Clinical trial NCT00622869: Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Liver Transplantation
Keywords: Liver transplantation
everolimus
calcineurin inhibitors
tacrolimus
renal function
MDRD formula
progression of fibrosis
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-02-25
Enrollment: 719
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

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.

Primary outcomes:
measure: Incidence Rate of Composite Efficacy Failure From Randomization to Month 12
timeFrame: Randomization to Month 12
Secondary outcomes:
measure: Incidence Rate of Composite Efficacy Failure From Randomization to Month 24
timeFrame: Randomization to Month 24
measure: Incidence Rate of Treated Biopsy Proven Acute Rejection (tBPAR) at Months 12 and 24
timeFrame: Randomization to Month 24
measure: Change in Renal Function From Randomization to Months 12 and 24
timeFrame: Randomization to Month 24
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Washington
country: United States
facility: Novartis Investigative Site
state: District of Columbia
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Lexington
country: United States
facility: Novartis Investigative Site
state: Kentucky
city: Detroit
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Rochester
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: St. Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Newark
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Chapel Hill
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Durham
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Oklahoma City
country: United States
facility: Novartis Investigative Site
state: Oklahoma
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Charleston
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Martin
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Camperdown
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Bedford Park
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Blumenau
country: Brazil
facility: Novartis Investigative Site
state: SC
city: Ribeirao Preto
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Bogotá
country: Colombia
facility: Novartis Investigative Site
city: Cali
country: Colombia
facility: Novartis Investigative Site
city: Medellín
country: Colombia
facility: Novartis Investigative Site
city: Praha 4
country: Czech Republic
facility: Novartis Investigative Site
city: Bordeaux Cedex
country: France
facility: Novartis Investigative Site
city: Clichy
country: France
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Dublin 4
country: Ireland
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Tel-Aviv
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Pisa
country: Italy
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluña
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluña
city: Hospitalet de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Cataluña
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Majadanonda
country: Spain
facility: Novartis Investigative Site
state: Madrid
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: Baracaldo
country: Spain
facility: Novartis Investigative Site
state: País Vasco
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Edinburgh
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.