Hepatitis C
Conditions
Brief summary
The predominant remaining questions for post-transplant treatment of Hepatitis C virus (HCV) in the DAA (direct acting anti-virals) era are whether a ribavirin-free regimen is possible and whether pre-emptive treatment is now a potential option to prevent long-term damage to the allograft. Our aim is to provide answers to these primary questions with our multicenter, prospective, randomized, open-label intent-to-treat phase IV study
Detailed description
This is a multicenter, prospective, randomized, open-label phase IV study. Compare ledipasvir/sofosbuvir + ribavirin for 12 weeks vs ledipasvir/sofosbuvir alone for 12 weeks in patients over 90 days post-liver transplant
Interventions
DRUGSofosbuvir/Ledipasvir x 12 weeks
DRUGSofosbuvir/Ledipasvir + Ribavirin x 12 weeks
Sponsors
Medical University of South Carolina
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. At least 18 years of age and able to give informed consent 2. History of HCV genotype 1 or 4 3. Normal EKG 4. At least 91 days post orthotopic liver transplant 5. Screening laboratory values within defined thresholds 6. Detectable HCV RNA at screening 7. Creatinine Clearance of at least 40ml/min using the Cockcroft Gault equation 8. Negative pregnancy test for female subjects within 48 hours prior to receiving study medication 9. Use of two effective contraception methods if female of childbearing potential or sexually active male unless status post bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or vasectomy
Exclusion criteria
1. Serious or active medical or psychiatric illness 2. History of significant or unstable cardiac disease 3. Stomach disorder that could interfere with the absorption of the study drug 4. Pregnant or nursing females or males with a pregnant female partner 5. Co-infected with Hepatits B (HBV) or HIV 6. Recipients of an allograft from a donor that was infected with HCV with an unknown genotype or non-genotype 1 or 4 unless the recipient is demonstrated to have only genotype 1 or 4 HCV replication post-transplant 7. Allergic to or intolerant of sofosbuvir, ledipasvir, or ribavirin 8. History of exposure to an Nonstructural protein (NS5A) inhibitor 9. Within 1 year of transplant AND history of Hepatocellular Carcinoma (HCC) with tumor burden outside of the Milan Criteria (See Appendix II) prior to transplant 10. Participated in a clinical study with an investigational drug or biologic within the last 30 days 11. Combined liver/kidney transplant 12. History of organ transplant other than liver 13. Childs Turcotte Pugh (CTP) B or C 14. Patients with fibrosing cholestatic hepatitis 15. Platelet count of ≤ 30 k/mm3 16. Hemoglobin \< 10g/dL 17. Total bilirubin \> 10mg/dL 18. Alanine aminotransferase (ALT),aspartate aminotransferase (AST), or alkaline phosphatase ≥ 10x upper limit normal 19. Serum sodium \< 125mmol/L 20. Current use of any of the Prohibited Interventions (Section 5.3.2) and un-willing to discontinue use, or use of amiodarone within 6 months of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Efficacy | 12 Weeks | Treatment efficacy, defined as the percentage of patients achieving sustained virologic response 12 (SVR12) weeks after completing the antiviral regimen |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Virologic Failure | 12 weeks | Number of participants who had a nonresponse to treatment or a relapse of disease under study. |
| Hemoglobin Levels | Week 4, Week 8, Week 12, Week 16 | Change in hemoglobin levels over the course of the study |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Late Cohort, Arm 1 LDV/SOF monotherapy x 12 weeks
Sofosbuvir/Ledipasvir x 12 weeks | 16 |
| Late Cohort, Arm 2 LDV/SOF+ribavirin x 12 weeks
Sofosbuvir/Ledipasvir + Ribavirin x 12 weeks | 16 |
| Total | 32 |
Baseline characteristics
| Characteristic | Late Cohort, Arm 1 | Late Cohort, Arm 2 | Total |
|---|---|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 4 | 60 years STANDARD_DEVIATION 4 | 61 years STANDARD_DEVIATION 4 |
| Calculated MELD at Transplant | 22.3 units on a scale STANDARD_DEVIATION 6.4 | 24.7 units on a scale STANDARD_DEVIATION 8.7 | 23.5 units on a scale STANDARD_DEVIATION 7.6 |
| Days since transplant | 1862 days STANDARD_DEVIATION 1309 | 2611 days STANDARD_DEVIATION 1998 | 2237 days STANDARD_DEVIATION 1654 |
| Donor age | 36 years STANDARD_DEVIATION 13 | 37 years STANDARD_DEVIATION 14 | 37 years STANDARD_DEVIATION 14 |
| Number of patients with prior HCV Treatment | 7 Participants | 8 Participants | 15 Participants |
| Number of subjects with an HCV positive donor | 2 Participants | 0 Participants | 2 Participants |
| Number of subjects with a previous transplant | 0 Participants | 1 Participants | 1 Participants |
| Number of subjects with CMV positive serostatus | 12 Participants | 13 Participants | 25 Participants |
| Number of subjects with history of anemia | 6 Participants | 6 Participants | 12 Participants |
| Number of subjects with history of chronic kidney disease | 4 Participants | 5 Participants | 9 Participants |
| Number of subjects with history of depression | 3 Participants | 6 Participants | 9 Participants |
| Number of subjects with history of insomnia | 3 Participants | 4 Participants | 7 Participants |
| Number of subjects with history of leukopenia | 4 Participants | 3 Participants | 7 Participants |
| Number of subjects with history of thrombocytopenia | 4 Participants | 4 Participants | 8 Participants |
| Number of subjects with resistant mutations NS5A Resistant Mutation | 2 Participants | 0 Participants | 2 Participants |
| Number of subjects with resistant mutations NS5B Resistant Mutation | 0 Participants | 0 Participants | 0 Participants |
| Number of subjects with Split Liver | 1 Participants | 2 Participants | 3 Participants |
| Percent of participants with Previous Interferon use Previous Interferon use | 38 % | 50 % | 14 % |
| Percent of participants with Previous Interferon use Stopped interferon prematurely | 67 % | 100 % | 12 % |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 14 Participants | 23 Participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 22 Participants |
| Type of HCV Genotype Genotype 1a | 13 Participants | 14 Participants | 27 Participants |
| Type of HCV Genotype Genotype 1b | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 16 | 0 / 16 |
| other Total, other adverse events | 11 / 16 | 16 / 16 |
| serious Total, serious adverse events | 4 / 16 | 12 / 16 |
Outcome results
Primary
Treatment Efficacy
Treatment efficacy, defined as the percentage of patients achieving sustained virologic response 12 (SVR12) weeks after completing the antiviral regimen
Time frame: 12 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Late Cohort, Arm 1 | Treatment Efficacy | 88 % of participants |
| Late Cohort, Arm 2 | Treatment Efficacy | 75 % of participants |
Secondary
Hemoglobin Levels
Change in hemoglobin levels over the course of the study
Time frame: Week 4, Week 8, Week 12, Week 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Late Cohort, Arm 1 | Hemoglobin Levels | Hemoglobin levels at Week 4 | 13.1 g/dL | Standard Deviation 2.3 |
| Late Cohort, Arm 1 | Hemoglobin Levels | Hemoglobin levels at Week 8 | 13.3 g/dL | Standard Deviation 1.7 |
| Late Cohort, Arm 1 | Hemoglobin Levels | Hemoglobin levels at Week 12 | 13.7 g/dL | Standard Deviation 1.9 |
| Late Cohort, Arm 1 | Hemoglobin Levels | Hemoglobin levels at Week 16 | 13.6 g/dL | Standard Deviation 1.9 |
| Late Cohort, Arm 2 | Hemoglobin Levels | Hemoglobin levels at Week 16 | 13.1 g/dL | Standard Deviation 1.9 |
| Late Cohort, Arm 2 | Hemoglobin Levels | Hemoglobin levels at Week 4 | 12.9 g/dL | Standard Deviation 1.5 |
| Late Cohort, Arm 2 | Hemoglobin Levels | Hemoglobin levels at Week 12 | 12.0 g/dL | Standard Deviation 2.3 |
| Late Cohort, Arm 2 | Hemoglobin Levels | Hemoglobin levels at Week 8 | 11.2 g/dL | Standard Deviation 1.7 |
Secondary
Number of Participants With Virologic Failure
Number of participants who had a nonresponse to treatment or a relapse of disease under study.
Time frame: 12 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Late Cohort, Arm 1 | Number of Participants With Virologic Failure | Nonresponse | 0 Participants |
| Late Cohort, Arm 1 | Number of Participants With Virologic Failure | Relapse | 1 Participants |
| Late Cohort, Arm 2 | Number of Participants With Virologic Failure | Nonresponse | 1 Participants |
| Late Cohort, Arm 2 | Number of Participants With Virologic Failure | Relapse | 2 Participants |