Extension Study to Evaluate the Long-term Efficacy and Safety of Everolimus in Liver Transplant Recipients

Liver Transplant Recipient Clinical Trial

Official title:

Extension Study to the Multicenter, Open-label, Randomized, Controlled Study CRAD001H2304 to Evaluate the Long-term Efficacy and Safety of Concentration-controlled Everolimus in Liver Transplant Recipient

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01150097
• Other study ID #: CRAD001H2304E1
• Secondary ID: 2009-017311-15
• Status: Completed
• Phase: Phase 3
• Start date: March 31, 2010
• Est. completion date: May 3, 2013

Study information

• Verified date: October 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The reason for this extension is to evaluate the long-term safety and efficacy of two concentration-controlled everolimus regimen in de novo liver transplant recipients. The most important long-term safety assessments include evaluation of renal function, progression of HCV related allograft fibrosis, and other treatment related effects at Month 36 post-transplantation compared to extension baseline (Months 24 post-transplantation).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 284
• Est. completion date: May 3, 2013
• Est. primary completion date: May 3, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 75 Years

Eligibility

Inclusion Criteria:

• Written informed consent

• Ability and willingness to adhere to study regimen

• Completed core study with assigned regimen;

Exclusion Criteria:

Patients fulfilling any of the following criteria are not eligible for inclusion in this study:

• Severe hypercholesterolemia or hypertriglyceridemia.

• Low platelet count.

• Low white blood cell count.

• Positive test for human immunodeficiency virus (HIV).

• Systemic infection requiring active use of IV antibiotics.

• Patients in a critical care setting.

• Use of prohibited medication.

• Use of immunosuppressive agents not utilized in the protocol.

• Hypersensitivity to any of the study drugs or similar drugs.

• Pregnant or nursing (lactating) women

• Women of child-bearing potential not using a highly effective method of birth control.

Other protocol-defined inclusion/exclusion criteria may apply

Related Conditions & MeSH terms

• Liver Transplant Recipient

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.
• 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.
• 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.
• 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.
• 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.
• 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. The corticosteroids were not specified in the protocol because they were adminsitered to the participants according to local practice as part of standard of care.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
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
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Cali	Valle Del Cauca
Czechia	Novartis Investigative Site	Praha 4	Czech Republic
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Clichy
France	Novartis Investigative Site	Creteil
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	Leipzig
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Regensburg	Bavaria
Ireland	Novartis Investigative Site	Dublin 4
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Pisa	PI
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	Vizcaya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de Llobregat	Barcelona
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Stockholm
United Kingdom	Novartis Investigative Site	Edinburgh
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Charleston	South Carolina
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	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	Rochester	Minnesota
United States	Novartis Investigative Site	Saint 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,  Colombia,  Czechia,  France,  Germany,  Ireland,  Italy,  Netherlands,  Russian Federation,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death	The number of participants who experienced composite efficacy failure was analyzed. 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, and 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, received a graft re-transplant, or died.	from months 24 to 36
Primary	Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death	The number of participants who experienced composite efficacy failure was analyzed. 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, and 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, received a graft re-transplant, or died.	from months 36 to 48
Primary	Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death	The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.	from months 24 to 36
Primary	Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death	The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.	from months 36 - 48
Primary	Change in Renal Function	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.	from months 24 to 36
Secondary	Incidence Rate of tBPAR	The number of participants who had a tBPAR was analyzed. 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, and 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.	from months 24 - 36