Directly Observed Therapy for HCV in Chennai, India

Study Overview
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Brief Summary
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The primary objective of this pilot trial is to evaluate the feasibility of 12 weeks vs. 24 weeks of field-based directly observed therapy (DOT) for HCV therapy in a resource-limited setting. The investigators will compare treatment completion rates among 50 persons chronically infected with HCV who will be randomized to receive either 1) 12 weeks of sofosbuvir (SOF) + ribavirin (RBV) + pegylated interferon alfa-2a (PEG); or 2) 24 weeks of SOF + RBV. Treatment will be delivered daily by field workers at a location of a participants choosing. Secondary objectives are 1) To compare the efficacy of SOF+RBV with or without PEG as measured by the proportion of subjects with sustained viral response at 12 weeks after discontinuation of therapy (SVR12); 2) To evaluate the safety and tolerability of SOF+RBV with or without PEG; 3) To assess the impact of SVR12 on insulin resistance.

Detailed Description
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This will be a non-blinded randomized clinical trial with 50 participants randomized at a 1:1 allocation ratio to one of two treatment arms. Arm 1: Sofosbuvir (400mg/daily) + Pegylated Interferon alfa-2a (180µg/weekly) + Ribavirin (800mg/daily) for 12 weeks Arm 2: Sofosbuvir (400mg/daily) + Ribavirin (800mg/daily) for 24 weeks Pegylated-interferon alfa-2a (PEG) will be delivered subcutaneously once weekly. Sofosbuvir (SOF) and ribavirin (RBV) will be taken orally once daily for the entire study period. The study will take place at the YR Gaitonde Centre for AIDS Research and Education (YRGCARE). YRG CARE is a non-profit medical and research institution in Chennai. YRGCARE Medical Centre provides medical care for more than 18,000 persons with HIV disease. Currently more than 8000 persons are receiving highly active antiretroviral therapy at the center. Participants will be recruited from the YR Gaitonde Centre for Substance Abuse Research (YRGCSAR), which is affiliated with YRGCARE. The investigators will primarily recruit subjects from a cohort study of current and former people who inject drugs (PWID) that is ongoing at the same center. Eligible participants will be randomized to one of the two treatment arms after providing written informed consent. Treatment will be delivered directly to participants daily by field workers at a location of the participants choosing. Participants will be asked to visit the study clinic every four weeks during treatment and 12 weeks after completing treatment for additional study procedures. In addition, participants in Arm 1 will be asked to visit the clinic every week to receive their PEG injection. The primary outcome is treatment completion. Secondary outcomes include SVR12, safety and tolerability and insulin resistance.

Official Title
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Directly Observed Therapy for the Delivery of HCV Therapy Among HCV-infected Individuals in Chennai, India

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Sofosbuvir
* Drug: Pegylated Interferon alfa-2a
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing/able to provide consent Age ≥ 18 Chronic HCV (HCV RNA positive) Resident of Chennai and can provide locator information If co-infected with HIV, must have CD4 (Cluster of Differentation 4) > 350 cells/mm3 and either: 1) ART naïve or 2) if on ART be on a tenofovir-containing regimen. If a participant's CD4 drops below 350 cells/μl (threshold for treatment in India), will have to initiate a tenofovir-containing regimen (current standard of care). Participants must have the following at screening: Alanine Aminotransferase (ALT) ≤ 10 x the upper limit of normal (ULN) Aspartate Aminotransferase (AST) ≤ 10 x ULN Hemoglobin ≥ 12 g/dl for males and 11 g/dl for females International normalized ratio (INR) ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR Albumin ≥ 3 g/dl Direct bilirubin ≤ 1.5 x ULN Creatinine clearance ≥ 60 ml/min (Cockgroft-Gault Equation) Alpha fetoprotein < 50 ng/ml Absolute neutrophil count (ANC) ≥ 1,500/μL Platelets ≥ 90,000/μL Thyroid stimulating hormone (TSH) ≤ ULN A female subject is eligible if it is confirmed that she is: Not pregnant or nursing Of non-childbearing potential (i.e., women who have had hysterectomy, have both ovaries removed or medically documented ovarian failure, or are postmenopausal women > 50 years of age with cessation (for ≥12 months) of previously occurring menses Of childbearing potential and negative urine pregnancy test prior to randomization and agree to one of the following from 3 weeks prior to Baseline/Day 1 until 6 months after the last dose of RBV. Complete abstinence from intercourse. Or • Consistent use of approved methods of birth control in addition to a male partner who correctly uses a condom from 3 weeks prior to Baseline/Day 1 until 6 months after the last dose of RBV. Male participants must agree to consistently and correctly use a condom. If their female partner is of childbearing potential, their partner must agree to use one of the study approved non-hormonal methods of birth control or a hormone-containing contraceptive, from the date of screening until 7 months after their last dose of RBV Male participants must agree to refrain from sperm donation for at least 7 months after the last dose of RBV. Of generally good health as determined by the investigator. Able to comply with the dosing instructions for study drug administration and willing to complete the study schedule of assessments. Exclusion Criteria: Pregnant/nursing female or male with pregnant/nursing female partner. Current or prior history of clinical hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage, MELD<12) Prior hepatitis C treatment Infection with hepatitis B virus Chronic use of systematically administered immunosuppressive agents (e.g., prednisone equivalent >10 mg/day) Use of any prohibited concomitant medications within 28 days of the Baseline/Day 1 visit. Contraindications to RBV therapy or PEG/RBV Known hypersensitivity to RBV or PEG, the metabolites or formulation excipients Additional exclusion criteria related to Aim 1 regimen Pre-existing significant psychiatric condition(s) including severe depression, severe bipolar disorder and schizophrenia. Other psychiatric disorders are permitted if the condition is well controlled with a stable treatment regimen for ≥ 1 year from screening. Presence of autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis). History of clinical significant retinal disease.

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 |
| --- | --- |
| Active Comparator: SOF+PEG+RBV<br>Sofosbuvir (400mg/daily) + Pegylated Interferon alfa-2a (180µg/weekly) + Ribavirin (800mg/daily) for 12 weeks | Drug: Sofosbuvir<br>* Direct acting antiviral agent used for the treatment of hepatitis C<br>* Other names: Sovaldi, Hepcvir, MyHep, Hepcinat, Resof, SoviHep;Drug: Pegylated Interferon alfa-2a<br>* Antiviral agent used for the treatment of hepatitis C<br>* Other names: Pegasys, Taspiance;Drug: Ribavirin<br>* Antiviral agent (guanosine analogue) used for the treatment of hepatitis C<br>* Other names: Rebetol, Copegus, Univirin;|
| Active Comparator: SOF+RBV<br>Sofosbuvir (400mg/daily) + Ribavirin (800mg/daily) for 24 weeks | Drug: Sofosbuvir<br>* Direct acting antiviral agent used for the treatment of hepatitis C<br>* Other names: Sovaldi, Hepcvir, MyHep, Hepcinat, Resof, SoviHep;Drug: Ribavirin<br>* Antiviral agent (guanosine analogue) used for the treatment of hepatitis C<br>* Other names: Rebetol, Copegus, Univirin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HCV Treatment Completion | The percentage of subjects that complete their course of treatment | 12 weeks from baseline for SOF+PEG+RBV and 24 weeks from baselne for SOF+RBV | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response (SVR) | The percentage of participants who achieve SVR as assessed by undetectable HCV RNA measured 12 weeks after treatment completion | 24 weeks from baseline for SOF+PEG+RBV and 36 weeks from baseline for SOF+RBV | 
| Serious Adverse Events | Number of participants with treatment-related serious adverse events by laboratory tests and physician examination | 24 weeks from baseline SOF+PEG+RBV and 36 weeks from baseline for SOF+RBV | 
| Change in Insulin Resistance | Change in insulin resistance while on treatment by the homeostasis model assessment - insulin resistance (HOMA-IR). HOMA-IR is calculated according to the formula (fasting insulin (microU/L)+fasting glucose (nmol/L)/22.5. Fasting insulin and glucose measurements are obtained using whole blood. | Difference from entry to 24 weeks for SOF+PEG+RBV and difference from entry to 36 weeks for SOF+RBV | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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directly observed therapy, sofosbuvir, ribavirin, pegylated interferon, resource-limited setting