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

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ClinicalTrials.gov Identifier: NCT01888432
Recruitment Status : Completed
First Posted : June 27, 2013
Results First Posted : November 12, 2018
Last Update Posted : March 18, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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).


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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

Resource links provided by the National Library of Medicine


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.




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



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01888432


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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01888432     History of Changes
Other Study ID Numbers: CRAD001H2307
2010-024527-25 ( EudraCT Number )
First Posted: June 27, 2013    Key Record Dates
Results First Posted: November 12, 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


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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:
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Tacrolimus
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents