Asses Immunosuppression Modulation on Renal Recovery Post LT
Conditions
Brief summary
This is a study to help understand how well new combinations of immunosuppressive medications (medications that weaken your immune system to prevent your body from rejecting the transplanted liver) work compared to standard immunosuppressive medications after your liver transplant. Also the study will assess how safe the new combination of immunosuppressive medicines are and if there are any changes in how your kidneys work after taking these medicines.
Detailed description
A single center, open label, randomized, prospective, pilot study of induction and maintenance immunosuppression in adult subjects \>18 years undergoing orthotopic liver transplantation (OLT) with Basiliximab, delayed dose tacrolimus plus mycophenolate mofetil and standard of care (SOC) corticosteroids (Group 1) versus basiliximab, delayed dose tacrolimus plus mycophenolate mofetil, SOC corticosteroids, with addition of delayed maintenance Everolimus at one month post OLT with subsequent mycophenolate mofetil minimization (Group 2) versus standard dose tacrolimus plus mycophenolate mofetil plus SOC corticosteroids (Group 3; control) with concomitant renal dysfunction prior to OLT.
Interventions
DRUGBasiliximab 20 MG
Basiliximab induction followed by tacrolimus, corticosteroids and mycophenolic acid with a switch to everolimus by post operative day 30
Sponsors
Fady M Kaldas, M.D., F.A.C.S.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
To assess the efficacy and safety of basiliximab, delayed dose tacrolimus plus mycophenolate mofetil, and SOC corticosteroids versus basiliximab, delayed dose tacrolimus plus mycophenolate mofetil, and SOC corticosteroids and addition of delayed everolimus/mycophenolate minimization at one month post OLT compared to standard triple immunosuppression (tacrolimus, mycophenolate mofetil and corticosteroids) for prevention of acute organ rejection in liver transplant recipients with a high risk of developing renal dysfunction following OLT or with concomitant renal dysfunction prior to OLT.
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
Inclusion criteria
* Patients eligible for inclusion in this study have to fulfill all of the following criteria: 1. A signed informed consent prior to patient participation in the study and before any assessment is performed. 2. Patients who are able to take oral medication. 3. 18 years old 4. Undergoing first OLT 5. Dialysis for 45 days or less at time of transplant 6. Able and willing to conform to requirements of the study 7. Able and willing to provide informed consent
Exclusion criteria
<!-- --> 1. \< 18 years old 2. Autoimmune liver disease, Primary Sclerosing Cholangitis, Primary Biliary Cirrhosis 3. Dialysis greater than 45 days 4. Receiving ATG, IVIG therapy, or sirolimus/everolimus around time of transplant or sirolimus/everolimus after transplant 5. Unable to take oral medications 6. Participating in another clinical research study involving the evaluation of another investigational drug or device 7. Documented allergy to basiliximab, TAC, MMF or any macrolide antibiotic. 8. Presence of thrombosis of any major hepatic arteries 9. Complex/high risk arterial reconstruction at any time (graft vessel patency by Doppler ultrasound confirmed and documented). 10. Patients who are recipients of multiple solid organ transplants, (e.g., multivisceral or combined liver-kidney transplants), or have previously received an organ or tissue transplanted, or who received an ABO incompatible transplant. 11. Patients who have severe hypercholesterolemia (\>215 mg/dL; \>5.5 mmol/L) or hypertriglyceridemia (\>265 mg/dL; \>3.0 mmol/L) at Baseline. 12. Patients who have severe thrombocytopenia or neutropenia (platelet count \>20 and MLCs\>1000) 13. Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study drugs 14. Patients with a known hypersensitivity to the drugs used on study or their class, or to any of the excipients. 15. Patients with clinically significant systemic infection 16. Pregnant or nursing (lactating) female patients, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive βHCG laboratory test (\>9 mIU/mL) at Baseline.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants Who Have Recovered Renal Function | 6 months | Assessment of dialysis independence (patients no longer requiring dialysis post LT) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Allograft Rejection | 6 months | Liver biopsy-proven rejection |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Basiliximab With Delayed TAC Basiliximab
* Dose #1: 20mg IV within 2 hours of transplant
* Dose #2: 20mg IV Post-operative day #4
Tacrolimus (with basiliximab induction) o Beginning day #5 post-transplant or when SCr \< 1.8 mg/dl (subjects off dialysis) to six months: 0.03-0.1mg/kg q12h PO to maintain whole blood trough concentration of 4-6ng/mL
Mycophenolate mofetil
o 1000 mg po bid
Corticosteroids (SOC): Per UCLA protocol
Post-operative taper:
* Post-op day 1- methylprednisolone 50mg IVP Q6H
* Post-op day 2- methylprednisolone 40mg IVP Q6H
* Post-op day 3- methylprednisolone 30mg IVP Q6H
* Post-op day 4- methylprednisolone 20mg IVP Q6H
* Post-op day 5- methylprednisolone 20mg IVP Q12H
* Post-op day 6- methylprednisolone 10mg IVP Q12H until taking PO, then change to: prednisone 20mg PO QAM
Basiliximab 20 MG: Basiliximab induction followed by tacrolimus, corticosteroids and mycophenolic acid with a switch to everolimus by post operative day 30 | 30 |
| Basliximab, Delayed TAC With Everolimus Basiliximab
Tacrolimus (with basiliximab induction)
o Beginning day #5 post-transplant or when SCr \< 1.8 mg/dl (subjects off dialysis) to POD 30: 0.03-0.1mg/kg q12h PO to maintain whole blood trough concentration of 4-6ng/mL
Mycophenolate mofetil o 1000 mg po bid up to POD 30: reduce mycophenolate mofetil following achievement of steady state everolimus (POD 35) as clinically indicated
Corticosteroids (SOC): Per UCLA protocol
Everolimus (delayed)
o Add by POD 30: 1 mg po bid and adjusted to maintain whole blood trough concentrations of 3-8 ng/ml.
Basiliximab 20 MG: Basiliximab induction followed by tacrolimus, corticosteroids and mycophenolic acid with a switch to everolimus by post operative day 30 | 28 |
| Control: Standard TAC With Steroids and MMF Tacrolimus (without basiliximab induction)
* Beginning day #1 post-transplant to six months: 0.03-0.1mg/kg q12h po to maintain whole blood trough concentration of 5-12ng/mL
* Six months to one year: maintain whole blood trough concentration of 5-10ng/mL
Mycophenolate mofetil
o 1000 mg po bid
Corticosteroids (SOC): Per UCLA protocol | 13 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 0 |
| Overall Study | Death | 2 | 1 | 2 |
| Overall Study | Disenrolled due to noncompliance | 0 | 1 | 0 |
| Overall Study | everolimus not started due to bile duct injury | 0 | 1 | 0 |
| Overall Study | stopped due to possible operation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Basiliximab With Delayed TAC | Basliximab, Delayed TAC With Everolimus | Control: Standard TAC With Steroids and MMF | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 5 Participants | 3 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 23 Participants | 10 Participants | 55 Participants |
| Age, Continuous | 55 years | 55 years | 59 years | 56 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 18 Participants | 7 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 10 Participants | 6 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized African American | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Caucasian | 5 Participants | 7 Participants | 2 Participants | 14 Participants |
| Race/Ethnicity, Customized More than 1 race | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other race | 20 Participants | 18 Participants | 8 Participants | 46 Participants |
| Region of Enrollment United States | 30 participants | 28 participants | 13 participants | 71 participants |
| Sex: Female, Male Female | 13 Participants | 13 Participants | 6 Participants | 32 Participants |
| Sex: Female, Male Male | 17 Participants | 15 Participants | 7 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 30 | 1 / 28 | 2 / 13 |
| other Total, other adverse events | 14 / 30 | 18 / 28 | 8 / 13 |
| serious Total, serious adverse events | 14 / 30 | 7 / 28 | 1 / 13 |
Outcome results
Primary
Participants Who Have Recovered Renal Function
Assessment of dialysis independence (patients no longer requiring dialysis post LT)
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Basiliximab With Delayed TAC | Participants Who Have Recovered Renal Function | 28 Participants |
| Basliximab, Delayed TAC With Everolimus | Participants Who Have Recovered Renal Function | 20 Participants |
| Control: Standard TAC With Steroids and MMF | Participants Who Have Recovered Renal Function | 11 Participants |
Other Pre-specified
Cumulative Allograft Rejection
Liver biopsy-proven rejection
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Basiliximab With Delayed TAC | Cumulative Allograft Rejection | 2 Participants |
| Basliximab, Delayed TAC With Everolimus | Cumulative Allograft Rejection | 3 Participants |
| Control: Standard TAC With Steroids and MMF | Cumulative Allograft Rejection | 2 Participants |