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

April 23, 2010
July 17, 2014
March 2010
May 2013   (final data collection date for primary outcome measure)
  • 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.
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 ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01150097 on ClinicalTrials.gov Archive Site
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.
  • Incidence of hypertension, neurotoxicity, or new-onset diabetes mellitus (NODM) [ Time Frame: 36 and 48 months post-transplantation ] [ Designated as safety issue: Yes ]
  • Incidence of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 36 and 48 months post-transplantation ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Extension Study to Evaluate the Long-term Efficacy and Safety of Everolimus in Liver Transplant Recipients
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

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).

Not Provided
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Liver Transplant Recipient
  • 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.
  • 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
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
284
May 2013
May 2013   (final data collection date for primary outcome measure)

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

Both
20 Years to 75 Years
No
Contact information is only displayed when the study is recruiting subjects
Argentina,   United States,   United Kingdom,   Australia,   Belgium,   Brazil,   Colombia,   Czech Republic,   France,   Germany,   Ireland,   Italy,   Netherlands,   Russian Federation,   Spain,   Sweden
 
NCT01150097
CRAD001H2304E1, 2009-017311-15
Yes
Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
July 2014

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