Hepatitis C, Chronic
Conditions
Keywords
directly observed therapy, sofosbuvir, ribavirin, pegylated interferon, resource-limited setting
Brief summary
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
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.
Interventions
DRUGSofosbuvir
Direct acting antiviral agent used for the treatment of hepatitis C
DRUGPegylated Interferon alfa-2a
Antiviral agent used for the treatment of hepatitis C
DRUGRibavirin
Antiviral agent (guanosine analogue) used for the treatment of hepatitis C
Sponsors
National Institute on Drug Abuse (NIDA)
YR Gaitonde Centre for AIDS Research and Education
Johns Hopkins Bloomberg School of Public Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Willing/able to provide consent 2. Age ≥ 18 3. Chronic HCV (HCV RNA positive) 4. Resident of Chennai and can provide locator information 5. 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). 6. Participants must have the following at screening: 1. Alanine Aminotransferase (ALT) ≤ 10 x the upper limit of normal (ULN) 2. Aspartate Aminotransferase (AST) ≤ 10 x ULN 3. Hemoglobin ≥ 12 g/dl for males and 11 g/dl for females 4. International normalized ratio (INR) ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR 5. Albumin ≥ 3 g/dl 6. Direct bilirubin ≤ 1.5 x ULN 7. Creatinine clearance ≥ 60 ml/min (Cockgroft-Gault Equation) 8. Alpha fetoprotein \< 50 ng/ml 9. Absolute neutrophil count (ANC) ≥ 1,500/μL 10. Platelets ≥ 90,000/μL 11. Thyroid stimulating hormone (TSH) ≤ ULN 7. A female subject is eligible if it is confirmed that she is: 1. Not pregnant or nursing 2. 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 3. 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. 8. 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 9. Male participants must agree to refrain from sperm donation for at least 7 months after the last dose of RBV. 10. Of generally good health as determined by the investigator. 11. Able to comply with the dosing instructions for study drug administration and willing to complete the study schedule of assessments.
Exclusion criteria
1. Pregnant/nursing female or male with pregnant/nursing female partner. 2. Current or prior history of clinical hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage, MELD\<12) 3. Prior hepatitis C treatment 4. Infection with hepatitis B virus 5. Chronic use of systematically administered immunosuppressive agents (e.g., prednisone equivalent \>10 mg/day) 6. Use of any prohibited concomitant medications within 28 days of the Baseline/Day 1 visit. 7. Contraindications to RBV therapy or PEG/RBV 8. Known hypersensitivity to RBV or PEG, the metabolites or formulation excipients 9. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HCV Treatment Completion | 12 weeks from baseline for SOF+PEG+RBV and 24 weeks from baselne for SOF+RBV | The percentage of subjects that complete their course of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virologic Response (SVR) | 24 weeks from baseline for SOF+PEG+RBV and 36 weeks from baseline for SOF+RBV | The percentage of participants who achieve SVR as assessed by undetectable HCV RNA measured 12 weeks after treatment completion |
| Serious Adverse Events | 24 weeks from baseline SOF+PEG+RBV and 36 weeks from baseline for SOF+RBV | Number of participants with treatment-related serious adverse events by laboratory tests and physician examination |
| Change in Insulin Resistance | Difference from entry to 24 weeks for SOF+PEG+RBV and difference from entry to 36 weeks for SOF+RBV | 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. |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SOF+PEG+RBV Sofosbuvir (400mg/daily) + Pegylated Interferon alfa-2a (180µg/weekly) + Ribavirin (800mg/daily) for 12 weeks
Sofosbuvir: Direct acting antiviral agent used for the treatment of hepatitis C
Pegylated Interferon alfa-2a: Antiviral agent used for the treatment of hepatitis C
Ribavirin: Antiviral agent (guanosine analogue) used for the treatment of hepatitis C | 25 |
| SOF+RBV Sofosbuvir (400mg/daily) + Ribavirin (800mg/daily) for 24 weeks
Sofosbuvir: Direct acting antiviral agent used for the treatment of hepatitis C
Ribavirin: Antiviral agent (guanosine analogue) used for the treatment of hepatitis C | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | SOF+PEG+RBV | SOF+RBV | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 25 Participants | 50 Participants |
| Age, Continuous | 46 years | 46 years | 46 years |
| Alcohol Use: Alcohol Dependence | 10 Participants | 9 Participants | 19 Participants |
| Alcohol Use: Harmful/Hazardous Alcohol Use | 1 Participants | 2 Participants | 3 Participants |
| Alcohol Use in Prior 6 Months: 1-4 Drinks Daily | 9 Participants | 9 Participants | 18 Participants |
| Alcohol Use in Prior 6 Months: >5 Drinks Daily | 2 Participants | 3 Participants | 5 Participants |
| Alcohol Use: No/Mild Alcohol Use | 14 Participants | 14 Participants | 28 Participants |
| HCV Genotype 1a | 2 Participants | 5 Participants | 7 Participants |
| HCV Genotype 3a | 22 Participants | 20 Participants | 42 Participants |
| HCV Genotype 6n | 1 Participants | 0 Participants | 1 Participants |
| Injection Drug use in Prior 6 Months | 1 Participants | 0 Participants | 1 Participants |
| Lifetime Injection Drug Use: Heroin | 24 Participants | 25 Participants | 49 Participants |
| Lifetime Injection Drug Use: Other Opioids | 24 Participants | 23 Participants | 47 Participants |
| Lifetime Injection Drug Use: Sedatives | 19 Participants | 16 Participants | 35 Participants |
| Marijuana Use in Prior 6 Months | 4 Participants | 1 Participants | 5 Participants |
| No Alcohol Use in Prior 6 Months | 14 Participants | 13 Participants | 27 Participants |
| NonInjection Drug Use in Prior 6 Months | 7 Participants | 2 Participants | 9 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment India | 25 participants | 25 participants | 50 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 25 Participants | 25 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 25 | 0 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 |
Outcome results
Primary
HCV Treatment Completion
The percentage of subjects that complete their course of treatment
Time frame: 12 weeks from baseline for SOF+PEG+RBV and 24 weeks from baselne for SOF+RBV
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF+PEG+RBV | HCV Treatment Completion | 22 Participants |
| SOF+RBV | HCV Treatment Completion | 22 Participants |
Secondary
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.
Time frame: Difference from entry to 24 weeks for SOF+PEG+RBV and difference from entry to 36 weeks for SOF+RBV
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SOF+PEG+RBV | Change in Insulin Resistance | 1.2 HOMA-IR |
| SOF+RBV | Change in Insulin Resistance | 0.2 HOMA-IR |
Secondary
Serious Adverse Events
Number of participants with treatment-related serious adverse events by laboratory tests and physician examination
Time frame: 24 weeks from baseline SOF+PEG+RBV and 36 weeks from baseline for SOF+RBV
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF+PEG+RBV | Serious Adverse Events | 0 Participants |
| SOF+RBV | Serious Adverse Events | 0 Participants |
Secondary
Sustained Virologic Response (SVR)
The percentage of participants who achieve SVR as assessed by undetectable HCV RNA measured 12 weeks after treatment completion
Time frame: 24 weeks from baseline for SOF+PEG+RBV and 36 weeks from baseline for SOF+RBV
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF+PEG+RBV | Sustained Virologic Response (SVR) | 22 Participants |
| SOF+RBV | Sustained Virologic Response (SVR) | 15 Participants |