Liver Transplantation
Conditions
Keywords
Liver transplantation, everolimus, calcineurin inhibitor, renal function
Brief summary
The purpose of the study is to assess the effect of everolimus initiation together with reduction or discontinuation of calcineurin inhibitor (CNI) on renal function in maintenance liver transplant recipients with CNI-related renal impairment, while maintaining efficacy.
Interventions
DRUGEverolimus
1.5 mg bid adjusted in order to achieve a trough level between 3 and 8 ng/mL while in combination with CNI and between 6 and 12 ng/mL after CNI discontinuation
DRUGMycophenolate acid (MPA)/ Azathioprine (AZA)
DRUGSteroids
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Inclusion criteria
* Male or female 18 - 70 years old * Patient who has undergone a primary liver transplantation 12 to 60 months ago from a cadaveric or a living donor * Patient with a calculated GFR ≤ 60 and ≥ 20mL/min * Patient receiving tacrolimus with C0-h level ≥ 3 and ≤ 8 ng/mL or Neoral® with C0-h level ≥ 50 and ≤ 150 ng/mL or with C2-h level ≥ 250 ng/mL and ≤ 650 ng/mL with or without any of the following (MPA or AZA or steroids) * Patient willing and capable of giving written informed consent for study participation and able to participate in the study for 6 months * Patient in whom an allograft biopsy will not be contraindicated * Female capable of becoming pregnant must have a negative pregnancy test prior to randomization and are required to practice a medically approved method of birth control for the duration of the study
Exclusion criteria
* Recipient of multiple solid organ transplants * Patient on dialysis * Patient with an identifiable cause of renal dysfunction other than CNI toxicity * Patient with proteinuria ≥ 1.0 g/24h * Patient with any acute rejection within 6 months prior to randomization * Patient with platelet count of ≤ 50,000/mm³ or white blood cell count of ≤ 2,000/mm³ or hemoglobin value ≤ 8 g/dL * Undergone a liver transplantation for a hepatocellular carcinoma with sign of recurrence; * Severe graft dysfunction; * HCV positive patient who needs an active anti-viral treatment * HIV positive patient * Patient who is breast feeding * Patient with a current severe systemic infection * Patient who has received an unlicensed drug or therapy within one month prior to study entry * Presence of any hypersensitivity to drugs similar to everolimus (e.g. macrolides) * Use of any other immunosuppressive drugs than tacrolimus/cyclosporine microemulsion, steroids, azathioprine and mycophenolic acid Additional protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Cockcroft-Gault Calculated Creatinine Clearance (CrCl) | From baseline to 6 months | The primary variable was renal function assessed by calculated creatinine clearance using the Cockcroft-Gault formula, and was assessed at all visits. CrCl\[mL/min\] = (140 - A) \* W / (72 \* C) \* R. Where A is age at sample date \[years\], W is body weight at specific visit \[kg\], C is the serum concentration of creatinine \[mg/dL\], R = 1 if the patient is male and = 0.85 if female. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | 6 months | The composite efficacy failure endpoint encompasses at least one of: biopsy proven acute rejection, graft loss, or death for the patient. BPAR was defined as a clinically suspected acute rejection confirmed by biopsy. Acute rejection episodes were recorded as Liver Allograft Rejection. The allograft was presumed to be lost if a patient had a liver retransplant or died. |
| Number of Patients With Discontinuation of Study Medication | 6 months | — |
Countries
Germany, Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 (Everolimus) Reduced or discontinued CNI dose + everolimus (3-12 ng/mL) ± steroids | 72 |
| Group 2 (Control) Standard CNI dose ± mycophenolate acid (MPA)/azathioprine (AZA) ± steroids | 73 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Missing | 3 | 0 |
| Overall Study | Patient withdrew consent | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Group 1 (Everolimus) | Group 2 (Control) |
|---|---|---|---|
| Age Continuous | 57.4 Years STANDARD_DEVIATION 7.7 | 57.0 Years STANDARD_DEVIATION 8.45 | 57.8 Years STANDARD_DEVIATION 6.93 |
| Age, Customized >= 40 - < 50 years | 19 Paricipants | 12 Paricipants | 7 Paricipants |
| Age, Customized < 40 years | 3 Paricipants | 1 Paricipants | 2 Paricipants |
| Age, Customized >= 50 - < 60 years | 62 Paricipants | 29 Paricipants | 33 Paricipants |
| Age, Customized >= 60 years | 61 Paricipants | 30 Paricipants | 31 Paricipants |
| Sex: Female, Male Female | 60 Participants | 27 Participants | 33 Participants |
| Sex: Female, Male Male | 85 Participants | 45 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 58 / 72 | 31 / 73 |
| serious Total, serious adverse events | 18 / 72 | 14 / 73 |
Outcome results
Primary
Mean Change From Baseline in Cockcroft-Gault Calculated Creatinine Clearance (CrCl)
The primary variable was renal function assessed by calculated creatinine clearance using the Cockcroft-Gault formula, and was assessed at all visits. CrCl\[mL/min\] = (140 - A) \* W / (72 \* C) \* R. Where A is age at sample date \[years\], W is body weight at specific visit \[kg\], C is the serum concentration of creatinine \[mg/dL\], R = 1 if the patient is male and = 0.85 if female.
Time frame: From baseline to 6 months
Population: Intention to treat (ITT) population includes all patients who were randomized to one of the treatment groups and received at least one dose of study medication. Patients with baseline and 6 month creatinine clearance were included in analysis. Missing values at 6 months were imputed using the last observation carried forward (LOCF) approach.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 (Everolimus) | Mean Change From Baseline in Cockcroft-Gault Calculated Creatinine Clearance (CrCl) | 0.99 mL/min | Standard Deviation 10.25 |
| Group 2 (Control) | Mean Change From Baseline in Cockcroft-Gault Calculated Creatinine Clearance (CrCl) | 2.26 mL/min | Standard Deviation 7.79 |
Secondary
Number of Patients With Discontinuation of Study Medication
Time frame: 6 months
Population: Intention to treat (ITT) population includes all patients who were randomized to one of the treatment groups and received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 (Everolimus) | Number of Patients With Discontinuation of Study Medication | Adverse Event | 14 Patients |
| Group 1 (Everolimus) | Number of Patients With Discontinuation of Study Medication | Abnormal laboratory value(s) | 1 Patients |
| Group 1 (Everolimus) | Number of Patients With Discontinuation of Study Medication | Patient withdrew consent | 2 Patients |
| Group 1 (Everolimus) | Number of Patients With Discontinuation of Study Medication | Administrative problems | 1 Patients |
| Group 1 (Everolimus) | Number of Patients With Discontinuation of Study Medication | Total # of discontinuation of study medication | 18 Patients |
| Group 2 (Control) | Number of Patients With Discontinuation of Study Medication | Administrative problems | 0 Patients |
| Group 2 (Control) | Number of Patients With Discontinuation of Study Medication | Total # of discontinuation of study medication | 1 Patients |
| Group 2 (Control) | Number of Patients With Discontinuation of Study Medication | Adverse Event | 0 Patients |
| Group 2 (Control) | Number of Patients With Discontinuation of Study Medication | Patient withdrew consent | 1 Patients |
| Group 2 (Control) | Number of Patients With Discontinuation of Study Medication | Abnormal laboratory value(s) | 0 Patients |
Secondary
Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death)
The composite efficacy failure endpoint encompasses at least one of: biopsy proven acute rejection, graft loss, or death for the patient. BPAR was defined as a clinically suspected acute rejection confirmed by biopsy. Acute rejection episodes were recorded as Liver Allograft Rejection. The allograft was presumed to be lost if a patient had a liver retransplant or died.
Time frame: 6 months
Population: Intention to treat (ITT) population includes all patients who were randomized to one of the treatment groups and received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 (Everolimus) | Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | Composite efficacy failure (total) | 2.8 Percentage of patients |
| Group 1 (Everolimus) | Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | Biopsy proven acute rejection | 1.4 Percentage of patients |
| Group 1 (Everolimus) | Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | Graft Loss | 0 Percentage of patients |
| Group 1 (Everolimus) | Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | Death | 1.4 Percentage of patients |
| Group 2 (Control) | Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | Death | 0 Percentage of patients |
| Group 2 (Control) | Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | Composite efficacy failure (total) | 1.4 Percentage of patients |
| Group 2 (Control) | Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | Graft Loss | 0 Percentage of patients |
| Group 2 (Control) | Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | Biopsy proven acute rejection | 1.4 Percentage of patients |