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

This study has been completed.
Sponsor:
Information provided by:
Novartis
ClinicalTrials.gov Identifier:
NCT01150097
First received: April 23, 2010
Last updated: May 29, 2014
Last verified: May 2014
  Purpose

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).


Condition Intervention Phase
Liver Transplant Recipient
Drug: Tacrolimus
Drug: Tacrolimus + everolimus
Drug: Everolimus
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Incidence Rate of tBPAR [ Time Frame: from months 24 - 36 ] [ Designated as safety issue: No ]
    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.


Enrollment: 282
Study Start Date: April 2010
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Tacrolimus Drug: Tacrolimus
Experimental: Low dose tacrolimus + everolimus Drug: Tacrolimus + everolimus
Experimental: Everolimus Drug: Everolimus

  Eligibility

Ages Eligible for Study:   20 Years to 72 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01150097

  Hide Study Locations
Locations
United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
University of Southern CA
Los Angeles, California, United States, 90033
UCLA
Los Angeles, California, United States, 90095
UCSF
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado / Anchutz Cancer Pavilion
Aurora, Colorado, United States, 80045
United States, District of Columbia
Georgetown University
Washington, District of Columbia, United States, 20007
United States, Florida
Lifelink, Inc
Tampa, Florida, United States, 33606
United States, Georgia
Piedmont Hospital
Atlanta, Georgia, United States, 30309
United States, Illinois
University of Chicago Medical Center
Chicago, Illinois, United States, 60637
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536
United States, Michigan
Henry Ford Hospital Transplant Institute
Detroit, Michigan, United States, 48202
United States, Minnesota
Mayo Clinic Transplant Center
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
St Louis, Missouri, United States, 63110
United States, New Jersey
UMD, Division of Transplant Surgery
Newark, New Jersey, United States, 07101
United States, New York
New York University
New York, New York, United States, 10016
Columbia University Medical Center
New York, New York, United States, 10032
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Oklahoma
Integris Baptist Medical Center
Oklahoma City, Oklahoma, United States, 73112
United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Tennessee
Vanderbuilt Transplant Center
Nashville, Tennessee, United States, 37232
United States, Texas
Baylor College of Medicine
Dallas, Texas, United States, 75246
Methodist Dallas Liver Insititute
Dallas, Texas, United States, 75203
The Baylor College of Medicine
Dallas, Texas, United States, 75203
Memorial Hermann Hospital
Houston, Texas, United States, 77030
Methodist Hospital
Houston, Texas, United States, 77030
Argentina
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Buenos Aires, Argentina
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Rosario, Argentina
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San Martin, Argentina
Australia
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Bedford Park, Australia
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Camperdown, Australia
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Heidelburg, Australia
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Nedlands, Australia
Belgium
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Gent, Belgium
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Leuven, Belgium
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Liege, Belgium
Brazil
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Blumenau, Brazil
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Porto Alegre, Brazil
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Ribeirao Preto, Brazil
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Rio de Janeiro, Brazil
Canada, Alberta
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Edmonton, Alberta, Canada
Canada, Ontario
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London, Ontario, Canada
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Toronto, Ontario, Canada
Canada
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Vancouver, Canada
Colombia
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Bogota, Colombia
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Cali, Colombia
Czech Republic
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Prague, Czech Republic, 14021
France
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Bordeaux, France
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Clichy, France
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Creteil, France
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Lille, France
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Lyon, France
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Marseille, France
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Montpellier, France
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Rennes Cedex, France
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Villejuif, France
Germany
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Berlin, Germany
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Essen, Germany, 45359
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Hamburg, Germany
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Heidelberg, Germany
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Leipzig, Germany, 04257
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Mainz, Germany
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Regensburg, Germany
Hungary
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Budapest, Hungary
Ireland
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Dublin, Ireland
Italy
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Milano, Italy
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Modena, Italy
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Pisa, Italy
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Roma, Italy
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Torino, Italy
Netherlands
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Rotterdam, Netherlands
Russian Federation
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Moscow, Russian Federation, 123182
Novartis Investigative Site
Moscow, Russian Federation, 129110
Spain
Novartis Investigative Site
Barakaldo, Spain, 48903
Novartis Investigative Site
Barcelona, Spain, 08907
Novartis Investigative Site
Barcelona, Spain, 08025
Novartis Investigative Site
Hospitalet de Llobregat, Spain, 08907
Novartis Investigative Site
Madrid, Spain, 28035
Novartis Investigative Site
Madrid, Spain, 28034
Novartis Investigative Site
Malaga, Spain, 28041
Novartis Investigative Site
Pamplona, Spain, 31008
Novartis Investigative Site
Valencia, Spain, 46009
Sweden
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Stockholm, Sweden
United Kingdom
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Edinburgh, United Kingdom, ED16 4SA
Novartis Investigative Site
Leeds, United Kingdom, LS9 7TF
Novartis Investigative Site
London, United Kingdom, SE1 9RS
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: External Affairs, Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01150097     History of Changes
Other Study ID Numbers: CRAD001H2304E1
Study First Received: April 23, 2010
Results First Received: May 1, 2014
Last Updated: May 29, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Liver transplantation
Everolimus
Calcineurin inhibitors
Tacrolimus
Renal function
Progression of HCV related allograft fibrosis

Additional relevant MeSH terms:
Everolimus
Sirolimus
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 22, 2014