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

• ClinicalTrials.gov Identifier: NCT01888432
• Recruitment Status: Completed
• First Posted: June 27, 2013
• Results First Posted: November 13, 2018
• Last Update Posted: March 18, 2019
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Liver Transplantation	Drug: Everolimus + reduced tacrolimus; Drug: Standard tacrolimus	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 285 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.
• Masking: Single (Care Provider)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: September 25, 2013
• Actual Primary Completion Date: October 19, 2016
• Actual Study Completion Date: April 21, 2018

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

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 [ Time Frame: 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 Outcome Measures :

1. Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization [ Time Frame: 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.
2. Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization [ Time Frame: 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.
3. Number of Participants With Composite of tBPAR, Graft Loss, and Death [ Time Frame: Month 24 post transplantation ]
   Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of tBPAR, graft loss, death
4. Compare Incidence of tBPAR [ Time Frame: Month 12 and Month 24 post transplantation ]
   Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of tBPAR
5. Compare Incidence of BPAR [ Time Frame: 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)
6. Compare Incidence of Graft Loss [ Time Frame: Month 12 and Month 24 post transplantation ]
   Compare between the treatment group EVR with rTAC vs standard TAC: incidence of graft loss
7. Compare Incidence of a Composite of Death or Graft Loss [ Time Frame: 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
8. Compare Incidence of Death [ Time Frame: Month 12 and Month 24 post transplantation ]
   Compare between the treatment group EVR with rTAC vs standard TAC: incidence of death
9. Compare Incidence of AR [ Time Frame: Month 12 and Month 24 post transplantation ]
   Compare between the treatment group EVR with rTAC vs standard TAC: incidence of acute rejection (AR)
10. Compare Incidence of tAR [ Time Frame: Month 12 and Month 24 post transplantation ]
    Compare between the treatment group EVR with rTAC vs standard TAC: incidence of treated acute rejection (tAR).
11. Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation [ Time Frame: 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.
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) [ Time Frame: Month 24 ]
    Notable events include death, Serious AE/infection,, and AE/infection leading to discontinuation of study medication.
14. Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only [ Time Frame: 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

15. Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients) [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

Novartis Investigative Site

Los Angeles, California, United States, 90033

Novartis Investigative Site

San Francisco, California, United States, 94143

United States, Maryland

Novartis Investigative Site

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Novartis Investigative Site

Boston, Massachusetts, United States, 02114

Novartis Investigative Site

Burlington, Massachusetts, United States, 01805

United States, Michigan

Novartis Investigative Site

Detroit, Michigan, United States, 48202

United States, Minnesota

Novartis Investigative Site

Minneapolis, Minnesota, United States, 55455

United States, New York

Novartis Investigative Site

New York, New York, United States, 10032

United States, Virginia

Novartis Investigative Site

Charlottesville, Virginia, United States, 22908

Canada, Ontario

Novartis Investigative Site

Toronto, Ontario, Canada, M5G 2N2

Egypt

Novartis Investigative Site

Cairo, Egypt

Germany

Novartis Investigative Site

Regensburg, Bavaria, Germany, 93053

Novartis Investigative Site

Berlin, Germany, 13353

Novartis Investigative Site

Jena, Germany, 07740

Novartis Investigative Site

Kiel, Germany, 24105

India

Novartis Investigative Site

Gurgaon, Haryana, India, 122 001

Novartis Investigative Site

Kochi, Kerala, India, 682 026

Novartis Investigative Site

Chennai, Tamil Nadu, India, 600006

Novartis Investigative Site

Chennai, Tamil Nadu, India, 600100

Italy

Novartis Investigative Site

Milano, MI, Italy, 20162

Japan

Novartis Investigative Site

Nagoya, Aichi, Japan, 466 8560

Novartis Investigative Site

Fukuoka city, Fukuoka, Japan, 812-8582

Novartis Investigative Site

Hiroshima city, Hiroshima, Japan, 734-8551

Novartis Investigative Site

Kumamoto City, Kumamoto, Japan, 860-8556

Novartis Investigative Site

Sakyo Ku, Kyoto, Japan, 606 8507

Novartis Investigative Site

Nagasaki-city, Nagasaki, Japan, 852-8501

Novartis Investigative Site

Okayama-city, Okayama, Japan, 700-8558

Novartis Investigative Site

Bunkyo ku, Tokyo, Japan, 113 8655

Novartis Investigative Site

Shinjuku-ku, Tokyo, Japan, 160-8582

Korea, Republic of

Novartis Investigative Site

Seoul, Gyeonggi Do, Korea, Republic of, 03080

Novartis Investigative Site

Seoul, Korea, Korea, Republic of, 05505

Novartis Investigative Site

Seoul, Korea, Korea, Republic of, 06351

Novartis Investigative Site

Seoul, Korea, Republic of, 03722

Russian Federation

Novartis Investigative Site

Moscow, Russian Federation, 123182

Saudi Arabia

Novartis Investigative Site

Riyadh, Saudi Arabia, 11211

Singapore

Novartis Investigative Site

Singapore, Singapore, 119260

Taiwan

Novartis Investigative Site

Kaohsiung City, Taiwan, 83301

Novartis Investigative Site

Taichung, Taiwan, 40447

Novartis Investigative Site

Taipei, Taiwan, 11217

Novartis Investigative Site

Taoyuan, Taiwan, 33305

Turkey

Novartis Investigative Site

Malatya, Turkey, 44280

Novartis Investigative Site

Mecidiyekoy/Istanbul, Turkey, 34394

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01888432
• Other Study ID Numbers: CRAD001H2307; 2010-024527-25 ( EudraCT Number )
• First Posted: June 27, 2013
• Results First Posted: November 13, 2018
• Last Update Posted: March 18, 2019
• Last Verified: February 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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

Additional relevant MeSH terms:

Everolimus; Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents