Concentration-Controlled Ribavirin for the Treatment of Patients With Chronic Hepatitis C Virus Infection

Study Overview
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Brief Summary
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The purpose of this study is to determine if concentration-controlled ribavirin dosing can achieve a targeted level of plasma exposures and if it appears safe and effective compared with standard weight-based ribavirin dosing. Forty, previously treatment-naive participants with genotype 1 disease will be randomized to receive concentration-guided or standard weight-based ribavirin. Peginterferon alfa 2a,ribavirin, and telaprevir will be provided through the study.

Official Title
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Concentration-Controlled Ribavirin for the Treatment of Patients With Chronic Hepatitis C Virus Infection

Conditions
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Hepatitis C Virus

Intervention / Treatment
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* Drug: ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic HCV-infected men and women 18-70 years HCV genotype 1 Deemed ready for HCV treatment by hepatology provider and patient Allowed medications: all those not specifically listed in the exclusion criteria below including medications for peginterferon / ribavirin - related adverse effects: acetaminophen, ibuprofen, diphenhydramine, selective serotonin reuptake inhibitors, darbepoeitin, erythropoietin, GCSF Exclusion Criteria: previous treatment with interferon, peginterferon, investigational HCV drugs, boceprevir, or ribavirin; baseline absolute neutrophil count (ANC) < 1000/mm3, platelets < 100,000/mm3, hemoglobin < 12 g/dL for women and < 13 g/dL for men; HIV positive serostatus; HBV positive serostatus; decompensated liver disease (i.e., ascites, history of esophageal variceal bleeding, hepatic encephalopathy); autoimmune hepatitis hemoglobinopathy (e.g., sickle cell anemia, thalassemia) Cockcroft and Gault estimated creatinine clearance < 50 mL/min; alcohol or illicit drug use that in the opinion of the investigator would interfere with study participation and/or impact study results for females, active pregnancy or any intent to become pregnant during study period or for up to 6 months after completing treatment for males, a pregnant female partner or intent to impregnate a female during study period or for up to 6 months after completing treatment for both sexes an unwillingness to use two forms of contraception during the study period and for 6 months after completing treatment. While on telaprevir and for 2 weeks following discontinuation of telaprevir, females must use two non-hormonal forms of contraception; history of significant or unstable cardiac disease including severe coronary artery disease (unstable angina, recent myocardial infarction, chest pain with exertion) or congestive heart failure; receipt of an organ transplant; malignant neoplastic disease; chronic pulmonary disease that in the opinion of the study hepatologists would preclude treatment with peginterferon and ribavirin (e.g., pulmonary function tests ≤70% within the previous 2 years); history of admission to a psychiatric facility within the previous year; suicide attempt within the previous 3 years; concomitant medications including: amantadine, mycophenolate mofetil, and investigational HCV compounds, alfuzosin, alfentanil, ergot derivatives (dihydroergotamine/ergotamine/ergonovine/methylergonovine), meperidine, anti-arrhythmics (quinidine, flecainide, propafenone, amiodarone, bepridil), astemizole, terfenadine, buspirone, diazepam, estazolam, oral midazolam, triazolam, budesonide, domperidone, eletriptan, eplerenone, fluticasone, pimozide, salmeterol, calcium channel blockers (diltiazem, felodipine, nifedipine, nisoldipine, verapamil), cisapride, cyclosporine, sirolimus, systemic tacrolimus, atorvastatin, lovastatin, simvistatin, sildenafil, tadalafil, verdenafil, antibiotics (clarithromycin, erythromycin, telithromycin, troleandomycin), carbamazepine, Phenobarbital, phenytoin, nefazodone, St. Johns Wort, antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), rifampin, rifabutin, aprepitant, cholestyramine, fluvoxamine, mifepreistone, modafinil, systemic dexamethasone. With the exception of St. Johns Wort, investigators may use their discretion on use of herbal and dietary supplements. Evidence of severe retinopathy or clinically relevant ophthalmologic disorders

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Weight-Based Ribavirin Dosing<br>1000 mg daily in patients weighing <75 kg and 1200 mg daily in patients weighing ≥ 75 kg | Drug: ribavirin<br>* Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12<br>|
| Experimental: Concentration-Controlled Ribavirin Dosing<br>Dose adjusted based on first dose AUC0-12 | Drug: ribavirin<br>* Randomization to standard weight based ribavirin dosing (1000 or 1200 mg daily) or concentration-guided dosing based on first dose AUC0-12<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ribavirin AUC-12 Variability | Demonstrate that concentration-controlled ribavirin dosing can achieve a targeted level of plasma exposure with reduced variability in the steady-state area-under-the-concentration-time curve (AUC0-12) compared with standard weight-based ribavirin dosing | steady state ( weeks 9-10) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Absolute Hemoglobin Declines |  | from baseline through end of treatment, up to 48 weeks | 
| Sustained Virologic Response (i.e., Cure) | Compare proportions with SVR in standard weight-based vs. concentration-guided ribavirin dosing groups. Number of participants with sustained virologic response is reported. | assessed 12 weeks after stopping treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ribavirin, pharmacokinetics, Hepatitis C virus