Liver Transplantation
Conditions
Keywords
liver transplantation, immunosuppression, everolimus, tacrolimus, kidney function, liver function, biomarkers
Brief summary
Most patients who get a liver transplant must take immunosuppressants for the rest of their lives. However, this has occurred at the expense of chronic CNI toxicity, e.g. chronic kidney disease (CKD), metabolic complications, infections and malignancy. Everolimus (EVL) is a drug that may stabilize or improve kidney function for patients with chronic kidney disease (CKD) that has been caused by immunosuppressants. EVL is used for standard of care treatment to prevent transplant liver rejection in combination with other immunosuppressants, such as tacrolimus. The overall aim of this study is to examine a combination of two different immunosuppressants and EVL to determine if patients may have stabilized and/or improved kidney function without liver rejection. This study will look at how safe it is to slowly withdraw one anti-rejection medication while continuing to take the other medicine, and whether this can be done without liver rejection occurrence.
Interventions
DRUGTacrolimus Withdrawal and Everolimus Monotherapy
During the first month post-transplant, the subject receives everolimus (about 5-8 ng/mL) and tacrolimus with or without mycophenolic acid as part of standard of care procedures. At one month post-transplant, mycophenolic acid will be stopped and tacrolimus dosage will be reduced while continuing the dosage of everolimus. At three months post-transplant, tacrolimus dosage will be reduced by 50% of the daily dose each week. At four months post-transplant, tacrolimus will be discontinued.
Sponsors
Novartis Pharmaceuticals
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* Adult LT candidates ≥ 18 years of age * Listed for or recent (within 1 month) recipient of deceased or living donor liver transplantation
Exclusion criteria
* Combined or previous organ transplantation * Human immunodeficiency virus (HIV) infection * Inability to provide informed consent or comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Amount of Treg Cells Observed in Peripheral Blood in Patients With and Without Rejection | Six months post transplantation | flow cytometry immunophenotyping and gene expression microassays to assess amount of Treg cells and mRNA in peripheral blood in patients with and without rejection (after Tacc withdrwal) |
Countries
United States
Participant flow
Recruitment details
From May 2016 to May 2018, 170 adult primary LT were performed at our center. 20 Subjects underwent tac (Tacrolimus)withdrwal. 28 patients consented but 8 were removed Final sample for analysis is n=20
Pre-assignment details
28 patients consented but 8 were removed (n=1 withdrew, n=2 non compliant with protocol, n=2 new wound issues, n=1 high urine protein/creatinine ration and n=2 had neutropenia) Final sample for analysis is n=20
Participants by arm
| Arm | Count |
|---|---|
| Graft Rejection After Tacrolimus Was Discontinued (REJ) Incidence of Acute Rejection after the initiation of Tacrolimus Withdrawl at Month 3 and 6 | 5 |
| No Graft Rejection After Tacrolimus Weaning (Non REJ) NON-REJ patients did not required liver biopsy during the trial | 15 |
| Withdrew From Study Before Tacrolimus Weaning These subjects were removed after consenting. These subjects were not initiated on TAC weaning | 8 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Non Compliant | 0 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Graft Rejection After Tacrolimus Was Discontinued (REJ) | No Graft Rejection After Tacrolimus Weaning (Non REJ) | Withdrew From Study Before Tacrolimus Weaning | Total |
|---|---|---|---|---|
| Age, Continuous | 67.4 years STANDARD_DEVIATION 4.2 | 58.8 years STANDARD_DEVIATION 6.8 | 56 years STANDARD_DEVIATION 10.1 | 61.1 years STANDARD_DEVIATION 7.1 |
| Everolimus Trough | 5.3 ng/ml STANDARD_DEVIATION 1.2 | 5.3 ng/ml STANDARD_DEVIATION 2.3 | — | 5.3 ng/ml STANDARD_DEVIATION 2.1 |
| Hepatocellular Carcinoma | 3 participants | 4 participants | — | 7 participants |
| Lab Value -Alk Phos | 95.2 u/l STANDARD_DEVIATION 47.7 | 69.9 u/l STANDARD_DEVIATION 24.6 | — | 75.9 u/l STANDARD_DEVIATION 32.1 |
| Lab Value -ALT | 28.2 u/l STANDARD_DEVIATION 6.3 | 19.1 u/l STANDARD_DEVIATION 7.3 | — | 21.3 u/l STANDARD_DEVIATION 8 |
| Lab Value -AST | 23.6 u/l STANDARD_DEVIATION 5.4 | 15.4 u/l STANDARD_DEVIATION 6.9 | — | 17.3 u/l STANDARD_DEVIATION 7.4 |
| Lab Value -eGFR-MDRD | 55.2 mL/min/1.73 m^2 STANDARD_DEVIATION 15.6 | 60.3 mL/min/1.73 m^2 STANDARD_DEVIATION 17.7 | — | 59 mL/min/1.73 m^2 STANDARD_DEVIATION 17 |
| Lab Value -Hb | 11.9 g/dl STANDARD_DEVIATION 1.1 | 10.7 g/dl STANDARD_DEVIATION 2.5 | — | 11 g/dl STANDARD_DEVIATION 2.3 |
| Lab Value -Platelet count | 144.6 1000 *cells*/mm^3 STANDARD_DEVIATION 47.6 | 111.9 1000 *cells*/mm^3 STANDARD_DEVIATION 59.2 | — | 119.7 1000 *cells*/mm^3 STANDARD_DEVIATION 57.3 |
| Lab Value -Total Bilirubin | 0.36 mg/dl STANDARD_DEVIATION 0.1 | 0.8 mg/dl STANDARD_DEVIATION 0.8 | — | 0.7 mg/dl STANDARD_DEVIATION 0.7 |
| Lab Value -White Blood Count | 5.6 1000 *cells*/mm^3 STANDARD_DEVIATION 1.9 | 3.7 1000 *cells*/mm^3 STANDARD_DEVIATION 1.7 | — | 4.2 1000 *cells*/mm^3 STANDARD_DEVIATION 1.9 |
| Primary Liver Disease- Alcohol | 1 participants | 5 participants | 0 participants | 6 participants |
| Primary Liver Disease- Hep C | 3 participants | 2 participants | 0 participants | 5 participants |
| Primary Liver Disease- Non Alcoholic Fatty Liver | 1 participants | 4 participants | 0 participants | 5 participants |
| Primary Liver Disease- Other | 0 participants | 4 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized Caucasian | 5 Participants | 15 Participants | 8 Participants | 28 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 10 Participants | 6 Participants | 20 Participants |
| Tacrolimus Trough | 5.4 ng/ml STANDARD_DEVIATION 0.8 | 5.2 ng/ml STANDARD_DEVIATION 1.4 | — | 5.2 ng/ml STANDARD_DEVIATION 1.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 15 | 0 / 8 |
| other Total, other adverse events | 0 / 5 | 0 / 15 | 0 / 8 |
| serious Total, serious adverse events | 0 / 5 | 0 / 15 | 0 / 8 |
Outcome results
Primary
Amount of Treg Cells Observed in Peripheral Blood in Patients With and Without Rejection
flow cytometry immunophenotyping and gene expression microassays to assess amount of Treg cells and mRNA in peripheral blood in patients with and without rejection (after Tacc withdrwal)
Time frame: Six months post transplantation
Population: 15 patients did not reject and 5 had mild rejection responding to tacrolimus resumption.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Graft Rejection After Tacrolimus Was Discontinued (REJ) | Amount of Treg Cells Observed in Peripheral Blood in Patients With and Without Rejection | 10 percentage of CD4 positive cell | Standard Deviation 1 |
| No Graft Rejection After Tacrolimus Weaning (Non REJ) | Amount of Treg Cells Observed in Peripheral Blood in Patients With and Without Rejection | 5 percentage of CD4 positive cell | Standard Deviation 0.2 |