End Stage Renal Disease
Conditions
Keywords
end-stage renal disease
Brief summary
This study is being conducted to determine safety and effectiveness of transplanting kidneys from Hepatitis C-positive donors into Hepatitis C-negative patients on the kidney transplant waitlist, who will then be treated with the appropriate direct-acting antiviral (DAA) after the single kidney transplantation.
Detailed description
Open-labelled pilot clinical trial of Zepatier (Grazoprevir + Elbasvir), Mavyret (Glecaprevir + Pibrentasvir), Epclusa (Sofosbuvir + Velpatasvir), or another appropriate DAA in at least 75 HCV-negative subjects with end-stage renal disease receiving a kidney transplant from a HCV-positive donor. Eligible subjects will receive a kidney transplant from a deceased-donor, and then will receive DAA treatment after kidney transplantation when infection with HCV is confirmed in these kidney transplant recipients. Treatment will be complete after 12 weeks for most subjects.
Interventions
DRUGZepatier
Zepatier (grazoprevir 100mg and elbasvir 50 mg once daily) is taken by mouth for 12 weeks unless a genetic variation is detected. In this case treatment with Zepatier will be extended to 16 weeks. Study subjects with treatment failure will be provided open-label Zepatier + sofosbuvir (sovaldi) 400mg + Ribavirin (generic), renally dosed based on creatinine clearance per the manufacturer guidelines.
DRUGMavyret
Mavyret (glecaprevir 100 mg and pibrentasvir 40 mg) is taken by mouth for 8 weeks. Study subjects with treatment failure will be provided an alternative DAA + sofosbuvir (sovaldi) 400mg + Ribavirin (generic), renally dosed based on creatinine clearance per the manufacturer guidelines.
Sponsors
Merck Sharp & Dohme LLC
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Subject: Inclusion criteria * Must be waitlisted for a kidney transplant (dialysis is not a requirement if a patient is waitlisted) * Listed for an isolated kidney transplant with ≤2555 days of accrued transplant waiting time and/or ≤2555 days of dialysis time for blood group A, B, or O, by enrollment * Listed for an isolated kidney transplant with ≤1825 days of accrued transplant waiting time and/or ≤1825 days of dialysis time for blood group AB, by enrollment * No available living kidney donor * Between 30-70 years of age, by enrollment * Have a panel reactive antibody level ≤97% * eGFR \<15ml/min/1.73m2 as calculated using the 4 variable MDRD equation * Obtained agreement for participation from the patient's treating transplant nephrologist * Able to travel to the University of Pennsylvania for routine post-transplant visits and study visits for a minimum of 6 months after transplantation * No active illicit substance abuse * Weigh at least 50kg * Women must agree to use birth control in accordance with Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) following transplant due to the increased risk of birth defects and/or miscarriage * Both men and women must agree to use at least one barrier method to prevent any secretion exchange * Inclusion criteria for treatment (not for entry as study patient) will include any detectable HCV RNA * Able to provide informed consent
Exclusion criteria
* Hepatocellular carcinoma * Patients with primary focal segmental glomerulosclerosis (FSGS), FSGS recurring after previous transplant, or disease process with increased risk of causing early graft failure as per the treating nephrologist * HIV positive * HCV RNA positive (can be isolated HCV antibody positive provided the subject has no history of previously treated HCV) * Hepatitis B surface antigen positive * Any other chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD) with abnormal liver enzymes * Persistently elevated liver transaminases * Significant hepatic fibrosis on screening elastography (≥f2 fibrosis) * Pregnant or nursing (lactating) women * Known allergy or intolerance to tacrolimus that would require post-transplant administration of cyclosporine, rather than tacrolimus given the drug-drug interaction between cyclosporine and Zepatier * Waitlisted for a multi-organ transplant (e.g., pancreas-kidney, heart-kidney, etc.) * Significant cardiomyopathy defined as either: * Left ventricular ejection fraction \<40% on most recent echocardiogram * Left ventricular ejection fraction ≥40% but \<50% on most recent echocardiogram with an \<5 METS of exercise tolerance * Reversible ischemia on stress testing without revascularization Donor Organ Selection: Inclusion Criteria * Detectable HCV RNA * Age ≤60 years * Study modified Kidney donor profile index (KDPI) score ≤0.856 - calculated as if the kidney were HCV-negative (https://optn.transplant.hrsa.gov/resources/allocation-calculators/kdpi-calculator/)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Cured | Baseline to 24 weeks | Subjects with post-treatment sustained virologic response (SVR) = Number of subjects with negative HCV RNA 12 weeks after completing therapy / number of subjects treated post-kidney transplantation |
| Number of Subjects With SAE Attributable to HCV Therapy | Baseline to 52 weeks | Number of subjects with major adverse events attributable to HCV therapy in post-kidney transplant |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Direct-acting Antiviral Treatment for HCV Zepatier: Zepatier (grazoprevir 100mg and elbasvir 50 mg once daily) is taken by mouth for 12 weeks unless a genetic variation is detected. In this case treatment with Zepatier will be extended to 16 weeks. Study subjects with treatment failure will be provided open-label Zepatier + sofosbuvir (sovaldi) 400mg + Ribavirin (generic), renally dosed based on creatinine clearance per the manufacturer guidelines.
Mavyret: Mavyret (glecaprevir 100 mg and pibrentasvir 40 mg) is taken by mouth for 8 weeks. Study subjects with treatment failure will be provided an alternative DAA + sofosbuvir (sovaldi) 400mg + Ribavirin (generic), renally dosed based on creatinine clearance per the manufacturer guidelines. | 62 |
| Total | 62 |
Baseline characteristics
| Characteristic | Direct-acting Antiviral Treatment for HCV |
|---|---|
| Age, Customized | 57 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment United States | 62 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 62 |
| other Total, other adverse events | 0 / 62 |
| serious Total, serious adverse events | 2 / 62 |
Outcome results
Primary
Number of Subjects Cured
Subjects with post-treatment sustained virologic response (SVR) = Number of subjects with negative HCV RNA 12 weeks after completing therapy / number of subjects treated post-kidney transplantation
Time frame: Baseline to 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Direct-acting Antiviral Treatment for HCV | Number of Subjects Cured | 62 Participants |
Primary
Number of Subjects With SAE Attributable to HCV Therapy
Number of subjects with major adverse events attributable to HCV therapy in post-kidney transplant
Time frame: Baseline to 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Direct-acting Antiviral Treatment for HCV | Number of Subjects With SAE Attributable to HCV Therapy | 1 Participants |