Please note that the copy function is not enabled for this field.
If you wish to
modify
existing outcomes, please copy and paste the current outcome text into the Update field.
LOGIN
CREATE ACCOUNT
LOGIN
CREATE ACCOUNT
MY TRIALS
REGISTER TRIAL
FAQs
HINTS AND TIPS
DEFINITIONS
Trial Review
The ANZCTR website will be unavailable from 1pm until 3pm (AEDT) on Wednesday the 30th of October for website maintenance. Please be sure to log out of the system in order to avoid any loss of data.
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 endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this
information for consumers
Download to PDF
Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/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
Query!
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
Query!
Secondary ID [1]
0
0
2007-001821-85
Query!
Secondary ID [2]
0
0
CRAD001H2304
Query!
Universal Trial Number (UTN)
Query!
Trial acronym
RAD
Query!
Linked study record
Query!
Health condition
Health condition(s) or problem(s) studied:
Liver Transplantation
0
0
Query!
Condition category
Condition code
Intervention/exposure
Study type
Interventional
Query!
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.
Query!
Intervention code [1]
0
0
Treatment: Drugs
Query!
Comparator / control treatment
Query!
Control group
Query!
Outcomes
Primary outcome [1]
0
0
Incidence Rate of Composite Efficacy Failure From Randomization to Month 12
Query!
Assessment method [1]
0
0
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, 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, they received a graft re-transplant, or they died.
The incidence rates of composite efficacy failure were estimated with a Kaplan-Meier product-limit formula.
Query!
Timepoint [1]
0
0
Randomization to Month 12
Query!
Secondary outcome [1]
0
0
Incidence Rate of Composite Efficacy Failure From Randomization to Month 24
Query!
Assessment method [1]
0
0
Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death.
The incidence rates of composite efficacy failure were estimated with a Kaplan-Meier product-limit formula.
Query!
Timepoint [1]
0
0
Randomization to Month 24
Query!
Secondary outcome [2]
0
0
Incidence Rate of Treated Biopsy Proven Acute Rejection (tBPAR) at Months 12 and 24
Query!
Assessment method [2]
0
0
tBPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score = 3, which was treated with anti-rejection therapy. Liver biopsies were collected for all cases of suspected acute rejection preferably within 24 hours, at the latest within 48 hours, whenever clinically possible. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, 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, they received a graft re-transplant, or they died.
The incidence rates of tBPAR were estimated with a Kaplan-Meier product-limit formula.
Query!
Timepoint [2]
0
0
Randomization to Month 24
Query!
Secondary outcome [3]
0
0
Change in Renal Function From Randomization to Months 12 and 24
Query!
Assessment method [3]
0
0
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.
The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported.
Query!
Timepoint [3]
0
0
Randomization to Month 24
Query!
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.
Query!
Minimum age
18
Years
Query!
Query!
Maximum age
70
Years
Query!
Query!
Sex
Both males and females
Query!
Can healthy volunteers participate?
No
Query!
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.
Query!
Study design
Purpose of the study
Treatment
Query!
Allocation to intervention
Randomised controlled trial
Query!
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Query!
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Query!
Masking / blinding
Open (masking not used)
Query!
Who is / are masked / blinded?
Query!
Query!
Query!
Query!
Intervention assignment
Parallel
Query!
Other design features
Query!
Phase
Phase 3
Query!
Type of endpoint/s
Query!
Statistical methods / analysis
Query!
Recruitment
Recruitment status
Completed
Query!
Data analysis
Query!
Reason for early stopping/withdrawal
Query!
Other reasons
Query!
Date of first participant enrolment
Anticipated
Query!
Actual
1/01/2008
Query!
Date of last participant enrolment
Anticipated
Query!
Actual
Query!
Date of last data collection
Anticipated
Query!
Actual
1/04/2012
Query!
Sample size
Target
Query!
Accrual to date
Query!
Final
719
Query!
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC,WA
Query!
Recruitment hospital [1]
0
0
Novartis Investigative Site - Camperdown
Query!
Recruitment hospital [2]
0
0
Novartis Investigative Site - Bedford Park
Query!
Recruitment hospital [3]
0
0
Novartis Investigative Site - Heidelberg
Query!
Recruitment hospital [4]
0
0
Novartis Investigative Site - Nedlands
Query!
Recruitment postcode(s) [1]
0
0
2050 - Camperdown
Query!
Recruitment postcode(s) [2]
0
0
5042 - Bedford Park
Query!
Recruitment postcode(s) [3]
0
0
3084 - Heidelberg
Query!
Recruitment postcode(s) [4]
0
0
6009 - Nedlands
Query!
Recruitment outside Australia
Country [1]
0
0
United States of America
Query!
State/province [1]
0
0
California
Query!
Country [2]
0
0
United States of America
Query!
State/province [2]
0
0
Colorado
Query!
Country [3]
0
0
United States of America
Query!
State/province [3]
0
0
District of Columbia
Query!
Country [4]
0
0
United States of America
Query!
State/province [4]
0
0
Florida
Query!
Country [5]
0
0
United States of America
Query!
State/province [5]
0
0
Georgia
Query!
Country [6]
0
0
United States of America
Query!
State/province [6]
0
0
Illinois
Query!
Country [7]
0
0
United States of America
Query!
State/province [7]
0
0
Kentucky
Query!
Country [8]
0
0
United States of America
Query!
State/province [8]
0
0
Michigan
Query!
Country [9]
0
0
United States of America
Query!
State/province [9]
0
0
Minnesota
Query!
Country [10]
0
0
United States of America
Query!
State/province [10]
0
0
Missouri
Query!
Country [11]
0
0
United States of America
Query!
State/province [11]
0
0
New Jersey
Query!
Country [12]
0
0
United States of America
Query!
State/province [12]
0
0
New York
Query!
Country [13]
0
0
United States of America
Query!
State/province [13]
0
0
North Carolina
Query!
Country [14]
0
0
United States of America
Query!
State/province [14]
0
0
Ohio
Query!
Country [15]
0
0
United States of America
Query!
State/province [15]
0
0
Oklahoma
Query!
Country [16]
0
0
United States of America
Query!
State/province [16]
0
0
Oregon
Query!
Country [17]
0
0
United States of America
Query!
State/province [17]
0
0
Pennsylvania
Query!
Country [18]
0
0
United States of America
Query!
State/province [18]
0
0
South Carolina
Query!
Country [19]
0
0
United States of America
Query!
State/province [19]
0
0
Tennessee
Query!
Country [20]
0
0
United States of America
Query!
State/province [20]
0
0
Texas
Query!
Country [21]
0
0
Argentina
Query!
State/province [21]
0
0
Buenos Aires
Query!
Country [22]
0
0
Argentina
Query!
State/province [22]
0
0
Santa Fe
Query!
Country [23]
0
0
Belgium
Query!
State/province [23]
0
0
Gent
Query!
Country [24]
0
0
Belgium
Query!
State/province [24]
0
0
Leuven
Query!
Country [25]
0
0
Belgium
Query!
State/province [25]
0
0
Liege
Query!
Country [26]
0
0
Brazil
Query!
State/province [26]
0
0
RJ
Query!
Country [27]
0
0
Brazil
Query!
State/province [27]
0
0
RS
Query!
Country [28]
0
0
Brazil
Query!
State/province [28]
0
0
SC
Query!
Country [29]
0
0
Brazil
Query!
State/province [29]
0
0
SP
Query!
Country [30]
0
0
Canada
Query!
State/province [30]
0
0
Alberta
Query!
Country [31]
0
0
Canada
Query!
State/province [31]
0
0
British Columbia
Query!
Country [32]
0
0
Canada
Query!
State/province [32]
0
0
Ontario
Query!
Country [33]
0
0
Colombia
Query!
State/province [33]
0
0
Bogotá
Query!
Country [34]
0
0
Colombia
Query!
State/province [34]
0
0
Cali
Query!
Country [35]
0
0
Colombia
Query!
State/province [35]
0
0
Medellín
Query!
Country [36]
0
0
Czech Republic
Query!
State/province [36]
0
0
Praha 4
Query!
Country [37]
0
0
France
Query!
State/province [37]
0
0
Bordeaux Cedex
Query!
Country [38]
0
0
France
Query!
State/province [38]
0
0
Clichy
Query!
Country [39]
0
0
France
Query!
State/province [39]
0
0
Creteil
Query!
Country [40]
0
0
France
Query!
State/province [40]
0
0
Lille
Query!
Country [41]
0
0
France
Query!
State/province [41]
0
0
Marseille
Query!
Country [42]
0
0
France
Query!
State/province [42]
0
0
Montpellier
Query!
Country [43]
0
0
France
Query!
State/province [43]
0
0
Villejuif
Query!
Country [44]
0
0
Germany
Query!
State/province [44]
0
0
Berlin
Query!
Country [45]
0
0
Germany
Query!
State/province [45]
0
0
Essen
Query!
Country [46]
0
0
Germany
Query!
State/province [46]
0
0
Hamburg
Query!
Country [47]
0
0
Germany
Query!
State/province [47]
0
0
Heidelberg
Query!
Country [48]
0
0
Germany
Query!
State/province [48]
0
0
Jena
Query!
Country [49]
0
0
Germany
Query!
State/province [49]
0
0
Leipzig
Query!
Country [50]
0
0
Germany
Query!
State/province [50]
0
0
Mainz
Query!
Country [51]
0
0
Germany
Query!
State/province [51]
0
0
Regensburg
Query!
Country [52]
0
0
Hungary
Query!
State/province [52]
0
0
Budapest
Query!
Country [53]
0
0
Ireland
Query!
State/province [53]
0
0
Dublin 4
Query!
Country [54]
0
0
Israel
Query!
State/province [54]
0
0
Jerusalem
Query!
Country [55]
0
0
Israel
Query!
State/province [55]
0
0
Tel-Aviv
Query!
Country [56]
0
0
Italy
Query!
State/province [56]
0
0
MI
Query!
Country [57]
0
0
Italy
Query!
State/province [57]
0
0
MO
Query!
Country [58]
0
0
Italy
Query!
State/province [58]
0
0
RM
Query!
Country [59]
0
0
Italy
Query!
State/province [59]
0
0
TO
Query!
Country [60]
0
0
Italy
Query!
State/province [60]
0
0
Pisa
Query!
Country [61]
0
0
Netherlands
Query!
State/province [61]
0
0
Rotterdam
Query!
Country [62]
0
0
Russian Federation
Query!
State/province [62]
0
0
Moscow
Query!
Country [63]
0
0
Spain
Query!
State/province [63]
0
0
Cataluña
Query!
Country [64]
0
0
Spain
Query!
State/province [64]
0
0
Comunidad Valenciana
Query!
Country [65]
0
0
Spain
Query!
State/province [65]
0
0
Madrid
Query!
Country [66]
0
0
Spain
Query!
State/province [66]
0
0
Navarra
Query!
Country [67]
0
0
Spain
Query!
State/province [67]
0
0
País Vasco
Query!
Country [68]
0
0
Sweden
Query!
State/province [68]
0
0
Stockholm
Query!
Country [69]
0
0
United Kingdom
Query!
State/province [69]
0
0
Edinburgh
Query!
Country [70]
0
0
United Kingdom
Query!
State/province [70]
0
0
London
Query!
Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Query!
Name
Novartis Pharmaceuticals
Query!
Address
Query!
Country
Query!
Ethics approval
Ethics application status
Query!
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.
Query!
Trial website
https://clinicaltrials.gov/study/NCT00622869
Query!
Trial related presentations / publications
Charlton M, Rinella M, Patel D, McCague K, Heimbach J, Watt K. Everolimus Is Associated With Less Weight Gain Than Tacrolimus 2 Years After Liver Transplantation: Results of a Randomized Multicenter Study. Transplantation. 2017 Dec;101(12):2873-2882. doi: 10.1097/TP.0000000000001913. Fischer L, Saliba F, Kaiser GM, De Carlis L, Metselaar HJ, De Simone P, Duvoux C, Nevens F, Fung JJ, Dong G, Rauer B, Junge G; H2304 Study Group. Three-year Outcomes in De Novo Liver Transplant Patients Receiving Everolimus With Reduced Tacrolimus: Follow-Up Results From a Randomized, Multicenter Study. Transplantation. 2015 Jul;99(7):1455-62. doi: 10.1097/TP.0000000000000555. Saliba F, De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, Jonas S, Sudan D, Fischer L, Duvoux C, Chavin KD, Koneru B, Huang MA, Chapman WC, Foltys D, Dong G, Lopez PM, Fung J, Junge G; H2304 Study Group. Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant. 2013 Jul;13(7):1734-45. doi: 10.1111/ajt.12280. Epub 2013 May 28.
Query!
Public notes
Query!
Contacts
Principal investigator
Name
0
0
Novartis Pharmaceuticals
Query!
Address
0
0
Novartis Pharmaceuticals
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for public queries
Name
0
0
Query!
Address
0
0
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT00622869
Download to PDF