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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01150097
Registration number
NCT01150097
Ethics application status
Date submitted
23/04/2010
Date registered
24/06/2010
Date last updated
7/11/2018
Titles & IDs
Public title
Extension Study to Evaluate the Long-term Efficacy and Safety of Everolimus in Liver Transplant Recipients
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Scientific 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
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Secondary ID [1]
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2009-017311-15
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Secondary ID [2]
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CRAD001H2304E1
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Liver Transplant Recipient
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Condition category
Condition code
Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Tacrolimus (reduced tacrolimus)
Treatment: Drugs - Everolimus (reduced tacrolimus)
Treatment: Drugs - Tacrolimus (tacrolimus elimination)
Treatment: Drugs - Everolimus (tacrolimus elimination)
Treatment: Drugs - Tacrolimus (tacrolimus control)
Treatment: Drugs - Corticosteroids
Experimental: Everolimus + reduced tacrolimus - Participants were maintained on whole blood trough levels of 3 - 8 ng/mL everolimus and 3 - 5 ng/mL tacrolimus.
Experimental: Tacrolimus elimination - Participants were maintained on a whole blood trough level of 6 - 10 ng/mL everolimus.
Active Comparator: Tacrolimus control - Participants were maintained on a whole blood trough level of 6 - 10 ng/mL tacrolimus.
Treatment: Drugs: 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.
Treatment: Drugs: 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.
Treatment: Drugs: 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.
Treatment: Drugs: 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.
Treatment: Drugs: 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.
Treatment: Drugs: 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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death
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Assessment method [1]
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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.
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Timepoint [1]
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from months 24 to 36
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Primary outcome [2]
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Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death
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Assessment method [2]
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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.
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Timepoint [2]
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from months 36 to 48
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Primary outcome [3]
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Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death
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Assessment method [3]
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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.
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Timepoint [3]
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from months 24 to 36
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Primary outcome [4]
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Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death
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Assessment method [4]
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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.
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Timepoint [4]
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from months 36 - 48
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Primary outcome [5]
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Change in Renal Function
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Assessment method [5]
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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.
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Timepoint [5]
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from months 24 to 36
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Secondary outcome [1]
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Incidence Rate of tBPAR
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Assessment method [1]
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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.
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Timepoint [1]
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from months 24 - 36
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Eligibility
Key inclusion criteria
- Written informed consent
- Ability and willingness to adhere to study regimen
- Completed core study with assigned regimen;
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Minimum age
20
Years
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Maximum age
75
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
31/03/2010
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
3/05/2013
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Sample size
Target
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Accrual to date
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Final
284
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Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
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Recruitment hospital [1]
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Novartis Investigative Site - Camperdown
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Recruitment hospital [2]
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Novartis Investigative Site - Bedford Park
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Recruitment hospital [3]
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Novartis Investigative Site - Heidelberg
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Recruitment postcode(s) [1]
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2050 - Camperdown
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Recruitment postcode(s) [2]
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5041 - Bedford Park
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Recruitment postcode(s) [3]
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3084 - Heidelberg
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Recruitment outside Australia
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United States of America
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District of Columbia
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Florida
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Buenos Aires
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Gent
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Belgium
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Leuven
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Leipzig
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Mainz
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Dublin 4
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TO
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Rotterdam
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Russian Federation
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Barcelona
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Vizcaya
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Sweden
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Stockholm
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United Kingdom
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Edinburgh
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01150097
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01150097
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