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CompletedNCT01888432Updated Mar 18, 2019Results posted

Efficacy and Safety of Everolimus in Liver Transplant Recipients of Living Donor Liver Transplants

A Phase 3 interventional study of Everolimus + reduced tacrolimus and Standard tacrolimus in Liver Transplantation, sponsored by Novartis Pharmaceuticals. Completed at 42 sites in 13 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-03-18.

Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
285
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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.

Read the 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).

02

Conditions studied

  • Liver Transplantation

Keywords

  • liver transplantation
  • everolimus
  • tacrolimus
  • reduced calcineuron inhibitor
  • renal function
  • living donor
  • RAD001H2307
  • RAD001H
03

In context

Lead sponsor

Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.

Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

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

Exclusion criteria at Randomization:

  • Any post-transplant history of thrombosis, occlusion or stent placement in any major hepatic arteries, hepatic veins, portal vein or inferior vena cava at any time during the run-in period prior to randomization.
  • Subjects with a confirmed spot urine protein/creatinine ratio that indicates ≥ 1.0 g/24 hrs of proteinuria
  • Subjects who have severe hypercholesterolemia (>350 mg/dL; >9.1 mmol/L) or hypertriglyceridemia (>500 mg/dL; >5.6 mmol/L) at randomization.
  • Subjects with platelet count \< 30,000/mm3.
  • Subjects with an absolute neutrophil count of \< 1,000/mm³ or white blood cell count of \< 2,000/mm³.
  • Subjects with systemic infection requiring active use of IV antibiotics.
  • Subjects requiring life support measures such as ventilation, dialysis, vasopressor agents.
  • Subjects who require renal replacement therapy within 7 days prior to randomization.
  • Subjects with detectable HBV DNA at time of randomization

  • Subjects meeting the following criteria for acute rejection during the run in period:

    • Any acute rejection in the week prior to randomization.
    • 2 treated acute rejections.
    • Any rejection requiring antibody treatment.
    • Any severe cellular (and/or any humoral) rejection.

Long term extension for patients in Japan:

Inclusion criteria

  • Written informed consent must be obtained before any extension specific assessment is performed.
  • Ability and willingness to adhere to study regimen.
  • Completed Month 24 visit of core study and continuously being treated with assigned regimen.

Exclusion criteria:

  • Use of medication that is prohibited by the study protocol at Month 24.
  • 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.
  • History of hypersensitivity to any of the study drugs or to drugs with similar chemical class, or to any of the excipients
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Single (Care provider)
Enrollment
285 participants (actual)

Study arms

  • Experimental
    Everolimus + reduced tacrolimus

    Everolimus + reduced tacrolimus ± corticosteroids

    Drug: Everolimus + reduced tacrolimus

  • Active comparator
    Standard tacrolimus

    Standard tacrolimus ± corticosteroids

    Drug: Standard tacrolimus

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.

  • DrugStandard tacrolimus

    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.

06

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. Number of Subjects Experiencing Adverse Events/Infections by SOC

    Time frame: Month 24

  13. 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

  14. 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

  15. 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

07

Results

Posted Nov 13, 2018

Participant flow

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.

12-month Analysis (FAS)
Participant flow — 12-month Analysis (FAS)
MilestoneEVR+Reduced TACTAC Control
Started142142
Completed131133
Not completed119
Withdrew: Lost to follow-up02
Withdrew: Physician decision11
Withdrew: Withdrawal by subject63
Withdrew: Death43
24-month Analysis (FAS)
Participant flow — 24-month Analysis (FAS)
MilestoneEVR+Reduced TACTAC Control
Started142142
Completed125125
Not completed1717
Withdrew: Graft loss01
Withdrew: Lost to follow-up02
Withdrew: Physician decision24
Withdrew: Withdrawal by subject76
Withdrew: Death84
36-month Analysis (Extension)
Participant flow — 36-month Analysis (Extension)
MilestoneEVR+Reduced TACTAC Control
Started135
Completed125
Not completed10
Withdrew: Death10

Outcome measures

PrimaryNumber 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
Reported as:
Count of participants · Participants
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
ParticipantsEVR+Reduced TACTAC 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 Tacrolimus78
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Z-test · p = < 0.001 (Z-test p-value for non-inferiority test (non-inferiority margin = 12%) is for one-sided test and should be compared to 0.05 significance level.) · Kaplan-meier: -0.7 · 90% CI -5.2 to 3.7
SecondaryRenal 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
Reported as:
Least squares mean · mL/min/1.73 m^2
Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization
mL/min/1.73 m^2EVR+Reduced TACTAC Control
Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization-7.94 ± 1.839-12.09 ± 1.824
Statistical analysis
  • EVR+Reduced TAC · ANCOVA · p = < 0.001 · Mean difference (net): 4.15 · 90% CI -0.09 to 8.40
SecondaryCompare 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
Reported as:
Least squares mean · mL/min/1.73 m2
Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization
mL/min/1.73 m2EVR+Reduced TACTAC Control
Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization-11.01 ± 1.928-14.26 ± 1.914
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · ANCOVA · p = <0.001 · Mean difference (final values): 3.25 · 90% CI -1.21 to 7.70
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Composite of tBPAR, Graft Loss, and Death
ParticipantsEVR+Reduced TACTAC Control
tBPAR/graft loss/death1211
On-treatment tBPAR/graft loss/death79
SecondaryCompare 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
Reported as:
Count of participants · Participants
Compare Incidence of tBPAR
ParticipantsEVR+Reduced TACTAC Control
tBPAR - month 1235
tBPAR - month 2446
On-treatment tBPAR - month 2436
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: -1.4 · 90% CI -4.7 to 2.0KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: -1.2 · 90% CI -5.1 to 2.6KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: -2.1 · 90% CI -5.7 to 1.4KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
SecondaryCompare 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
Reported as:
Count of participants · Participants
Compare Incidence of BPAR
ParticipantsEVR+Reduced TACTAC Control
Month 1276
Month 2487
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: 0.9 · 90% CI -3.4 to 5.1KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: 1.0 · 90% CI -3.6 to 5.6KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
SecondaryCompare 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
Reported as:
Count of participants · Participants
Compare Incidence of Graft Loss
ParticipantsEVR+Reduced TACTAC Control
Month 1200
month 2401
month 24 (on-treatment graft loss)00
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: -0.8 · 90% CI -2.1 to 0.5KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
SecondaryCompare 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
Reported as:
Count of participants · Participants
Compare Incidence of a Composite of Death or Graft Loss
ParticipantsEVR+Reduced TACTAC Control
Month 1243
Month 2485
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: 0.7 · 90% CI -2.5 to 3.8KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: 2.3 · 90% CI -2.1 to 6.6KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
SecondaryCompare 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
Reported as:
Count of participants · Participants
Compare Incidence of Death
ParticipantsEVR+Reduced TACTAC Control
Month 1243
Month 2484
Month 24 (on-treatment death)43
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: 0.7 · 90% CI -2.5 to 3.8KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: 3.0 · 90% CI -1.1 to 7.2KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
  • EVR+Reduced TAC vs TAC Control · Kaplan-meier: 0.7 · 90% CI -2.5 to 3.9KM rate and 90% CI are obtained using KM probability estimates of composite efficacy failure rates and standard error derived based on Greenwood's formula.
SecondaryCompare 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
Reported as:
Count of participants · Participants
Compare Incidence of AR
ParticipantsEVR+Reduced TACTAC Control
Month 1298
Month 24129
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Risk difference (rd): 0.7 · 90% CI -3.9 to 5.3Month 12
  • EVR+Reduced TAC vs TAC Control · Risk difference (rd): 2.1 · 90% CI -3.0 to 7.2Month 24
SecondaryCompare 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
Reported as:
Count of participants · Participants
Compare Incidence of tAR
ParticipantsEVR+Reduced TACTAC Control
Month 1256
Month 2477
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Risk ratio (rr): -0.7 · 90% CI -4.5 to 3.1Month 12
  • EVR+Reduced TAC vs TAC Control · Risk ratio (rr): 0.0 · 90% CI -4.2 to 4.2Month 24
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation
ParticipantsEVR+Reduced TACTAC Control
HCC recurrence (n/M) - month 1205
HCC recurrence (n/M) - month 2416
SecondaryNumber of Subjects Experiencing Adverse Events/Infections by SOC
Time frame:
Month 24
Reported as:
Count of participants · Participants
Number of Subjects Experiencing Adverse Events/Infections by SOC
ParticipantsEVR+Reduced TACTAC Control
Any AE/infection140136
Blood and lymphatic system disorders4432
Cardiac disorders1512
Congenital, familial and genetic disorders12
Ear and labyrinth disorders25
Endocrine disorders12
Eye disorders1715
Gastrointestinal disorders9874
General disorders&admin site conditions4842
Hepatobiliary disorders4440
Immune system disorders811
Infections and infestations8470
Injury, poisoning&proced. complications3628
Investigations6168
Metabolism and nutrition disorders8760
Musculoskeletal and connective tissue disorders3043
Neoplasms benign, malig&unspecified (cysts&polyps)1017
Nervous system disorders3844
Product issues#11
Psychiatric disorders3326
Renal and urinary disorders4636
Reproductive system&breast dis.912
Respiratory, thoracic&mediastinal dis.3439
Skin&subcutaneous tissue disorders3944
Vascular disorders3830
SecondaryCompare 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
Reported as:
Count of participants · Participants
Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation)
ParticipantsEVR+Reduced TACTAC Control
Any notable events8682
Death84
Serious AE/Infection8378
AE/Infection lead. to premature disc of study med2118
SecondaryComposite 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
Reported as:
Number · Participants
Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only
ParticipantsEVR+Reduced TACTAC Control
Composite endpoint21
On-treatment composite endpoint10
Graft loss/death11
tBPAR20
Graft loss01
Death10
AR32
tAR20
BPR63
BPAR32
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 5.4 · 95% CI -19.9 to 30.6Composite endpoint
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 6.7 · 95% CI -6.0 to 19.3On-treatment composite endpoint
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 2.0 · 95% CI -24.6 to 28.7Graft loss/death
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 14.4 · 95% CI -4.2 to 33.1tBPAR
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 11.1 · 95% CI -9.4 to 31.6Death
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 3.2 · 95% CI -28.9 to 35.2AR
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 14.4 · 95% CI -4.2 to 33.1tAR
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 14.9 · 95% CI -22.3 to 52.1BPR
  • EVR+Reduced TAC vs TAC Control · Difference in kaplan-meier estimate: 3.2 · 95% CI -28.9 to 35.2BPAR
SecondaryRenal 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
Reported as:
Least squares mean · mL/min/1.73m2
Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients)
mL/min/1.73m2EVR+Reduced TACTAC Control
Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients)-26.88 ± 10.114-16.87 ± 19.412
Statistical analysis
  • EVR+Reduced TAC vs TAC Control · Mean difference (final values): -10.01 · 95% CI -59.91 to 39.89

Adverse events

Collected over Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 4 years. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
AE From Day 1 to Month 24_EVR+Reduced TAC8/142 (5.6%)83/142 (58.5%)127/142 (89.4%)
AE From Day 1 to Month 24_TAC Control4/141 (2.8%)78/141 (55.3%)122/141 (86.5%)
AE From Month 24 to Month 36_EVR+Reduced TAC1/13 (7.7%)5/13 (38.5%)13/13 (100%)
AE From Month 24 to Month 36_TAC Control0/5 (0%)0/5 (0%)4/5 (80%)
Most frequent serious events
Showing 10 of 233
Most frequent serious events
EventAE From Day 1 to Month 24_EVR+Reduced TACAE From Day 1 to Month 24_TAC ControlAE From Month 24 to Month 36_EVR+Reduced TACAE From Month 24 to Month 36_TAC Control
PyrexiaGeneral disorders11/1428/1410/130/5
Cardiac failureCardiac disorders0/1420/1411/130/5
Ileus paralyticGastrointestinal disorders1/1420/1411/130/5
Bile duct stenosisHepatobiliary disorders10/1426/1411/130/5
Bacterial infectionInfections and infestations0/1420/1411/130/5
Incisional herniaInjury, poisoning and procedural complications5/1421/1411/130/5
Oropharyngeal cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/1420/1411/130/5
Spondylitic myelopathyNervous system disorders0/1420/1411/130/5
Renal impairmentRenal and urinary disorders0/1421/1411/130/5
Pleural effusionRespiratory, thoracic and mediastinal disorders1/1421/1411/130/5
Most frequent other events
Showing 10 of 88
Most frequent other events
EventAE From Day 1 to Month 24_EVR+Reduced TACAE From Day 1 to Month 24_TAC ControlAE From Month 24 to Month 36_EVR+Reduced TACAE From Month 24 to Month 36_TAC Control
NasopharyngitisInfections and infestations20/14216/1415/133/5
PyrexiaGeneral disorders18/14220/1413/131/5
Procedural painInjury, poisoning and procedural complications1/1421/1413/130/5
DiarrhoeaGastrointestinal disorders32/14219/1412/130/5
HypertensionVascular disorders29/14223/1411/130/5
ConstipationGastrointestinal disorders13/14216/1412/131/5
EnteritisGastrointestinal disorders0/1421/1410/131/5
CellulitisInfections and infestations1/1426/1410/131/5
Wound complicationInjury, poisoning and procedural complications2/1426/1410/131/5
Post herpetic neuralgiaNervous system disorders0/1421/1410/131/5

Baseline characteristics

Full Analysis Set (FAS): patients were analyzed according to treatment assigned at randomization. Any subject without written informed consent signed did not have their data included. Mis-randomized patients, who were not eligible but randomized in IRT by mistake and to whom no study medication was given, did not have their data included.

Age, Continuous
Age, Continuous(Years)EVR+Reduced TACTAC ControlTotal
Mean54.2 ± 8.9552.7 ± 10.4153.5 ± 9.72
Sex: Female, Male
Sex: Female, Male(Participants)EVR+Reduced TACTAC ControlTotal
Female384381
Male10499203
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)EVR+Reduced TACTAC ControlTotal
Caucasian303060
Asian111112223
Other101
08

Study locations

42 sites
  • Novartis Investigative Site
    Los Angeles, California 90033, United States
  • Novartis Investigative Site
    San Francisco, California 94143, United States
  • Novartis Investigative Site
    Baltimore, Maryland 21201, United States
  • Novartis Investigative Site
    Boston, Massachusetts 02114, United States
  • Novartis Investigative Site
    Burlington, Massachusetts 01805, United States
  • Novartis Investigative Site
    Detroit, Michigan 48202, United States
  • Novartis Investigative Site
    Minneapolis, Minnesota 55455, United States
  • Novartis Investigative Site
    New York, New York 10032, United States
  • Novartis Investigative Site
    Charlottesville, Virginia 22908, United States
  • Novartis Investigative Site
    Toronto, Ontario M5G 2N2, Canada
  • Novartis Investigative Site
    Cairo, Egypt
  • Novartis Investigative Site
    Regensburg, Bavaria 93053, Germany
  • Novartis Investigative Site
    Berlin, 13353, Germany
  • Novartis Investigative Site
    Jena, 07740, Germany
  • Novartis Investigative Site
    Kiel, 24105, Germany
  • Novartis Investigative Site
    Gurgaon, Haryana 122 001, India
  • Novartis Investigative Site
    Kochi, Kerala 682 026, India
  • Novartis Investigative Site
    Chennai, Tamil Nadu 600006, India
  • Novartis Investigative Site
    Chennai, Tamil Nadu 600100, India
  • Novartis Investigative Site
    Milano, MI 20162, Italy
  • Novartis Investigative Site
    Nagoya, Aichi 466 8560, Japan
  • Novartis Investigative Site
    Fukuoka city, Fukuoka 812-8582, Japan
  • Novartis Investigative Site
    Hiroshima city, Hiroshima 734-8551, Japan
  • Novartis Investigative Site
    Kumamoto City, Kumamoto 860-8556, Japan
  • Novartis Investigative Site
    Sakyo Ku, Kyoto 606 8507, Japan
  • Novartis Investigative Site
    Nagasaki-city, Nagasaki 852-8501, Japan
  • Novartis Investigative Site
    Okayama-city, Okayama 700-8558, Japan
  • Novartis Investigative Site
    Bunkyo ku, Tokyo 113 8655, Japan
  • Novartis Investigative Site
    Shinjuku-ku, Tokyo 160-8582, Japan
  • Novartis Investigative Site
    Seoul, Gyeonggi Do 03080, Korea, Republic of
  • Novartis Investigative Site
    Seoul, Korea 05505, Korea, Republic of
  • Novartis Investigative Site
    Seoul, Korea 06351, Korea, Republic of
  • Novartis Investigative Site
    Seoul, 03722, Korea, Republic of
  • Novartis Investigative Site
    Moscow, 123182, Russian Federation
  • Novartis Investigative Site
    Riyadh, 11211, Saudi Arabia
  • Novartis Investigative Site
    Singapore, 119260, Singapore
  • Novartis Investigative Site
    Kaohsiung City, 83301, Taiwan
  • Novartis Investigative Site
    Taichung, 40447, Taiwan
  • Novartis Investigative Site
    Taipei, 11217, Taiwan
  • Novartis Investigative Site
    Taoyuan, 33305, Taiwan
  • Novartis Investigative Site
    Malatya, 44280, Turkey
  • Novartis Investigative Site
    Mecidiyekoy/Istanbul, 34394, Turkey
09

References and documents

Publications

  • Jeng LB, Lee SG, Soin AS, Lee WC, Suh KS, Joo DJ, Uemoto S, Joh J, Yoshizumi T, Yang HR, Song GW, Lopez P, Kochuparampil J, Sips C, Kaneko S, Levy G. Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study. Am J Transplant. 2018 Jun;18(6):1435-1446. doi: 10.1111/ajt.14623. Epub 2018 Jan 25. PubMed 29237235 ↗

Individual participant data

Plan to share: Undecided — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 18, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01888432
Lead sponsor
Novartis Pharmaceuticals
Responsible party
Sponsor
First posted
Jun 27, 2013
Start date
Sep 25, 2013
Primary completion
Oct 19, 2016
Completion
Apr 21, 2018
Results posted
Nov 13, 2018
Last update
Mar 18, 2019

Study contacts

Novartis Pharmaceuticals
study director · Novartis Pharmaceuticals

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Feb 2019. You cannot join it, but the record below documents what was studied.

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