Clinical trial NCT01888432: Efficacy and Safety of Everolimus in Liver Transplant Recipients of Living Donor Liver Transplants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Liver Transplantation
Keywords: liver transplantation
everolimus
tacrolimus
reduced calcineuron inhibitor
renal function
living donor
RAD001H2307
RAD001H
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-06-27
Enrollment: 285
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: 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
timeFrame: 12 months post transplantation
Secondary outcomes:
measure: Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization
timeFrame: From randomization to month 12
measure: Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization
timeFrame: From randomziation to month 24
measure: Number of Participants With Composite of tBPAR, Graft Loss, and Death
timeFrame: Month 24 post transplantation
measure: Compare Incidence of tBPAR
timeFrame: Month 12 and Month 24 post transplantation
measure: Compare Incidence of BPAR
timeFrame: Month 12 and Month 24 post transplantation
measure: Compare Incidence of Graft Loss
timeFrame: Month 12 and Month 24 post transplantation
measure: Compare Incidence of a Composite of Death or Graft Loss
timeFrame: Month 12 and Month 24 post transplantation
measure: Compare Incidence of Death
timeFrame: Month 12 and Month 24 post transplantation
measure: Compare Incidence of AR
timeFrame: Month 12 and Month 24 post transplantation
measure: Compare Incidence of tAR
timeFrame: Month 12 and Month 24 post transplantation
measure: Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation
timeFrame: Month 12 and Month 24
measure: Number of Subjects Experiencing Adverse Events/Infections by SOC
timeFrame: Month 24
measure: Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation)
timeFrame: Month 24
measure: Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only
timeFrame: randomization, 36 months post transplantion
measure: Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients)
timeFrame: randomization, at 36 months post transplantation
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Burlington
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Detroit
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Minneapolis
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Charlottesville
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Cairo
country: Egypt
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Gurgaon
country: India
facility: Novartis Investigative Site
state: Haryana
city: Kochi
country: India
facility: Novartis Investigative Site
state: Kerala
city: Chennai
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Chennai
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Hiroshima city
country: Japan
facility: Novartis Investigative Site
state: Hiroshima
city: Kumamoto City
country: Japan
facility: Novartis Investigative Site
state: Kumamoto
city: Sakyo Ku
country: Japan
facility: Novartis Investigative Site
state: Kyoto
city: Nagasaki-city
country: Japan
facility: Novartis Investigative Site
state: Nagasaki
city: Okayama-city
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Riyadh
country: Saudi Arabia
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Kaohsiung City
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Malatya
country: Turkey
facility: Novartis Investigative Site
city: Mecidiyekoy/Istanbul
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.