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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 (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01150097
First received: April 23, 2010
Last updated: July 17, 2014
Last verified: July 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 (reduced tacrolimus)
Drug: Everolimus (reduced tacrolimus)
Drug: Tacrolimus (tacrolimus elimination)
Drug: Everolimus (tacrolimus elimination)
Drug: Tacrolimus (tacrolimus control)
Drug: Corticosteroids
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: 284
Study Start Date: March 2010
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus + reduced tacrolimus
Participants were maintained on whole blood trough levels of 3 - 8 ng/mL everolimus and 3 - 5 ng/mL tacrolimus.
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: 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.
Experimental: Tacrolimus elimination
Participants were maintained on a whole blood trough level of 6 - 10 ng/mL everolimus.
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: 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.
Active Comparator: Tacrolimus control
Participants were maintained on a whole blood trough level of 6 - 10 ng/mL tacrolimus.
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.

  Eligibility

Ages Eligible for Study:   20 Years to 75 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, District of Columbia
Novartis Investigative Site
Washington, District of Columbia, United States, 20007-2197
United States, Florida
Novartis Investigative Site
Tampa, Florida, United States, 33606
United States, Kentucky
Novartis Investigative Site
Lexington, Kentucky, United States, 40536-0293
United States, Michigan
Novartis Investigative Site
Detroit, Michigan, United States, 48202-2689
United States, Minnesota
Novartis Investigative Site
Rochester, Minnesota, United States, 55905
United States, Missouri
Novartis Investigative Site
St. Louis, Missouri, United States, 63110
United States, New Jersey
Novartis Investigative Site
Newark, New Jersey, United States, 07101
United States, New York
Novartis Investigative Site
New York, New York, United States, 10032
Novartis Investigative Site
New York, New York, United States, 10016
United States, North Carolina
Novartis Investigative Site
Chapel Hill, North Carolina, United States, 27599
Novartis Investigative Site
Durham, North Carolina, United States, 27710
United States, Oklahoma
Novartis Investigative Site
Oklahoma City, Oklahoma, United States, 73112
United States, South Carolina
Novartis Investigative Site
Charleston, South Carolina, United States, 29425
United States, Texas
Novartis Investigative Site
Houston, Texas, United States, 77030-2400
Novartis Investigative Site
Houston, Texas, United States, 77030
Argentina
Novartis Investigative Site
Caba, Buenos Aires, Argentina, C1118AAT
Novartis Investigative Site
San Martin, Buenos Aires, Argentina, C1107BEA
Australia, New South Wales
Novartis Investigative Site
Camperdown, New South Wales, Australia, 2050
Australia, South Australia
Novartis Investigative Site
Bedford Park, South Australia, Australia, 5042
Australia, Victoria
Novartis Investigative Site
Heidelberg, Victoria, Australia, 3084
Belgium
Novartis Investigative Site
Gent, Belgium, 9000
Novartis Investigative Site
Leuven, Belgium, 3000
Novartis Investigative Site
Liege, Belgium, 4000
Brazil
Novartis Investigative Site
Rio de Janeiro, RJ, Brazil, 21041-030
Novartis Investigative Site
Porto Alegre, RS, Brazil, 90020-090
Colombia
Novartis Investigative Site
Bogotá, Colombia
Novartis Investigative Site
Cali, Colombia
Czech Republic
Novartis Investigative Site
Praha 4, Czech Republic, 140 21
France
Novartis Investigative Site
Bordeaux Cedex, France, 33076
Novartis Investigative Site
Clichy, France, 92110
Novartis Investigative Site
Creteil, France, 94010
Novartis Investigative Site
Marseille, France, 13385
Novartis Investigative Site
Montpellier, France, 34295
Novartis Investigative Site
Villejuif, France, 94805
Germany
Novartis Investigative Site
Berlin, Germany, 13353
Novartis Investigative Site
Essen, Germany, 45147
Novartis Investigative Site
Hamburg, Germany, 20246
Novartis Investigative Site
Heidelberg, Germany, 69120
Novartis Investigative Site
Leipzig, Germany, 04103
Novartis Investigative Site
Mainz, Germany, 55131
Novartis Investigative Site
Regensburg, Germany, 93053
Ireland
Novartis Investigative Site
Dublin 4, Ireland
Italy
Novartis Investigative Site
Milano, MI, Italy, 20162
Novartis Investigative Site
Modena, MO, Italy, 41100
Novartis Investigative Site
Pisa, PI, Italy, 56124
Novartis Investigative Site
Roma, RM, Italy, 00161
Novartis Investigative Site
Torino, TO, Italy, 10126
Netherlands
Novartis Investigative Site
Rotterdam, Netherlands, 3015 CE
Russian Federation
Novartis Investigative Site
Moscow, Russian Federation, 129010
Novartis Investigative Site
Moscow, Russian Federation, 123182
Spain
Novartis Investigative Site
Hospitalet de Llobregat, Barcelona, Spain, 08907
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site
Valencia, Comunidad Valenciana, Spain, 46026
Novartis Investigative Site
Baracaldo, Pais Vasco, Spain, 48903
Sweden
Novartis Investigative Site
Stockholm, Sweden, 141 86
United Kingdom
Novartis Investigative Site
Edinburgh, United Kingdom, EH16 4SA
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01150097     History of Changes
Other Study ID Numbers: CRAD001H2304E1, 2009-017311-15
Study First Received: April 23, 2010
Results First Received: May 1, 2014
Last Updated: July 17, 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
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014