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Extension Study to Evaluate the Long-term Efficacy and Safety of Everolimus in Liver Transplant Recipients

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ClinicalTrials.gov Identifier: NCT01150097
Recruitment Status : Completed
First Posted : June 24, 2010
Results First Posted : May 30, 2014
Last Update Posted : November 7, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE April 23, 2010
First Posted Date  ICMJE June 24, 2010
Results First Submitted Date  ICMJE May 1, 2014
Results First Posted Date  ICMJE May 30, 2014
Last Update Posted Date November 7, 2018
Actual Study Start Date  ICMJE March 31, 2010
Actual Primary Completion Date May 3, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 1, 2014)
  • Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death [ Time Frame: from months 24 to 36 ]
    The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
  • Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death [ Time Frame: from months 36 to 48 ]
    The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
  • Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death [ Time Frame: from months 24 to 36 ]
    The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
  • Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death [ Time Frame: from months 36 - 48 ]
    The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
  • Change in Renal Function [ Time Frame: from months 24 to 36 ]
    Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m^2) = 186.3*(C^-1.154)*(A^-0.203)*G*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2010)
Assessment of renal function by Estimated Glomerular Filtration Rate. Efficacy failure as treated biopsy proven acute rejection (BPAR ), graft loss or death. Rate of progression of HCV related allograft fibrosis [ Time Frame: at 36 and 48 months post-transplantation ]
Change History Complete list of historical versions of study NCT01150097 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 1, 2014)
Incidence Rate of tBPAR [ Time Frame: from months 24 - 36 ]
The number of participants who had a tBPAR was analyzed. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2010)
  • Incidence of hypertension, neurotoxicity, or new-onset diabetes mellitus (NODM) [ Time Frame: 36 and 48 months post-transplantation ]
  • Incidence of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 36 and 48 months post-transplantation ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Extension Study to Evaluate the Long-term Efficacy and Safety of Everolimus in Liver Transplant Recipients
Official Title  ICMJE Extension Study to the Multicenter, Open-label, Randomized, Controlled Study CRAD001H2304 to Evaluate the Long-term Efficacy and Safety of Concentration-controlled Everolimus in Liver Transplant Recipient
Brief Summary The reason for this extension is to evaluate the long-term safety and efficacy of two concentration-controlled everolimus regimen in de novo liver transplant recipients. The most important long-term safety assessments include evaluation of renal function, progression of HCV related allograft fibrosis, and other treatment related effects at Month 36 post-transplantation compared to extension baseline (Months 24 post-transplantation).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Liver Transplant Recipient
Intervention  ICMJE
  • Drug: Tacrolimus (reduced tacrolimus)
    After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization, a level which was maintained for the duration of the study.
    Other Names:
    • FK-506,
    • fujimycin,
    • Prograf,
    • Advagraf,
    • Protopic
  • Drug: Everolimus (reduced tacrolimus)
    Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL for the duration of the study.
    Other Names:
    • RAD001,
    • Zortress,
    • Certican,
    • Afinitor
  • Drug: Tacrolimus (tacrolimus elimination)
    After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization. Tacrolimus elimination was started beginning at Month 4. Tacrolimus was tapered after everolimus whole blood trough levels were within the target range of 6-10 ng/mL. Tacrolimus was completely eliminated by the end of Month 4.
    Other Names:
    • FK-506,
    • fujimycin,
    • Prograf,
    • Advagraf,
    • Protopic
  • Drug: Everolimus (tacrolimus elimination)
    Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL until Month 4; beginning with Month 4, the dose was adjusted to maintain everolimus trough blood levels between 6-10 ng/mL.
    Other Names:
    • RAD001,
    • Zortress,
    • Certican,
    • Afinitor
  • Drug: Tacrolimus (tacrolimus control)
    Tacrolimus trough levels were targeted to be maintained at 8-12 ng/mL until Month 4. At Month 4, tacrolimus whole blood trough levels were decreased to a target trough level of 6-10 ng/mL for the remainder of the study.
    Other Names:
    • FK-506,
    • fujimycin,
    • Prograf,
    • Advagraf,
    • Protopic
  • Drug: Corticosteroids
    For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids could be used for the duration of the study but could not be eliminated before Month 6. The corticosteroids were not specified in the protocol because they were adminsitered to the participants according to local practice as part of standard of care.
Study Arms  ICMJE
  • Experimental: Everolimus + reduced tacrolimus
    Participants were maintained on whole blood trough levels of 3 - 8 ng/mL everolimus and 3 - 5 ng/mL tacrolimus.
    Interventions:
    • Drug: Tacrolimus (reduced tacrolimus)
    • Drug: Everolimus (reduced tacrolimus)
    • Drug: Corticosteroids
  • Experimental: Tacrolimus elimination
    Participants were maintained on a whole blood trough level of 6 - 10 ng/mL everolimus.
    Interventions:
    • Drug: Tacrolimus (tacrolimus elimination)
    • Drug: Everolimus (tacrolimus elimination)
    • Drug: Corticosteroids
  • Active Comparator: Tacrolimus control
    Participants were maintained on a whole blood trough level of 6 - 10 ng/mL tacrolimus.
    Interventions:
    • Drug: Tacrolimus (tacrolimus control)
    • Drug: Corticosteroids
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 17, 2014)
284
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2010)
470
Actual Study Completion Date  ICMJE May 3, 2013
Actual Primary Completion Date May 3, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent
  • Ability and willingness to adhere to study regimen
  • Completed core study with assigned regimen;

Exclusion Criteria:

Patients fulfilling any of the following criteria are not eligible for inclusion in this study:

  • Severe hypercholesterolemia or hypertriglyceridemia.
  • Low platelet count.
  • Low white blood cell count.
  • Positive test for human immunodeficiency virus (HIV).
  • Systemic infection requiring active use of IV antibiotics.
  • Patients in a critical care setting.
  • Use of prohibited medication.
  • Use of immunosuppressive agents not utilized in the protocol.
  • Hypersensitivity to any of the study drugs or similar drugs.
  • Pregnant or nursing (lactating) women
  • Women of child-bearing potential not using a highly effective method of birth control.

Other protocol-defined inclusion/exclusion criteria may apply

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Brazil,   Colombia,   Czechia,   France,   Germany,   Ireland,   Italy,   Netherlands,   Russian Federation,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries Canada,   Czech Republic,   Hungary
 
Administrative Information
NCT Number  ICMJE NCT01150097
Other Study ID Numbers  ICMJE CRAD001H2304E1
2009-017311-15
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP