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

A 24 Month, Randomized, Controlled, Study to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus Plus Reduced Tacrolimus Compared to Standard Tacrolimus in Recipients of Living Donor Liver Transplants and Long Term Extension to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus Plus Reduced Tacrolimus Compared to Standard Tacrolimus in Recipients of Living Donor Liver Transplants in Japan

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.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: Everolimus + reduced tacrolimus; Drug: Standard tacrolimus

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).

• Study Type: Interventional
• Enrollment (Actual): 285
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Everolimus + reduced tacrolimus; Everolimus + reduced tacrolimus ± corticosteroids	Drug: Everolimus + 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.
ACTIVE_COMPARATOR: Standard tacrolimus; Standard tacrolimus ± corticosteroids	Drug: Standard 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	12 months post transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization to month 12
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.	From randomziation to month 24
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	Month 24 post transplantation
Compare Incidence of tBPAR	Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of tBPAR	Month 12 and Month 24 post transplantation
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)	Month 12 and Month 24 post transplantation
Compare Incidence of Graft Loss	Compare between the treatment group EVR with rTAC vs standard TAC: incidence of graft loss	Month 12 and Month 24 post transplantation
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	Month 12 and Month 24 post transplantation
Compare Incidence of Death	Compare between the treatment group EVR with rTAC vs standard TAC: incidence of death	Month 12 and Month 24 post transplantation
Compare Incidence of AR	Compare between the treatment group EVR with rTAC vs standard TAC: incidence of acute rejection (AR)	Month 12 and Month 24 post transplantation
Compare Incidence of tAR	Compare between the treatment group EVR with rTAC vs standard TAC: incidence of treated acute rejection (tAR).	Month 12 and Month 24 post transplantation
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.	Month 12 and Month 24
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)	Notable events include death, Serious AE/infection,, and AE/infection leading to discontinuation of study medication.	Month 24
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	randomization, 36 months post transplantion
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	randomization, at 36 months post transplantation

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 25, 2013
• Primary Completion (ACTUAL): October 19, 2016
• Study Completion (ACTUAL): April 21, 2018

Study Registration Dates

• First Submitted: June 15, 2013
• First Submitted That Met QC Criteria: June 25, 2013
• First Posted (ESTIMATE): June 27, 2013

Study Record Updates

• Last Update Posted (ACTUAL): March 18, 2019
• Last Update Submitted That Met QC Criteria: February 28, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: liver transplantation; everolimus; renal function; tacrolimus; living donor; reduced calcineuron inhibitor; RAD001H2307; RAD001H
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus; Everolimus
• Other Study ID Numbers: CRAD001H2307; 2010-024527-25 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No