1 infection that has not been treated with interferon, peginterferon, ribavirin or any experimental therapy for >28 days 2a Serum HCV RNA >2000 copies/mL (780 IU/mL) 2b Liver biopsy performed within 3 years prior to screening consistent with chronic HCV infection 2c Criteria for compensated HCV infection, including normal prothrombin time, serum albumin and bilirubin levels (unless due to non-hepatitis factors) and no history or evidence of bleeding esophageal varices, ascites, or hepatic encephalopathy 3 History of alanine aminotransferase (ALT) elevation either within 6 months prior to screening, at screening, or on retest 2 weeks after a negative screening test, or histologic evidence of HCV infection and a detectable viral load 4 Platelet count ≥90,000/mm3 5 Absolute neutrophil count ≥1200/mm3 6 Hemoglobin ≥12.0 g/dL for females or ≥13.0 g/dL for males 7 Antinuclear antibody (ANA) titer ≤1:320 8 Serum creatinine <1.5 mg/dL 9 HbA1c ≤8.5% for diabetic patients 10 Normal or adequately controlled TSH on prescription medication 11 Alpha fetoprotein (AFP) <20 ng/mL or hepatocellular carcinoma ruled out (ultrasound, CT or MRI scan) within 6 months prior to the study (Patients with an AFP >20 ng/mL must have ongoing hepatocellular carcinoma screening during study as part of the patient's routine medical care) 12 All other clinical laboratory values within normal limits, unless judged not clinically significant by the investigator 13 Sterile or infertile (defined as vasectomy, tubal ligation, postmenopausal, or hysterectomy), or willing to use an approved method of double-barrier contraception (hormonal plus barrier or barrier plus barrier, eg, diaphragm plus condom) from the time of first dose administration until 6 months after the last dose 14 Capable of understanding instructions, adhering to study schedules and requirements, and willing to provided informed consent Subject Exclusion Criteria Patients who have any of the following during the screening or Day 1 visit are not eligible for enrollment in this study: Positive HIV or HbsAg serology Severe psychiatric or neuropsychiatric disorders including severe depression, history of suicidal ideations or suicide attempt(s). (This would include patients with a history of suicidal ideations or suicide attempt(s) that occurred when the patient was a minor or many years ago; if the event occurred while under the influence of alcohol or drugs; if the suicidal ideations or suicide attempt(s) were connected to a traumatic event; if the patient was not hospitalized or treated; if the patient has obtained psychiatric clearance for treatment) History or clinical manifestations of significant metabolic, hematological, pulmonary, ischemic or unstable heart disease, gastrointestinal, neurological, renal, urological, endocrine, ophthalmologic (including severe retinopathy), or immune mediated disease History of thalassemia or other hemoglobinopathies (even if the hemoglobin is normal) Chronic hepatic disease other than hepatitis C Organ or bone marrow transplant Chronic (greater than 30 days) use of immunosuppressive medications including steroids in doses equivalent to 10 mg of prednisone or higher, 30 days prior to and anytime during the course of the study Female patients who are breast-feeding or have a positive pregnancy test at any time during the study Males whose female partners are pregnant Patients who have had a malignancy diagnosed and/or treated within the past 5 years, except for localized squamous or basal cell cancers treated by local excision Patients who have participated in a clinical trial and have received an investigational drug within 30 days prior to screening History of alcoholism or drug addiction 1 year prior to screening The use of methadone, buprenorphine or any similar drug, regardless of the prescribed indication or the length of time the patient has been on the drug Chronic (>4 weeks duration) diarrhea, including irritable bowel disease Fibrosis score F4 (cirrhosis) based on Metavir or equivalent index Weight >128 kg or <40 kg Patients infected with mixed HCV genotypes

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Drug<br>Oral taribavirin tablet 20 mg/kg/day (Actual doses were 20-24 mg/kg/day) BID plus weekly subcutaneous injections of peginterferon alfa-2b (1.5 ug/kg/wk) | Drug: Taribavirin<br>* Oral (200 mg) Tablet: 20mg/kg/day BID, patients will be treated for a total of 48 weeks. in addition, all patients will receive peginterferon alfa-2b (PEG-Intron) by weekly subcutaneous injection. Patients who complete treatment with study drug or discontinue treatment prematurely will enter a 24-week follow-up period.<br>* Other names: RNA003142-204;|
| Experimental: Group 2: Drug<br>Oral taribavirin tablet 25 mg/kg/day (Actual doses were 25-29 mg/kg/day) BID plus weekly subcutaneous injections of peginterferon alfa-2b (1.5 ug/kg/wk) | Drug: Taribavirin<br>* Oral (200 mg) Tablet: 25mg/kg/day BID, patients will be treated for a total of 48 weeks. in addition, all patients will receive peginterferon alfa-2b (PEG-Intron) by weekly subcutaneous injection. Patients who complete treatment with study drug or discontinue treatment prematurely will enter a 24-week follow-up period.<br>* Other names: RNA003142-204;|
| Experimental: Group 3: Drug<br>Oral taribavirin 30 mg/kg/day (Actual doses were 30-34 mg/kg/day) BID plus weekly subcutaneous injections of peginterferon alfa-2b (1.5 ug/kg/wk) | Drug: Taribavirin<br>* Oral (200mg)Tablet: 30mg/kg/day BID, patients will be treated for a total of 48 weeks. in addition, all patients will receive peginterferon alfa-2b (PEG-Intron) by weekly subcutaneous injection. Patients who complete treatment with study drug or discontinue treatment prematurely will enter a 24-week follow-up period.<br>* Other names: RNA003142-204;|
| Active Comparator: Group 4: Drug<br>Oral ribavirin 800 mg/day (body weight <65 kg), 1000 mg/day (body weight 65-84 kg), 1200 mg/day (body weight 85-104 kg) or 1400 mg/day (body weight greater than or equal to 105 kg) BID plus weekly subcutaneous injections of peginterferon alfa-2b (1.5 ug/kg/wk) | Drug: Ribavirin<br>* Oral (200mg)Tablet: 800 mg/day, 1000 mg/day, 1200 mg/day, or 1400 mg/day BID, patients will be treated for a total of 48 weeks. in addition, all patients will receive peginterferon alfa-2b (PEG-Intron) by weekly subcutaneous injection. Patients who complete treatment with study drug or discontinue treatment prematurely will enter a 24-week follow-up period.<br>* Other names: Virazole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Either Undetectable Serum HCV RNA (<100 Copies/ml) or at Least a 2-log Decrease From Baseline in Serum Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Treatment Week 12. | The primary efficacy endpoint was the numbers of responders at Treatment Week (TW) 12. Responders are defined as patients achieving either viral negativity or a partial response (PR). Viral negativity is defined as <100 copies/mL serum HCV RNA. A PR is defined as < 100 copies/mL serum HCV RNA and at least a 2-log decrease from baseline in serum HCV RNA levels. Responder rates with corresponding 95% confidence intervals were estimated for each treatment group. | Treatment Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Anemia (Hemoglobin <10 g/dL) Up to Follow-up Week 24 | The primary safety endpoint will be the numbers of patients with hemoglobin <10 g/dL (anemia) at any time during the treatment period. The comparison of anemia rates between taribavirin and ribavirin groups will be carried out using the Fisher's exact test or Chi-square test. The 95% confidence interval of the difference in proportion will be analyzed. | Treatment Week Follow-Up 24 | 
| Patients With Undetected Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) (<100 Copies/mL) at Treatment Week Follow-Up 24 |  | Treatment Week Follow-Up 24 | 
| Relapsers at Follow-Up Visit 24 | Includes patients who had undetectable Hepatitis Virus C (HVC) Ribonucleic Acid (RNA) at their last visit on drug. | Follow-Up Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 2b Dose-Ranging Study