ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01150097
Recruitment Status : Completed
First Posted : June 24, 2010
Results First Posted : May 30, 2014
Last Update Posted : April 2, 2015
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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).

Condition or disease Intervention/treatment 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  (Clinical Trial)
Actual Enrollment : 284 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : March 2010
Actual Primary Completion Date : May 2013
Actual Study Completion Date : May 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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. 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.

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. 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.

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. 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.




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.


Secondary Outcome Measures :
  1. 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.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   20 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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


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): NCT01150097


  Show 57 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01150097     History of Changes
Other Study ID Numbers: CRAD001H2304E1
2009-017311-15
First Posted: June 24, 2010    Key Record Dates
Results First Posted: May 30, 2014
Last Update Posted: April 2, 2015
Last Verified: March 2015

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

Additional relevant MeSH terms:
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