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

Liver Transplantation Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01888432
• Other study ID #: CRAD001H2307
• Secondary ID: 2010-024527-25
• Status: Completed
• Phase: Phase 3
• Start date: September 25, 2013
• Est. completion date: April 21, 2018

Study information

• Verified date: February 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 285
• Est. completion date: April 21, 2018
• Est. primary completion date: October 19, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Liver Transplantation

Intervention

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.
• 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.

Locations

Country	Name	City	State
Canada	Novartis Investigative Site	Toronto	Ontario
Egypt	Novartis Investigative Site	Cairo
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Jena
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Regensburg	Bavaria
India	Novartis Investigative Site	Chennai	Tamil Nadu
India	Novartis Investigative Site	Chennai	Tamil Nadu
India	Novartis Investigative Site	Gurgaon	Haryana
India	Novartis Investigative Site	Kochi	Kerala
Italy	Novartis Investigative Site	Milano	MI
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Hiroshima city	Hiroshima
Japan	Novartis Investigative Site	Kumamoto City	Kumamoto
Japan	Novartis Investigative Site	Nagasaki-city	Nagasaki
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Okayama-city	Okayama
Japan	Novartis Investigative Site	Sakyo Ku	Kyoto
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Korea, Republic of	Novartis Investigative Site	Seoul	Gyeonggi Do
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Russian Federation	Novartis Investigative Site	Moscow
Saudi Arabia	Novartis Investigative Site	Riyadh
Singapore	Novartis Investigative Site	Singapore
Taiwan	Novartis Investigative Site	Kaohsiung City
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
Turkey	Novartis Investigative Site	Malatya
Turkey	Novartis Investigative Site	Mecidiyekoy/Istanbul
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Burlington	Massachusetts
United States	Novartis Investigative Site	Charlottesville	Virginia
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  Egypt,  Germany,  India,  Italy,  Japan,  Korea, Republic of,  Russian Federation,  Saudi Arabia,  Singapore,  Taiwan,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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	12 months post transplantation
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.	From randomization to month 12
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.	From randomziation to month 24
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	Month 24 post transplantation
Secondary	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
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)	Month 12 and Month 24 post transplantation
Secondary	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
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	Month 12 and Month 24 post transplantation
Secondary	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
Secondary	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
Secondary	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
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.	Month 12 and Month 24
Secondary	Number of Subjects Experiencing Adverse Events/Infections by SOC		Month 24
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.	Month 24
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	randomization, 36 months post transplantion
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	randomization, at 36 months post transplantation