Liver TransplantationPhase 3RADNCT00622869
Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients
A Phase 3 study testing Tacrolimus (reduced tacrolimus), Tacrolimus (tacrolimus elimination) and Everolimus (reduced tacrolimus) in people with Liver Transplantation, run by Novartis Pharmaceuticals at 91 sites in 19 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Liver Transplantation
- What is being tested?
- Tacrolimus (reduced tacrolimus), Tacrolimus (tacrolimus elimination) and Everolimus (reduced tacrolimus)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 719 participants
- Where
- 91 sitesin 19 countries
- Study dates
- Jan 2008to Apr 2012
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 12Show fewer
- 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.
Trial locations and contacts
91 sites in 19 countries.
91 sites in 19 countries
United States28 sites
Novartis Investigative Site
Atlanta, Georgia, 30309
Novartis Investigative Site
Aurora, Colorado, 80045
Novartis Investigative Site
Chapel Hill, North Carolina, 27599
Novartis Investigative Site
Charleston, South Carolina, 29425
Novartis Investigative Site
Chicago, Illinois, 60637
Novartis Investigative Site
Cleveland, Ohio, 44195
Novartis Investigative Site
Dallas, Texas, 75208-2312
Novartis Investigative Site
Dallas, Texas, 75246
Novartis Investigative Site
Detroit, Michigan, 48202-2689
Novartis Investigative Site
Durham, North Carolina, 27710
Novartis Investigative Site
Houston, Texas, 77030-2400
Novartis Investigative Site
Houston, Texas, 77030
Novartis Investigative Site
Lexington, Kentucky, 40536-0293
Novartis Investigative Site
Los Angeles, California, 90033
Novartis Investigative Site
Los Angeles, California, 90048
Novartis Investigative Site
Los Angeles, California, 90095
Novartis Investigative Site
Nashville, Tennessee, 37232
Novartis Investigative Site
New York, New York, 10016
Novartis Investigative Site
New York, New York, 10032
Novartis Investigative Site
Newark, New Jersey, 07101
Novartis Investigative Site
Oklahoma City, Oklahoma, 73112
Novartis Investigative Site
Philadelphia, Pennsylvania, 19107
Novartis Investigative Site
Portland, Oregon, 97201-3098
Novartis Investigative Site
Rochester, Minnesota, 55905
Novartis Investigative Site
San Francisco, California, 94143
Novartis Investigative Site
St Louis, Missouri, 63110
Novartis Investigative Site
Tampa, Florida, 33606
Novartis Investigative Site
Washington D.C., District of Columbia, 20007-2197
Germany8 sites
Novartis Investigative Site
Berlin, Germany, 13353
Novartis Investigative Site
Essen, 45147
Novartis Investigative Site
Hamburg, 20246
Novartis Investigative Site
Heidelberg, 69120
Novartis Investigative Site
Jena, 07740
Novartis Investigative Site
Leipzig, 04103
Novartis Investigative Site
Mainz, Germany, 55131
Novartis Investigative Site
Regensburg, 93053
Spain8 sites
Novartis Investigative Site
Barakaldo, Basque Country, 48903
Novartis Investigative Site
Barcelona, Catalonia, 08035
Novartis Investigative Site
Barcelona, Catalonia, 08036
Novartis Investigative Site
L'Hospitalet de Llobregat, Catalonia, 08907
Novartis Investigative Site
Madrid, Madrid, 28007
Novartis Investigative Site
Majadanonda, Madrid, 28222
Novartis Investigative Site
Pamplona, Navarre, 31002
Novartis Investigative Site
Valencia, Valencia, 46026
France7 sites
Novartis Investigative Site
Bordeaux, 33076
Novartis Investigative Site
Clichy, 92110
Novartis Investigative Site
Créteil, 94010
Novartis Investigative Site
Lille, 59000
Novartis Investigative Site
Marseille, 13385
Novartis Investigative Site
Montpellier, 34295
Novartis Investigative Site
Villejuif, 94805
Argentina5 sites
Novartis Investigative Site
Buenos Aires, Buenos Aires, C1118AAT
Novartis Investigative Site
Buenos Aires, Buenos Aires, C1181ACH
Novartis Investigative Site
Buenos Aires, Buenos Aires, W3400ABH
Novartis Investigative Site
Rosario, Santa Fe Province, C2000DSR
Novartis Investigative Site
San Martín, Buenos Aires, C1107BEA
Brazil5 sites
Novartis Investigative Site
Blumenau, Santa Catarina, 89010-500
Novartis Investigative Site
Porto Alegre, Rio Grande do Sul, 90020-090
Novartis Investigative Site
Ribeirão Preto, São Paulo, 14048-900
Novartis Investigative Site
Rio de Janeiro, Rio de Janeiro, 21041-030
Novartis Investigative Site
São Paulo, São Paulo, 01323-900
Italy5 sites
Novartis Investigative Site
Milan, MI, 20162
Novartis Investigative Site
Modena, MO, 41100
Novartis Investigative Site
Pisa, Italy, 56124
Novartis Investigative Site
Roma, RM, 00161
Novartis Investigative Site
Torino, TO, 10126
Australia4 sites
Novartis Investigative Site
Bedford Park, South Australia, 5042
Novartis Investigative Site
Camperdown, New South Wales, 2050
Novartis Investigative Site
Heidelberg, Victoria, 3084
Novartis Investigative Site
Nedlands, Western Australia, 6009
Canada4 sites
Novartis Investigative Site
Edmonton, Alberta, T6G 2B7
Novartis Investigative Site
London, Ontario, N6A 5A5
Novartis Investigative Site
Toronto, Ontario, M5G 2C4
Novartis Investigative Site
Vancouver, British Columbia, V5Z 1M9
Belgium3 sites
Novartis Investigative Site
Ghent, 9000
Novartis Investigative Site
Leuven, 3000
Novartis Investigative Site
Liège, 4000
Colombia3 sites
Novartis Investigative Site
Bogotá
Novartis Investigative Site
Cali
Novartis Investigative Site
Medellín
Israel2 sites
Novartis Investigative Site
Jerusalem, 91120
Novartis Investigative Site
Tel Aviv, 64239
Russia2 sites
Novartis Investigative Site
Moscow, 123182
Novartis Investigative Site
Moscow, 129010
United Kingdom2 sites
Novartis Investigative Site
Edinburgh, ED16 4SA
Novartis Investigative Site
London, SE5 9RS
About this study
Official 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
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.
Read the detailed description
This 24-month study consisted of a screening period, a baseline period (3 to 7 days post-transplantation) followed by a run-in period that ended on the day of randomization at 30 days (± 5 days) post-transplantation. Patients were screened for eligibility prior to liver transplantation. Patients who had undergone successful liver transplantation were initiated on a tacrolimus-based regimen that included corticosteroids and entered the baseline period (between 3 and 7 days post-transplantation). At 30 (± 5) days post-transplantation, patients who met additional randomization inclusion/exclusion criteria were randomized into the study.
- Conditions
- Liver Transplantation
- Being tested
- Tacrolimus (reduced tacrolimus), Tacrolimus (tacrolimus elimination), Tacrolimus (tacrolimus control), Everolimus (reduced tacrolimus), Everolimus (tacrolimus elimination)
- Keywords
- Liver transplantation, everolimus, calcineurin inhibitors, tacrolimus, renal function, MDRD formula, progression of fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tacrolimus (reduced tacrolimus)Drug
Also called FK-506, fujimycin, Prograf, Advagraf
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.
Tacrolimus (tacrolimus elimination)Drug
Also called FK-506, fujimycin, Prograf, Advagraf
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.
Tacrolimus (tacrolimus control)Drug
Also called FK-506, fujimycin, Prograf, Advagraf
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.
Everolimus (reduced tacrolimus)Drug
Also called RAD-001, Zortress, Certican, Afinitor
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.
Everolimus (tacrolimus elimination)Drug
Also called RAD-001, Zortress, Certican, Afinitor
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.
CorticosteroidsDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Everolimus + reduced tacrolimus | Experimental | Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids. Receives: Drug: Tacrolimus (reduced tacrolimus); Drug: Everolimus (reduced tacrolimus); Drug: Corticosteroids |
| Tacrolimus elimination | Experimental | Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids. Receives: Drug: Tacrolimus (tacrolimus elimination); Drug: Everolimus (tacrolimus elimination); Drug: Corticosteroids |
| Tacrolimus control | Active comparator | Control dose tacrolimus + corticosteroids. Receives: Drug: Tacrolimus (tacrolimus control); Drug: Corticosteroids |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence Rate of Composite Efficacy Failure From Randomization to Month 12
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.
Measured: Randomization to Month 12
Secondary outcomes (3)
Incidence Rate of Composite Efficacy Failure From Randomization to Month 24
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.
Measured: Randomization to Month 24
Incidence Rate of Treated Biopsy Proven Acute Rejection (tBPAR) at Months 12 and 24
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.
Measured: Randomization to Month 24
Change in Renal Function From Randomization to Months 12 and 24
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.
Measured: Randomization to Month 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Feb 2008 (estimated)
- Study startJan 2008
- Primary completionApr 2012
- Study completionApr 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Liver TransplantationStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 719 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00622869
- Sponsor's protocol ID
- CRAD001H2304
- Other IDs
- 2007-001821-85
- Acronym
- RAD
- Status last verified
- May 2013
- First submitted
- 13 Feb 2008
- Last updated
- 27 May 2013
- Results posted
- Yes, on ClinicalTrials.gov
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.
PubMed 28817434Fischer 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.
PubMed 26151607Saliba 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.
PubMed 23714399
Study at a glance
From the registry record, last updated by the sponsor on 27 May 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT00622869
- Acronym / sponsor ID
- RAD / CRAD001H2304
- Conditions
- Liver Transplantation
- Keywords
- Liver transplantation, everolimus, calcineurin inhibitors, tacrolimus, renal function, MDRD formula, progression of fibrosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 719 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Jan 2008
- Primary completion
- Apr 2012 (actual)
- Study completion
- Apr 2012 (actual)
- First posted
- 25 Feb 2008 (estimated)
- Results
- Posted 20 May 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This 24-month study consisted of a screening period, a baseline period (3 to 7 days post-transplantation) followed by a run-in period that ended on the day of randomization at 30 days (± 5 days) post-transplantation. Patients were screened for eligibility prior to liver transplantation. Patients who had undergone successful liver transplantation were initiated on a tacrolimus-based regimen that included corticosteroids and entered the baseline period (between 3 and 7 days post-transplantation). At 30 (± 5) days post-transplantation, patients who met additional randomization inclusion/exclusion criteria were randomized into the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Everolimus + reduced tacrolimus | Experimental | Drug: Tacrolimus (reduced tacrolimus), Drug: Everolimus (reduced tacrolimus), Drug: CorticosteroidsLow dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids. |
| Tacrolimus elimination | Experimental | Drug: Tacrolimus (tacrolimus elimination), Drug: Everolimus (tacrolimus elimination), Drug: CorticosteroidsLow-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids. |
| Tacrolimus control | Active comparator | Drug: Tacrolimus (tacrolimus control), Drug: CorticosteroidsControl dose tacrolimus + corticosteroids. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (12 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tacrolimus (reduced tacrolimus)Also: FK-506, fujimycin, Prograf, AdvagrafAfter 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. | Drug | Everolimus + reduced tacrolimus |
| Tacrolimus (tacrolimus elimination)Also: FK-506, fujimycin, Prograf, AdvagrafAfter 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. | Drug | Tacrolimus elimination |
| Tacrolimus (tacrolimus control)Also: FK-506, fujimycin, Prograf, AdvagrafTacrolimus 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. | Drug | Tacrolimus control |
| Everolimus (reduced tacrolimus)Also: RAD-001, Zortress, Certican, AfinitorEverolimus 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. | Drug | Everolimus + reduced tacrolimus |
| Everolimus (tacrolimus elimination)Also: RAD-001, Zortress, Certican, AfinitorEverolimus 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. | Drug | Tacrolimus elimination |
| CorticosteroidsFor 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. | Drug | Everolimus + reduced tacrolimus, Tacrolimus control, Tacrolimus elimination |
Primary outcome
Incidence Rate of Composite Efficacy Failure From Randomization to Month 12
Time frame: Randomization to Month 12
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.
3 secondary outcomes
Incidence Rate of Composite Efficacy Failure From Randomization to Month 24
Time frame: Randomization to Month 24
Incidence Rate of Treated Biopsy Proven Acute Rejection (tBPAR) at Months 12 and 24
Time frame: Randomization to Month 24
Change in Renal Function From Randomization to Months 12 and 24
Time frame: Randomization to Month 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 May 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 28817434Charlton 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.
- Derived from this study: PubMed 26151607Fischer 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.
- Derived from this study: PubMed 23714399Saliba 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.
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Efficacy of Carnitine Complex in Improving Hepatic Steatosis in Potential Liver Donors
Hepatic Steatosis, Fatty Liver
Not yet recruiting
New Biomarkers for Organ Viability Assessment During Hypothermic Machine Perfusion in Liver Transplantation: the Role of Extemporaneous Histological Examination.
Liver Transplantation (LT), Early Allograft Dysfunction
RecruitingPhase 2
Expanding Liver Transplant Immunosuppression Minimization Via Everolimus
Liver Transplant
RecruitingObservational study
Long-term Follow-up (LTFU) Study of Participants in Any iECURE Protocol Using an Investigational Product (IP)
Ornithine Transcarbamylase Deficiency, Ornithine Transcarbamylase Deficiency Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
91 sites in 19 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tacrolimus (reduced tacrolimus), Tacrolimus (tacrolimus elimination) and Everolimus (reduced tacrolimus) in people with Liver Transplantation, run by Novartis Pharmaceuticals at 91 sites in 19 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 May 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 91 sites in United States, Germany, Spain, France, Argentina and 14 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 May 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence Rate of Composite Efficacy Failure From Randomization to Month 12 (time frame: Randomization to Month 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00622869, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 May 2013.