Liver Transplantation
Conditions
Keywords
liver transplantation, everolimus, tacrolimus, reduced calcineuron inhibitor, renal function, living donor, RAD001H2307, RAD001H
Brief summary
The purpose of this trial was to demonstrate the efficacy and safety of everolimus in combination with reduced tacrolimus, compared to tacrolimus control, in living donor liver transplant recipients.
Detailed description
This study was 24 month, multicenter study in 280 living donor liver transplant patients from Asia, Europe and Canada. The study has an long term extension in Japan and approximately 28 patients were to be included to evaluate the long-term efficacy and safety of concentration-controlled everolimus regimen plus reduced tacrolimus compared to standard tacrolimus in recipients of living donor liver transplants in Japan who participated in the CRAD001H2307 study. Data reported here are the CRAD001H2307 core study results and its extension (CRAD001H2307E1).
Interventions
DRUGEverolimus + reduced tacrolimus
Everolimus was initiated at Week 4 post transplantation. The dose was adjusted to maintain the everolimus trough blood levels between 3-8 ng/mL for the duration of the study. Tacrolimus was reduced to 3-5 ng/mL.
Tacrolimus was initiated as soon as possible after transplantation according to approved labeling recommendations. The trough level should've been 5-15 ng/mL until randomization, 8-12 ng/mL from randomization until month 4 and after month 4 until end of study reduced to 6 -10 ng/mL.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Caregiver)
Intervention model description
This was a 24-month, multicenter, open-label, randomized, controlled study. It included the extension to the 24-month, randomized, controlled, open-label CRAD001H2307 study in recipients of living donor liver transplants in Japan.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Subject aged ≥18 years of a primary, orthotopic liver allograft, from a living donor * Subject negative for HIV Incusion criteria at Randomization: \- Subject was initated on tacrolimus-based immunosuppressive regimen with steroids and other immunosuppression
Exclusion criteria
* Subjects transplanted for acute liver failure * HCV negativesubjects receiving a transplant from HCV positive donor * Subjects receiving multiple solid organ (including multiple liver lobes/segments) or islet cell tissue transplants, or have previously received an organ or tissue transplant. * Subjects receiving an ABO incompatible allograft. * MELD-score \> 35 within 1 month prior to transplantation. * Use of immunosuppressive or antibody induction agents not specified in the protocol. * History of malignancy of any organ system (except hepatocellular carcinoma or localized basal cell carcinoma of the skin) * Hepatocellular carcinoma with extrahepatic spread or macrovascular invasion * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 2 weeks after the last dose of study medication * History of hypersensitivity to any of the study drugs or to drugs with similar chemical class, or to any of the excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Composite Efficacy Failure of Treated Biopsy Proven Acute Rejection, Graft Loss or Death in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus | 12 months post transplantation | Rate of composite efficacy failure of treated biopsy proven acute rejection (tBPAR ≥ RAI score 3), graft loss (GL) or death (D) in everolimus with reduced tacrolimus group compared to standard tacrolimus at 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization | From randomziation to month 24 | Change in renal function from randomization to month 24 assessed by the change in estimated GFR (MDRD-4). Rate of change of renal function. |
| Number of Participants With Composite of tBPAR, Graft Loss, and Death | Month 24 post transplantation | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of tBPAR, graft loss, death |
| Compare Incidence of tBPAR | Month 12 and Month 24 post transplantation | Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of tBPAR |
| Compare Incidence of BPAR | Month 12 and Month 24 post transplantation | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of biopsy proven acute rejection (BPAR) |
| Compare Incidence of Graft Loss | Month 12 and Month 24 post transplantation | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of graft loss |
| Compare Incidence of a Composite of Death or Graft Loss | Month 12 and Month 24 post transplantation | Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of a composite of death or graft loss |
| Compare Incidence of Death | Month 12 and Month 24 post transplantation | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of death |
| Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization | From randomization to month 12 | Renal function (change in estimated glomerular filtration rate (eGFR)) from randomization to Month 12 post transplantation with everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared to standard exposure tacrolimus (TAC) in living donor liver transplant recipients. |
| Compare Incidence of tAR | Month 12 and Month 24 post transplantation | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of treated acute rejection (tAR). |
| Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation | Month 12 and Month 24 | Patients transplanted for HCC or with HCC diagnosed at time of transplantation were monitored for HCC recurrence according to local practice. For example routine laboratory monitoring/tests, tumor markers, hepatic ultrasound, computed tomography scans (CAT, CT) or MRI (especially Fe-MRI) on a regular basis per local practice. |
| Number of Subjects Experiencing Adverse Events/Infections by SOC | Month 24 | — |
| Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | Month 24 | Notable events include death, Serious AE/infection,, and AE/infection leading to discontinuation of study medication. |
| Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | randomization, 36 months post transplantion | Rate of composite efficacy failure of treated biopsy in everolimus with reduced tacrolimus group compared to standard tacrolimus from randomization in core study up to 36 months in the extension study. Composite endpoint = treated BPAR, graft loss or death. AR = Acute rejection; tAR = treated AR; BPR = biopsy proven rejection; BPAR = biopsy proven acute rejection; tBPAR = treated BPAR |
| Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients) | randomization, at 36 months post transplantation | Renal function (change in estimated glomerular filtration rate (eGFR)) from randomization to Month 36 post transplantation with everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared to standard exposure tacrolimus (TAC) in living donor liver transplant recipients in Japan |
| Compare Incidence of AR | Month 12 and Month 24 post transplantation | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of acute rejection (AR) |
Countries
Canada, Egypt, Germany, India, Italy, Japan, Russia, Saudi Arabia, Singapore, South Korea, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
In all, 284 patients were randomized after transplantation to EVR+Reduced TAC group and TAC Control group. Two patients were not eligible and randomized in IRT by mistake and to whom no study medication was given, and so did not have their data included.
Pre-assignment details
A total of 494 patients were screened. Of these, 448 patients received a liver transplant and entered the run-in period.
Participants by arm
| Arm | Count |
|---|---|
| EVR+Reduced TAC Everolimus + reduced tacrolimus ± corticosteroids | 142 |
| TAC Control Standard tacrolimus ± corticosteroids | 142 |
| Total | 284 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 12-month Analysis (FAS) | Death | 4 | 3 |
| 12-month Analysis (FAS) | Lost to Follow-up | 0 | 2 |
| 12-month Analysis (FAS) | Physician Decision | 1 | 1 |
| 12-month Analysis (FAS) | Withdrawal by Subject | 6 | 3 |
| 24-month Analysis (FAS) | Death | 8 | 4 |
| 24-month Analysis (FAS) | Graft loss | 0 | 1 |
| 24-month Analysis (FAS) | Lost to Follow-up | 0 | 2 |
| 24-month Analysis (FAS) | Physician Decision | 2 | 4 |
| 24-month Analysis (FAS) | Withdrawal by Subject | 7 | 6 |
| 36-month Analysis (Extension) | Death | 1 | 0 |
Baseline characteristics
| Characteristic | EVR+Reduced TAC | TAC Control | Total |
|---|---|---|---|
| Age, Continuous | 54.2 Years STANDARD_DEVIATION 8.95 | 52.7 Years STANDARD_DEVIATION 10.41 | 53.5 Years STANDARD_DEVIATION 9.72 |
| Race/Ethnicity, Customized Asian | 111 Participants | 112 Participants | 223 Participants |
| Race/Ethnicity, Customized Caucasian | 30 Participants | 30 Participants | 60 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 38 Participants | 43 Participants | 81 Participants |
| Sex: Female, Male Male | 104 Participants | 99 Participants | 203 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 142 | 4 / 141 | 1 / 13 | 0 / 5 |
| other Total, other adverse events | 127 / 142 | 122 / 141 | 13 / 13 | 4 / 5 |
| serious Total, serious adverse events | 83 / 142 | 78 / 141 | 5 / 13 | 0 / 5 |
Outcome results
Primary
Number of Participants With Composite Efficacy Failure of Treated Biopsy Proven Acute Rejection, Graft Loss or Death in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus
Rate of composite efficacy failure of treated biopsy proven acute rejection (tBPAR ≥ RAI score 3), graft loss (GL) or death (D) in everolimus with reduced tacrolimus group compared to standard tacrolimus at 12 months
Time frame: 12 months post transplantation
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EVR+Reduced TAC | Number of Participants With Composite Efficacy Failure of Treated Biopsy Proven Acute Rejection, Graft Loss or Death in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus | 7 Participants |
| TAC Control | Number of Participants With Composite Efficacy Failure of Treated Biopsy Proven Acute Rejection, Graft Loss or Death in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus | 8 Participants |
Comparison: non-inferior efficacy failure of the reduced tacrolimus regimen to control by rejecting the null hypothesis.p-value: <0.00190% CI: [-5.2, 3.7]Z-test
Secondary
Compare Incidence of a Composite of Death or Graft Loss
Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of a composite of death or graft loss
Time frame: Month 12 and Month 24 post transplantation
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Compare Incidence of a Composite of Death or Graft Loss | Month 12 | 4 Participants |
| EVR+Reduced TAC | Compare Incidence of a Composite of Death or Graft Loss | Month 24 | 8 Participants |
| TAC Control | Compare Incidence of a Composite of Death or Graft Loss | Month 12 | 3 Participants |
| TAC Control | Compare Incidence of a Composite of Death or Graft Loss | Month 24 | 5 Participants |
90% CI: [-2.5, 3.8]
90% CI: [-2.1, 6.6]
Secondary
Compare Incidence of AR
Compare between the treatment group EVR with rTAC vs standard TAC: incidence of acute rejection (AR)
Time frame: Month 12 and Month 24 post transplantation
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Compare Incidence of AR | Month 12 | 9 Participants |
| EVR+Reduced TAC | Compare Incidence of AR | Month 24 | 12 Participants |
| TAC Control | Compare Incidence of AR | Month 24 | 9 Participants |
| TAC Control | Compare Incidence of AR | Month 12 | 8 Participants |
90% CI: [-3.9, 5.3]
90% CI: [-3, 7.2]
Secondary
Compare Incidence of BPAR
Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of biopsy proven acute rejection (BPAR)
Time frame: Month 12 and Month 24 post transplantation
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Compare Incidence of BPAR | Month 12 | 7 Participants |
| EVR+Reduced TAC | Compare Incidence of BPAR | Month 24 | 8 Participants |
| TAC Control | Compare Incidence of BPAR | Month 12 | 6 Participants |
| TAC Control | Compare Incidence of BPAR | Month 24 | 7 Participants |
90% CI: [-3.4, 5.1]
90% CI: [-3.6, 5.6]
Secondary
Compare Incidence of Death
Compare between the treatment group EVR with rTAC vs standard TAC: incidence of death
Time frame: Month 12 and Month 24 post transplantation
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Compare Incidence of Death | Month 12 | 4 Participants |
| EVR+Reduced TAC | Compare Incidence of Death | Month 24 | 8 Participants |
| EVR+Reduced TAC | Compare Incidence of Death | Month 24 (on-treatment death) | 4 Participants |
| TAC Control | Compare Incidence of Death | Month 12 | 3 Participants |
| TAC Control | Compare Incidence of Death | Month 24 | 4 Participants |
| TAC Control | Compare Incidence of Death | Month 24 (on-treatment death) | 3 Participants |
90% CI: [-2.5, 3.8]
90% CI: [-1.1, 7.2]
90% CI: [-2.5, 3.9]
Secondary
Compare Incidence of Graft Loss
Compare between the treatment group EVR with rTAC vs standard TAC: incidence of graft loss
Time frame: Month 12 and Month 24 post transplantation
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Compare Incidence of Graft Loss | Month 12 | 0 Participants |
| EVR+Reduced TAC | Compare Incidence of Graft Loss | month 24 | 0 Participants |
| EVR+Reduced TAC | Compare Incidence of Graft Loss | month 24 (on-treatment graft loss) | 0 Participants |
| TAC Control | Compare Incidence of Graft Loss | Month 12 | 0 Participants |
| TAC Control | Compare Incidence of Graft Loss | month 24 | 1 Participants |
| TAC Control | Compare Incidence of Graft Loss | month 24 (on-treatment graft loss) | 0 Participants |
90% CI: [-2.1, 0.5]
Secondary
Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation)
Notable events include death, Serious AE/infection,, and AE/infection leading to discontinuation of study medication.
Time frame: Month 24
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | Death | 8 Participants |
| EVR+Reduced TAC | Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | Any notable events | 86 Participants |
| EVR+Reduced TAC | Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | Serious AE/Infection | 83 Participants |
| EVR+Reduced TAC | Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | AE/Infection lead. to premature disc of study med | 21 Participants |
| TAC Control | Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | AE/Infection lead. to premature disc of study med | 18 Participants |
| TAC Control | Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | Serious AE/Infection | 78 Participants |
| TAC Control | Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | Any notable events | 82 Participants |
| TAC Control | Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | Death | 4 Participants |
Secondary
Compare Incidence of tAR
Compare between the treatment group EVR with rTAC vs standard TAC: incidence of treated acute rejection (tAR).
Time frame: Month 12 and Month 24 post transplantation
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Compare Incidence of tAR | Month 12 | 5 Participants |
| EVR+Reduced TAC | Compare Incidence of tAR | Month 24 | 7 Participants |
| TAC Control | Compare Incidence of tAR | Month 12 | 6 Participants |
| TAC Control | Compare Incidence of tAR | Month 24 | 7 Participants |
90% CI: [-4.5, 3.1]
90% CI: [-4.2, 4.2]
Secondary
Compare Incidence of tBPAR
Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of tBPAR
Time frame: Month 12 and Month 24 post transplantation
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Compare Incidence of tBPAR | tBPAR - month 12 | 3 Participants |
| EVR+Reduced TAC | Compare Incidence of tBPAR | tBPAR - month 24 | 4 Participants |
| EVR+Reduced TAC | Compare Incidence of tBPAR | On-treatment tBPAR - month 24 | 3 Participants |
| TAC Control | Compare Incidence of tBPAR | tBPAR - month 12 | 5 Participants |
| TAC Control | Compare Incidence of tBPAR | tBPAR - month 24 | 6 Participants |
| TAC Control | Compare Incidence of tBPAR | On-treatment tBPAR - month 24 | 6 Participants |
90% CI: [-4.7, 2]
90% CI: [-5.1, 2.6]
90% CI: [-5.7, 1.4]
Secondary
Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization
Change in renal function from randomization to month 24 assessed by the change in estimated GFR (MDRD-4). Rate of change of renal function.
Time frame: From randomziation to month 24
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EVR+Reduced TAC | Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization | -11.01 mL/min/1.73 m2 | Standard Error 1.928 |
| TAC Control | Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization | -14.26 mL/min/1.73 m2 | Standard Error 1.914 |
p-value: <0.00190% CI: [-1.21, 7.7]ANCOVA
Secondary
Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only
Rate of composite efficacy failure of treated biopsy in everolimus with reduced tacrolimus group compared to standard tacrolimus from randomization in core study up to 36 months in the extension study. Composite endpoint = treated BPAR, graft loss or death. AR = Acute rejection; tAR = treated AR; BPR = biopsy proven rejection; BPAR = biopsy proven acute rejection; tBPAR = treated BPAR
Time frame: randomization, 36 months post transplantion
Population: All extension patients consisted of all patients enrolled into this extension study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Composite endpoint | 2 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | On-treatment composite endpoint | 1 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Graft loss/death | 1 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | tBPAR | 2 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Graft loss | 0 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Death | 1 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | AR | 3 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | tAR | 2 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | BPR | 6 Participants |
| EVR+Reduced TAC | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | BPAR | 3 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | tAR | 0 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Composite endpoint | 1 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Death | 0 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | On-treatment composite endpoint | 0 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | BPAR | 2 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Graft loss/death | 1 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | AR | 2 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | tBPAR | 0 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | BPR | 3 Participants |
| TAC Control | Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Graft loss | 1 Participants |
95% CI: [-19.9, 30.6]
95% CI: [-6, 19.3]
95% CI: [-24.6, 28.7]
95% CI: [-4.2, 33.1]
95% CI: [-9.4, 31.6]
95% CI: [-28.9, 35.2]
95% CI: [-4.2, 33.1]
95% CI: [-22.3, 52.1]
95% CI: [-28.9, 35.2]
Secondary
Number of Participants With Composite of tBPAR, Graft Loss, and Death
Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of tBPAR, graft loss, death
Time frame: Month 24 post transplantation
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Number of Participants With Composite of tBPAR, Graft Loss, and Death | tBPAR/graft loss/death | 12 Participants |
| EVR+Reduced TAC | Number of Participants With Composite of tBPAR, Graft Loss, and Death | On-treatment tBPAR/graft loss/death | 7 Participants |
| TAC Control | Number of Participants With Composite of tBPAR, Graft Loss, and Death | tBPAR/graft loss/death | 11 Participants |
| TAC Control | Number of Participants With Composite of tBPAR, Graft Loss, and Death | On-treatment tBPAR/graft loss/death | 9 Participants |
Secondary
Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation
Patients transplanted for HCC or with HCC diagnosed at time of transplantation were monitored for HCC recurrence according to local practice. For example routine laboratory monitoring/tests, tumor markers, hepatic ultrasound, computed tomography scans (CAT, CT) or MRI (especially Fe-MRI) on a regular basis per local practice.
Time frame: Month 12 and Month 24
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation | HCC recurrence (n/M) - month 12 | 0 Participants |
| EVR+Reduced TAC | Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation | HCC recurrence (n/M) - month 24 | 1 Participants |
| TAC Control | Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation | HCC recurrence (n/M) - month 12 | 5 Participants |
| TAC Control | Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation | HCC recurrence (n/M) - month 24 | 6 Participants |
Secondary
Number of Subjects Experiencing Adverse Events/Infections by SOC
Time frame: Month 24
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Cardiac disorders | 15 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Investigations | 61 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Gastrointestinal disorders | 98 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Metabolism and nutrition disorders | 87 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Ear and labyrinth disorders | 2 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Musculoskeletal and connective tissue disorders | 30 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | General disorders&admin site conditions | 48 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Neoplasms benign, malig&unspecified (cysts&polyps) | 10 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Blood and lymphatic system disorders | 44 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Nervous system disorders | 38 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Hepatobiliary disorders | 44 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Product issues# | 1 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Endocrine disorders | 1 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Psychiatric disorders | 33 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Immune system disorders | 8 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Renal and urinary disorders | 46 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Congenital, familial and genetic disorders | 1 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Reproductive system&breast dis. | 9 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Infections and infestations | 84 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Respiratory, thoracic&mediastinal dis. | 34 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Eye disorders | 17 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Skin&subcutaneous tissue disorders | 39 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Injury, poisoning&proced. complications | 36 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Vascular disorders | 38 Participants |
| EVR+Reduced TAC | Number of Subjects Experiencing Adverse Events/Infections by SOC | Any AE/infection | 140 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Vascular disorders | 30 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Any AE/infection | 136 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Blood and lymphatic system disorders | 32 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Cardiac disorders | 12 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Congenital, familial and genetic disorders | 2 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Ear and labyrinth disorders | 5 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Endocrine disorders | 2 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Eye disorders | 15 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Gastrointestinal disorders | 74 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | General disorders&admin site conditions | 42 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Hepatobiliary disorders | 40 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Immune system disorders | 11 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Infections and infestations | 70 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Injury, poisoning&proced. complications | 28 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Investigations | 68 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Metabolism and nutrition disorders | 60 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Musculoskeletal and connective tissue disorders | 43 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Neoplasms benign, malig&unspecified (cysts&polyps) | 17 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Nervous system disorders | 44 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Product issues# | 1 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Psychiatric disorders | 26 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Renal and urinary disorders | 36 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Reproductive system&breast dis. | 12 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Respiratory, thoracic&mediastinal dis. | 39 Participants |
| TAC Control | Number of Subjects Experiencing Adverse Events/Infections by SOC | Skin&subcutaneous tissue disorders | 44 Participants |
Secondary
Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients)
Renal function (change in estimated glomerular filtration rate (eGFR)) from randomization to Month 36 post transplantation with everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared to standard exposure tacrolimus (TAC) in living donor liver transplant recipients in Japan
Time frame: randomization, at 36 months post transplantation
Population: All extension patients consisted of all patients enrolled into this extension study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EVR+Reduced TAC | Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients) | -26.88 mL/min/1.73m2 | Standard Error 10.114 |
| TAC Control | Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients) | -16.87 mL/min/1.73m2 | Standard Error 19.412 |
95% CI: [-59.91, 39.89]
Secondary
Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization
Renal function (change in estimated glomerular filtration rate (eGFR)) from randomization to Month 12 post transplantation with everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared to standard exposure tacrolimus (TAC) in living donor liver transplant recipients.
Time frame: From randomization to month 12
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EVR+Reduced TAC | Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization | -7.94 mL/min/1.73 m^2 | Standard Error 1.839 |
| TAC Control | Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization | -12.09 mL/min/1.73 m^2 | Standard Error 1.824 |
p-value: <0.00190% CI: [-0.09, 8.4]ANCOVA