Hepatitis C, Chronic
Conditions
Keywords
directly observed therapy, sofosbuvir, daclatasvir, pegylated interferon, resource-limited setting
Brief summary
The primary objective of this pilot trial is to compare the efficacy, measured as sustained virologic response (SVR) at least 12 weeks after completion of therapy, across three study regimens/delivery modalities: Arm 1 - 4 weeks of sofosbuvir (SOF) + daclatasvir (DAC) + pegylated interferon alfa-2a (PEG) delivered using directly observed therapy (DOT); Arm 2 - 12 weeks of SOF+DAC delivered using DOT; and Arm 3 - 12 weeks of SOF+DAC delivered as per standard of care (monthly dispensation with no DOT). Secondary objectives are 1)To compare the cost per SVR for each of the three study arms; 2) To compare adherence among persons across the three study arms; 3) To evaluate the safety, tolerability and acceptability of treatment in the three arms.
Detailed description
This will be a non-blinded randomized clinical trial with 150 participants randomized at a 1:1:1 allocation ratio to one of three treatment arms. Arm 1: Sofosbuvir (400mg/daily) + Daclatasvir (60mg/daily) + Pegylated Interferon alfa-2a (180µg/weekly) for 4 weeks with a field-based DOT approach Arm 2: Sofosbuvir (400mg/daily) + Daclatasvir (60mg/daily) for 12 weeks with a field-based DOT approach Arm 3: Sofosbuvir (400mg/daily) + Daclatasvir (60mg/daily) for 12 weeks with standard of care dispensation (4 monthly doses) Pegylated-interferon alfa-2a (PEG) will be delivered subcutaneously once weekly. Sofosbuvir (SOF) and Daclatasvir (DAC) will be taken orally once daily for the entire study period. The study will take place at the YR Gaitonde Centre for AIDS Education (YRG) and Johns Hopkins University (JHU) Collaborative Integrated Care Center (YRG-JHU ICC) located within the premises of the Chattisgarh Institute of Medical Sciences (CIMS) in Bilaspur in the state of Chattisgarh, India. Participants will be recruited from the YRG-JHU ICC in Bilaspur, which currently has 514 registered HCV antibody positive clients. The Bilaspur ICC is in the Chattisgarh Institute for Medical Sciences (CIMS). The primary outcome will be sustained virologic response (SVR12). Secondary outcomes include cost per SVR12, adherence, safety and tolerability.
Interventions
DRUGSofosbuvir
Direct acting antiviral agent used for the treatment of hepatitis C
DRUGDaclatasvir
Direct acting antiviral agent used for the treatment of hepatitis C
DRUGPegylated Interferon alfa-2a
Antiviral agent 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 and able to provide written informed consent 2. Age ≥ 18 years 3. Documented evidence of chronic HCV infection (HCV RNA positive) 4. Participant is a resident of Bilaspur and can provide locator information that can be verified by one of the study staff 5. If participant is co-infected with HIV, he/she must have a cluster of differentiation 4 (CD4) \> 350 cells/mm3 and be either: 1) antiretroviral therapy (ART) naïve or 2) on ART be on a tenofovir-containing regimen. If a subject's CD4 drops below 350 cells/μl (current threshold for HIV treatment in India), he/she will be able to initiate ART but we will ensure that the subject starts on a tenofovir-containing regimen, which is currently the standard for persons newly initiating ART in India. 6. Subjects must have the following laboratory parameters at screening: 1. alanine aminotransferase (ALT) ≤ 10 x the upper limit of normal (ULN) 2. aspartate aminotransferase (AST) ≤ 10 x ULN 3. Hemoglobin ≥ 10 g/dl for male and 9 g/dl for female subjects 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 ≥ 30 ml/min as calculated by the Cockcroft-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 12. FIB-4 \<3.25. FIB-4 is a non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) which is calculated as the ratio of age in years and aminotransferase to platelet count. It is a non-invasive hepatic fibrosis index score combining standard biochemical values, platelets, alanine aminotransferase (ALT), AST and age that is calculated using formula: FIB-4 = (Age \[years\] x AST \[U/L\]) / (platelets \[10\^9/L\] x (square root of ALT \[U/L\])). A FIB-4 index of \< 1.45 indicated no or moderate fibrosis and an index of \> 3.25 indicated extensive fibrosis/cirrhosis.) Participants with a FIB-4 \>3.25 will be referred to the medical gastroenterology department for further assessment for cirrhosis. If cirrhosis is ruled out by medical gastroenterology, participants can be rescreened for the study. 7. A female subject is eligible to enroll in the study if it is confirmed that she is: 1. Not pregnant or nursing 2. Not of childbearing potential (i.e., women who have had a 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 (i.e., women who have not had a hysterectomy, both ovaries removed or medically documented ovarian failure). \[NOTE: Women ≤50 years of age with amenorrhea will be considered to be of childbearing potential.\] These women must have a negative urine pregnancy test at screening and a negative urine pregnancy test on the Baseline /Day 1 visit prior to randomization and agree to one of the following modes of contraception for the duration of treatment and 12 weeks thereafter. * Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, sumptothermal, post-ovulation methods) is NOT permitted. or i. Consistent and correct use of 1 of the following methods of birth control listed below in addition to a male partner who correctly uses a condom from 3 weeks prior to Baseline/Day 1 until the end of treatment. Women of childbearing potential must not rely on hormone-containing contraceptives as a form of birth control during the study. Female subjects using a hormone containing contraceptive prior to screening may continue their contraceptive regimen in addition to the study specified methods of birth control. * intrauterine device (IUD) with a documented failure rate of less than 1% per year * female barrier method: cervical cap or diaphragm with spermicidal agent * tubal sterilization * vasectomy in male partner 8. Subjects must be of generally good health as determined by the investigator. 9. Subjects must be able to comply with the dosing instructions for study drug administration and be willing to complete the study schedule of assessments.
Exclusion criteria
1. Pregnant or nursing female 2. Current or prior history of clinical hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage, model for end-stage liver disease (MELD)\<12) 3. Prior treatment for hepatitis C virus infection 4. Infection with hepatitis B virus (HBsAg positive) 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 PEG 8. Known hypersensitivity to the metabolites or formulation excipients of PEG (for Arm 1 subjects) 9. Active 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, or inactive for ≥ 1 year from screening. 10. Presence of autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, psoriasis of greater than mild severity) 11. History of clinical significant retinal disease 12. Clinical evidence of cirrhosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SVR12 | 12 weeks after treatment completion, 16 weeks for SOF+DAC+PEG and 24 weeks for SOF+DAC | Percentage of participants achieving sustained virologic response 12 weeks quantification) after treatment is completed (SVR12) as assessed by HCV RNA less than the lower limit of quantification measured 12 weeks after treatment completion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Events | 16 weeks for SOF+DAC+PEG and 24 weeks for SOF+DAC | Number of participants with treatment-related serious adverse events by laboratory tests and physician examination |
| Medication Adherence | 4 weeks for SOF+DAC+PEG and 12 weeks for SOF+DAC | Adherence to medication regimen defined using a combination of the biometric data for Arms 1 and 2 and self-report and pill counts for Arm 3. Percentage reporting at least 90% adherence |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SOF+DAC+PEG Sofosbuvir (400mg/daily) + Daclatasvir (60mg/daily) + Pegylated Interferon alfa-2a (180µg/weekly) for 4 weeks with a field-based DOT approach
Sofosbuvir: Direct acting antiviral agent used for the treatment of hepatitis C
Daclatasvir: Direct acting antiviral agent used for the treatment of hepatitis C
Pegylated Interferon alfa-2a: Antiviral agent used for the treatment of hepatitis C | 50 |
| SOF+DAC, DOT Sofosbuvir (400mg/daily) + Daclatasvir (60mg/daily) for 12 weeks with a field-based DOT approach
Sofosbuvir: Direct acting antiviral agent used for the treatment of hepatitis C
Daclatasvir: Direct acting antiviral agent used for the treatment of hepatitis C | 50 |
| SOF+DAC, Standard Sofosbuvir (400mg/daily) + Daclatasvir (60mg/daily) for 12 weeks with standard of care dispensation (4 monthly doses)
Sofosbuvir: Direct acting antiviral agent used for the treatment of hepatitis C
Daclatasvir: Direct acting antiviral agent used for the treatment of hepatitis C | 50 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 0 |
| Overall Study | Incarcerated | 2 | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | SOF+DAC, DOT | SOF+DAC, Standard | SOF+DAC+PEG | Total |
|---|---|---|---|---|
| Age, Continuous | 26 years | 25 years | 25 years | 25 years |
| Alcohol use Alcohol dependence | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Alcohol use Harmful/hazardous use | 2 Participants | 5 Participants | 3 Participants | 10 Participants |
| Alcohol use No/mild use | 47 Participants | 45 Participants | 46 Participants | 138 Participants |
| Depressive symptoms Mild | 17 Participants | 15 Participants | 10 Participants | 42 Participants |
| Depressive symptoms Moderate | 5 Participants | 3 Participants | 3 Participants | 11 Participants |
| Depressive symptoms Moderately severe to severe | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Depressive symptoms None | 28 Participants | 31 Participants | 37 Participants | 96 Participants |
| Educational attainment At least high school | 12 Participants | 12 Participants | 19 Participants | 43 Participants |
| Educational attainment None | 2 Participants | 6 Participants | 3 Participants | 11 Participants |
| Educational attainment Primary school | 16 Participants | 15 Participants | 19 Participants | 50 Participants |
| Educational attainment Secondary school | 20 Participants | 17 Participants | 9 Participants | 46 Participants |
| Employment Daily wages | 25 Participants | 28 Participants | 22 Participants | 75 Participants |
| Employment Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Employment Monthly wages | 16 Participants | 12 Participants | 19 Participants | 47 Participants |
| Employment Unemployment | 1 Participants | 7 Participants | 3 Participants | 11 Participants |
| Employment Weekly wages | 8 Participants | 3 Participants | 5 Participants | 16 Participants |
| HIV-infected | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Injection drug use frequency in prior month Daily | 13 Participants | 6 Participants | 8 Participants | 27 Participants |
| Injection drug use frequency in prior month None | 5 Participants | 4 Participants | 3 Participants | 12 Participants |
| Injection drug use frequency in prior month Once a week to less than twice a week | 17 Participants | 22 Participants | 24 Participants | 63 Participants |
| Injection drug use frequency in prior month Twice a week to six times a week | 15 Participants | 18 Participants | 15 Participants | 48 Participants |
| Marital status Currently married | 13 Participants | 17 Participants | 15 Participants | 45 Participants |
| Marital status Living with partner | 4 Participants | 3 Participants | 4 Participants | 11 Participants |
| Marital status Never married | 32 Participants | 30 Participants | 31 Participants | 93 Participants |
| Marital status Separated | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Median calculated fibrosis score (FIB-4) | 0.68 units on a scale | 0.73 units on a scale | 0.69 units on a scale | 0.68 units on a scale |
| Median HCV RNA | 5.6 log 10 copies/ml | 5.7 log 10 copies/ml | 5.4 log 10 copies/ml | 5.6 log 10 copies/ml |
| Non-injection drug use in prior month | 38 Participants | 41 Participants | 42 Participants | 121 Participants |
| Quality of life | 78 Self-rated health scale (0-100)) | 80 Self-rated health scale (0-100)) | 90 Self-rated health scale (0-100)) | 80 Self-rated health scale (0-100)) |
| Race/Ethnicity, Customized Indian | 50 Participants | 50 Participants | 50 Participants | 150 Participants |
| Region of Enrollment India | 50 participants | 50 participants | 50 participants | 150 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 50 Participants | 50 Participants | 50 Participants | 150 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 50 | 0 / 50 |
| other Total, other adverse events | 0 / 50 | 0 / 50 | 0 / 50 |
| serious Total, serious adverse events | 0 / 50 | 0 / 50 | 0 / 50 |
Outcome results
Primary
SVR12
Percentage of participants achieving sustained virologic response 12 weeks quantification) after treatment is completed (SVR12) as assessed by HCV RNA less than the lower limit of quantification measured 12 weeks after treatment completion
Time frame: 12 weeks after treatment completion, 16 weeks for SOF+DAC+PEG and 24 weeks for SOF+DAC
Population: Intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF+DAC+PEG | SVR12 | 26 Participants |
| SOF+DAC, DOT | SVR12 | 30 Participants |
| SOF+DAC, Standard | SVR12 | 17 Participants |
Secondary
Medication Adherence
Adherence to medication regimen defined using a combination of the biometric data for Arms 1 and 2 and self-report and pill counts for Arm 3. Percentage reporting at least 90% adherence
Time frame: 4 weeks for SOF+DAC+PEG and 12 weeks for SOF+DAC
Population: Intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF+DAC+PEG | Medication Adherence | 35 Participants |
| SOF+DAC, DOT | Medication Adherence | 31 Participants |
| SOF+DAC, Standard | Medication Adherence | 10 Participants |
Secondary
Serious Adverse Events
Number of participants with treatment-related serious adverse events by laboratory tests and physician examination
Time frame: 16 weeks for SOF+DAC+PEG and 24 weeks for SOF+DAC
Population: Intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF+DAC+PEG | Serious Adverse Events | 0 Participants |
| SOF+DAC, DOT | Serious Adverse Events | 0 Participants |
| SOF+DAC, Standard | Serious Adverse Events | 0 Participants |