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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/NCT00622869




Registration number
NCT00622869
Ethics application status
Date submitted
13/02/2008
Date registered
25/02/2008
Date last updated
27/05/2013

Titles & IDs
Public title
Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients
Scientific title
A 24 Month, Multicenter, Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients
Secondary ID [1] 0 0
2007-001821-85
Secondary ID [2] 0 0
CRAD001H2304
Universal Trial Number (UTN)
Trial acronym
RAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver Transplantation 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tacrolimus (reduced tacrolimus)
Treatment: Drugs - Tacrolimus (tacrolimus elimination)
Treatment: Drugs - Tacrolimus (tacrolimus control)
Treatment: Drugs - Everolimus (reduced tacrolimus)
Treatment: Drugs - Everolimus (tacrolimus elimination)
Treatment: Drugs - Corticosteroids

Experimental: Everolimus + reduced tacrolimus - Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.

Experimental: Tacrolimus elimination - Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.

Active Comparator: Tacrolimus control - Control dose tacrolimus + corticosteroids.


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: 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: 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: 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: 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: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence Rate of Composite Efficacy Failure From Randomization to Month 12
Timepoint [1] 0 0
Randomization to Month 12
Secondary outcome [1] 0 0
Incidence Rate of Composite Efficacy Failure From Randomization to Month 24
Timepoint [1] 0 0
Randomization to Month 24
Secondary outcome [2] 0 0
Incidence Rate of Treated Biopsy Proven Acute Rejection (tBPAR) at Months 12 and 24
Timepoint [2] 0 0
Randomization to Month 24
Secondary outcome [3] 0 0
Change in Renal Function From Randomization to Months 12 and 24
Timepoint [3] 0 0
Randomization to Month 24

Eligibility
Key inclusion criteria
- Ability and willingness to provide written informed consent and adhere to study
regimen.

- Recipients who are 18-70 years of age of a primary liver transplant from a deceased
donor.

- Recipients who have been initiated on an immunosuppressive regimen that contains
corticosteroids and tacrolimus, 3-7 days post-transplantation.

- Confirmed recipient hepatitis C virus (HCV) status at Screening (either by antibody or
by PCR (polymerase chain reaction).

- Allograft is functioning at an acceptable level by the time of randomization as
defined by protocol specific laboratory values.

- Abbreviated Modification of Diet in Renal Disease estimated glomerular filtration rate
(MDRD eGFR) = 30 mL/min/1.73m2. Results obtained within 5 days prior to randomization
are acceptable, however, no sooner than Day 25 post-transplantation.

- Verification of at least 1 tacrolimus trough level of = 8 ng/mL in the week prior to
randomization. Investigators should make adjustments in tacrolimus dosing to continue
to target trough levels above 8 ng/mL prior to randomization.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

- Patients who are recipients of multiple solid organ or islet cell tissue transplants,
or have previously received an organ or tissue transplant. Patients who have a
combined liver-kidney transplant.

- Recipients of a liver from a living donor, or of a split liver.

- History of malignancy of any organ system within the past 5 years whether or not there
is evidence of local recurrence or metastases, other than non-metastatic basal or
squamous cell carcinoma of the skin, or HCC (hepatocellular carcinoma) (see next
criteria).

- Hepatocellular carcinoma that does not fulfill Milan criteria (1 nodule = 5 cm, 2-3
nodules all < 3 cm) at the time of transplantation as per explant histology of the
recipient liver.

- Any use of antibody induction therapy.

- Patients with a known hypersensitivity to the drugs used on study or their class, or
to any of the excipients.

- Patients who are recipients of ABO incompatible transplant grafts.

- Recipients of organs from donors who test positive for Hepatitis B surface antigen or
HIV are excluded.

- Patients who have any surgical or medical condition, which in the opinion of the
investigator, might significantly alter the absorption, distribution, metabolism and
excretion of study drug.

- Women of child-bearing potential (WOCBP).

- Patients with any history of coagulopathy or medical condition requiring long-term
anticoagulation which would preclude liver biopsy after transplantation. (Low dose
aspirin treatment or interruption of chronic anticoagulant is allowed).

Other protocol-defined inclusion/exclusion criteria may apply.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/01/2008
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/04/2012
Sample size
Target
Accrual to date
Final
719
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC,WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Camperdown
Recruitment hospital [2] 0 0
Novartis Investigative Site - Bedford Park
Recruitment hospital [3] 0 0
Novartis Investigative Site - Heidelberg
Recruitment hospital [4] 0 0
Novartis Investigative Site - Nedlands
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
5042 - Bedford Park
Recruitment postcode(s) [3] 0 0
3084 - Heidelberg
Recruitment postcode(s) [4] 0 0
6009 - Nedlands
Recruitment outside Australia
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California
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Colorado
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Essen
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Jena
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Leipzig
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Mainz
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Regensburg
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Dublin 4
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Jerusalem
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Israel
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MI
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MO
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Italy
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Pisa
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This trial was designed to address important issues that impact recipients of liver
allografts as well as clinicians, ie, renal function, reduction or discontinuation of
tacrolimus early post-transplantation, and progression rate of fibrosis in hepatitis C virus
(HCV) positive patients.
Trial website
https://clinicaltrials.gov/ct2/show/NCT00622869
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT00622869