Liver Transplant Recipient
Conditions
Keywords
Liver transplantation, Everolimus, Calcineurin inhibitors, Tacrolimus, Renal function, Progression of HCV related allograft fibrosis
Brief summary
The reason for this extension is to evaluate the long-term safety and efficacy of two concentration-controlled everolimus regimen in de novo liver transplant recipients. The most important long-term safety assessments include evaluation of renal function, progression of HCV related allograft fibrosis, and other treatment related effects at Month 36 post-transplantation compared to extension baseline (Months 24 post-transplantation).
Interventions
After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization, a level which was maintained for the duration of the study.
Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL for the duration of the study.
After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization. Tacrolimus elimination was started beginning at Month 4. Tacrolimus was tapered after everolimus whole blood trough levels were within the target range of 6-10 ng/mL. Tacrolimus was completely eliminated by the end of Month 4.
Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL until Month 4; beginning with Month 4, the dose was adjusted to maintain everolimus trough blood levels between 6-10 ng/mL.
Tacrolimus trough levels were targeted to be maintained at 8-12 ng/mL until Month 4. At Month 4, tacrolimus whole blood trough levels were decreased to a target trough level of 6-10 ng/mL for the remainder of the study.
DRUGCorticosteroids
For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids could be used for the duration of the study but could not be eliminated before Month 6. The corticosteroids were not specified in the protocol because they were adminsitered to the participants according to local practice as part of standard of care.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Ability and willingness to adhere to study regimen * Completed core study with assigned regimen;
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study: * Severe hypercholesterolemia or hypertriglyceridemia. * Low platelet count. * Low white blood cell count. * Positive test for human immunodeficiency virus (HIV). * Systemic infection requiring active use of IV antibiotics. * Patients in a critical care setting. * Use of prohibited medication. * Use of immunosuppressive agents not utilized in the protocol. * Hypersensitivity to any of the study drugs or similar drugs. * Pregnant or nursing (lactating) women * Women of child-bearing potential not using a highly effective method of birth control. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death | from months 24 to 36 | The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died. |
| Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death | from months 24 to 36 | The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died. |
| Change in Renal Function | from months 24 to 36 | Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m\^2) = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of tBPAR | from months 24 - 36 | The number of participants who had a tBPAR was analyzed. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. |
Countries
Argentina, Australia, Belgium, Brazil, Colombia, Czechia, France, Germany, Ireland, Italy, Netherlands, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Two hundred eight four participants were eligible and enrolled into the extension. However, 2 participants withdrew from the extension prior to receiving treatment. Therefore, a total of 282 participants were accounted for in the extension.
Pre-assignment details
Participants in the tacrolimus control group were studied for 12 months (from months 24 to 36 post transplant). Participants in the tacrolimus elimination and everolimus + reduced tacrolimus groups were studied for a minimum of 12 months up to 24 months (from months 24 to 48 months post transplant) depending on the participant's study start.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus + Reduced Tacrolimus Participants were maintained on whole blood trough levels of 3 - 8 ng/mL everolimus and 3 - 5 ng/mL tacrolimus. | 106 |
| Tacrolimus Elimination Participants were maintained on a whole blood trough level of 6 - 10 ng/mL everolimus. | 51 |
| Tacrolimus Control Participants were maintained on a whole blood trough level of 6 - 10 ng/mL tacrolimus. | 125 |
| Total | 282 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Months 24 to 36 Post-transplantation | Administrative problems | 5 | 2 | 2 |
| Months 24 to 36 Post-transplantation | Death | 2 | 0 | 0 |
| Months 24 to 36 Post-transplantation | Lost to Follow-up | 0 | 0 | 3 |
| Months 24 to 36 Post-transplantation | Withdrawal by Subject | 3 | 0 | 3 |
| Months 24 to 48 Post-transplantation | Administrative problems | 5 | 4 | 0 |
| Months 24 to 48 Post-transplantation | Death | 2 | 0 | 0 |
| Months 24 to 48 Post-transplantation | Withdrawal by Subject | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | Everolimus + Reduced Tacrolimus | Tacrolimus Elimination | Tacrolimus Control | Total |
|---|---|---|---|---|
| Age, Continuous | 53.5 Years STANDARD_DEVIATION 9.57 | 54.9 Years STANDARD_DEVIATION 10.07 | 55.2 Years STANDARD_DEVIATION 8.1 | 54.5 Years STANDARD_DEVIATION 9.25 |
| Sex: Female, Male Female | 29 Participants | 18 Participants | 38 Participants | 85 Participants |
| Sex: Female, Male Male | 77 Participants | 33 Participants | 87 Participants | 197 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 38 / 106 | 29 / 51 | 43 / 125 | 43 / 106 | 36 / 51 |
| serious Total, serious adverse events | 32 / 106 | 16 / 51 | 28 / 125 | 34 / 106 | 24 / 51 |
Outcome results
Primary
Change in Renal Function
Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m\^2) = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1.
Time frame: from months 24 to 36
Population: The analysis population included extension participants who had both post-extension baseline and month 36 values only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus + Reduced Tacrolimus | Change in Renal Function | -0.9 mL/min/1.73m^2 | Standard Deviation 16.13 |
| Tacrolimus Elimination | Change in Renal Function | 2.5 mL/min/1.73m^2 | Standard Deviation 12.4 |
| Tacrolimus Control | Change in Renal Function | -3.3 mL/min/1.73m^2 | Standard Deviation 11.84 |
Primary
Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death
The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
Time frame: from months 24 to 36
Population: All extension participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Reduced Tacrolimus | Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death | 2 Participants |
| Tacrolimus Elimination | Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death | 0 Participants |
| Tacrolimus Control | Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death | 1 Participants |
Primary
Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death
The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
Time frame: from months 36 - 48
Population: Participants from the everolimus + reduced tacrolimus group and the tacrolimus elimination group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Reduced Tacrolimus | Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death | 0 Participants |
| Tacrolimus Elimination | Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death | 0 Participants |
Primary
Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death
The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
Time frame: from months 24 to 36
Population: All extension participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Reduced Tacrolimus | Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death | 2 Participants |
| Tacrolimus Elimination | Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death | 1 Participants |
| Tacrolimus Control | Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death | 3 Participants |
Primary
Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death
The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
Time frame: from months 36 to 48
Population: Participants from the everolimus + reduced tacrolimus group and the tacrolimus elimination group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Reduced Tacrolimus | Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death | 1 Participants |
| Tacrolimus Elimination | Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death | 0 Participants |
Secondary
Incidence Rate of tBPAR
The number of participants who had a tBPAR was analyzed. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection.
Time frame: from months 24 - 36
Population: All extension participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Reduced Tacrolimus | Incidence Rate of tBPAR | 0 Participants |
| Tacrolimus Elimination | Incidence Rate of tBPAR | 1 Participants |
| Tacrolimus Control | Incidence Rate of tBPAR | 2 Participants |