Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients

Liver Transplantation Clinical Trial

— RAD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00622869
• Other study ID #: CRAD001H2304
• Secondary ID: 2007-001821-85
• Status: Completed
• Phase: Phase 3
• First received: February 13, 2008
• Last updated: May 17, 2013
• Start date: January 2008
• Est. completion date: April 2012

Study information

• Verified date: May 2013
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationItaly: The Italian Medicines Agency
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 719
• Est. completion date: April 2012
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Liver Transplantation

Intervention

Drug:
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Martin	Buenos Aires
Australia	Novartis Investigative Site	Bedford Park	South Australia
Australia	Novartis Investigative Site	Camperdown	New South Wales
Australia	Novartis Investigative Site	Heidelberg	Victoria
Australia	Novartis Investigative Site	Nedlands	Western Australia
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Brazil	Novartis Investigative Site	Blumenau	SC
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Ribeirao Preto	SP
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Colombia	Novartis Investigative Site	Bogotá
Colombia	Novartis Investigative Site	Cali
Colombia	Novartis Investigative Site	Medellín
Czech Republic	Novartis Investigative Site	Praha 4
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Clichy
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Jena
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Regensburg
Hungary	Novartis Investigative Site	Budapest
Ireland	Novartis Investigative Site	Dublin 4
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Tel-Aviv
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Pisa
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Torino	TO
Netherlands	Novartis Investigative Site	Rotterdam
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Spain	Novartis Investigative Site	Baracaldo	País Vasco
Spain	Novartis Investigative Site	Barcelona	Cataluña
Spain	Novartis Investigative Site	Barcelona	Cataluña
Spain	Novartis Investigative Site	Hospitalet de Llobregat	Cataluña
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Majadanonda	Madrid
Spain	Novartis Investigative Site	Pamplona	Navarra
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Stockholm
United Kingdom	Novartis Investigative Site	Edinburgh
United Kingdom	Novartis Investigative Site	London
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Aurora	Colorado
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Charleston	South Carolina
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Durham	North Carolina
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Lexington	Kentucky
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	Newark	New Jersey
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Portland	Oregon
United States	Novartis Investigative Site	Rochester	Minnesota
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	St. Louis	Missouri
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  Colombia,  Czech Republic,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Netherlands,  Russian Federation,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Randomization to Month 12	No
Secondary	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.	Randomization to Month 24	No
Secondary	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.	Randomization to Month 24	No
Secondary	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.	Randomization to Month 24	No