C-DOT: Directly Observed Therapy for HCV in Chennai, India

• Sponsor: Johns Hopkins Bloomberg School of Public Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT02541409
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH), YR Gaitonde Centre for AIDS Research and Education (Other)
• Enrollment: 50
• Location: 1
• Arms: 2
• Actual Duration (Months): 15
• Patients Per Site Per Month: 3.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C, Chronic	Drug: Sofosbuvir; Drug: Pegylated Interferon alfa-2a; Drug: Ribavirin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Directly Observed Therapy for the Delivery of HCV Therapy Among HCV-infected Individuals in Chennai, India
• Actual Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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:

7. Alanine Aminotransferase (ALT) ≤ 10 x the upper limit of normal (ULN)

8. Aspartate Aminotransferase (AST) ≤ 10 x ULN

9. Hemoglobin ≥ 12 g/dl for males and 11 g/dl for females

10. International normalized ratio (INR) ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR

11. Albumin ≥ 3 g/dl

12. Direct bilirubin ≤ 1.5 x ULN

13. Creatinine clearance ≥ 60 ml/min (Cockgroft-Gault Equation)

14. Alpha fetoprotein < 50 ng/ml

15. Absolute neutrophil count (ANC) ≥ 1,500/μL

16. Platelets ≥ 90,000/μL

17. Thyroid stimulating hormone (TSH) ≤ ULN

18. A female subject is eligible if it is confirmed that she is:

19. Not pregnant or nursing

20. 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

21. 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.

1. 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

2. Male participants must agree to refrain from sperm donation for at least 7 months after the last dose of RBV.

3. Of generally good health as determined by the investigator.

4. 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 exclusion criteria related to Aim 1 regimen

10. 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.

11. Presence of autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis).

12. History of clinical significant retinal disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	YR Gaitonde Centre for AIDS Research and Education	Chennai	Tamil Nadu	India	600113

Sponsors and Collaborators

• Johns Hopkins Bloomberg School of Public Health
• National Institute on Drug Abuse (NIDA)
• YR Gaitonde Centre for AIDS Research and Education

Investigators

• Principal Investigator: Sunil S Solomon, MBBS, PhD, MPH, Johns Hopkins School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins Bloomberg School of Public Health
• ClinicalTrials.gov Identifier: NCT02541409
• Other Study ID Numbers: R01DA02672; R01DA026727
• First Posted: Sep 4, 2015
• Last Update Posted: Apr 15, 2021
• Last Verified: Mar 1, 2021

• Keywords provided by Johns Hopkins Bloomberg School of Public Health: directly observed therapy; sofosbuvir; ribavirin; pegylated interferon; resource-limited setting
• Additional relevant MeSH terms: Hepatitis C; Hepatitis C, Chronic; Interferons; Ribavirin; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a; Sofosbuvir

Study Results

Participant Flow

Arm/Group Title	SOF+PEG+RBV	SOF+RBV
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	25	25
COMPLETED	22	22
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	SOF+PEG+RBV	SOF+RBV	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	25	25	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	25 100%	25 100%	50 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	46	46	46
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	25 100%	25 100%	50 100%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
India	25 100%	25 100%	50 100%
HCV Genotype 3a (Count of Participants)
Count of Participants [Participants]	22 88%	20 80%	42 84%
HCV Genotype 1a (Count of Participants)
Count of Participants [Participants]	2 8%	5 20%	7 14%
HCV Genotype 6n (Count of Participants)
Count of Participants [Participants]	1 4%	0 0%	1 2%
Lifetime Injection Drug Use: Heroin (Count of Participants)
Count of Participants [Participants]	24 96%	25 100%	49 98%
Lifetime Injection Drug Use: Sedatives (Count of Participants)
Count of Participants [Participants]	19 76%	16 64%	35 70%
Lifetime Injection Drug Use: Other Opioids (Count of Participants)
Count of Participants [Participants]	24 96%	23 92%	47 94%
Injection Drug use in Prior 6 Months (Count of Participants)
Count of Participants [Participants]	1 4%	0 0%	1 2%
NonInjection Drug Use in Prior 6 Months (Count of Participants)
Count of Participants [Participants]	7 28%	2 8%	9 18%
Marijuana Use in Prior 6 Months (Count of Participants)
Count of Participants [Participants]	4 16%	1 4%	5 10%
No Alcohol Use in Prior 6 Months (Count of Participants)
Count of Participants [Participants]	14 56%	13 52%	27 54%
Alcohol Use in Prior 6 Months: 1-4 Drinks Daily (Count of Participants)
Count of Participants [Participants]	9 36%	9 36%	18 36%
Alcohol Use in Prior 6 Months: >5 Drinks Daily (Count of Participants)
Count of Participants [Participants]	2 8%	3 12%	5 10%
Alcohol Use: No/Mild Alcohol Use (Count of Participants)
Count of Participants [Participants]	14 56%	14 56%	28 56%
Alcohol Use: Harmful/Hazardous Alcohol Use (Count of Participants)
Count of Participants [Participants]	1 4%	2 8%	3 6%
Alcohol Use: Alcohol Dependence (Count of Participants)
Count of Participants [Participants]	10 40%	9 36%	19 38%

Outcome Measures

1. Primary Outcome

Title	HCV Treatment Completion
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SOF+PEG+RBV	SOF+RBV
Arm/Group Description	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	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
Measure Participants	25	25
Count of Participants [Participants]	22 88%	22 88%

2. Secondary Outcome

Title	Sustained Virologic Response (SVR)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SOF+PEG+RBV	SOF+RBV
Arm/Group Description	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	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
Measure Participants	25	25
Count of Participants [Participants]	22 88%	15 60%

3. Secondary Outcome

Title	Serious Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SOF+PEG+RBV	SOF+RBV
Arm/Group Description	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	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
Measure Participants	25	25
Count of Participants [Participants]	0 0%	0 0%

4. Secondary Outcome

Title	Change in Insulin Resistance
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SOF+PEG+RBV	SOF+RBV
Arm/Group Description	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	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
Measure Participants	25	25
Median (Inter-Quartile Range) [HOMA-IR]	1.2	0.2

Adverse Events

Time Frame	1 year, 5 months
Arm/Group Title	SOF+PEG+RBV		SOF+RBV
Arm/Group Description	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		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
All Cause Mortality
	SOF+PEG+RBV		SOF+RBV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	SOF+PEG+RBV		SOF+RBV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	SOF+PEG+RBV		SOF+RBV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.