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

NCT01150097 | Completed Phase 3 Results DMC

• 2 other identifiers: CRAD001H2304E12009-017311-15
• Study Type: interventional
• Target: 284
• Locations: 16 countries
• Sites: 57

Brief 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).

Conditions

Liver Transplant Recipient

Keywords

Liver transplantation; Everolimus; Calcineurin inhibitors; Tacrolimus; Renal function; Progression of HCV related allograft fibrosis

Outcome Measures

Primary Outcomes (5)

• 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

• 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

• 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

• 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

• 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 Outcomes (1)

• Incidence Rate of tBPAR

  from months 24 - 36

Study Arms (3)

Everolimus + reduced tacrolimus

EXPERIMENTAL

Participants were maintained on whole blood trough levels of 3 - 8 ng/mL everolimus and 3 - 5 ng/mL tacrolimus.

Drug: Tacrolimus (reduced tacrolimus); Drug: Everolimus (reduced tacrolimus); Drug: Corticosteroids

Tacrolimus elimination

EXPERIMENTAL

Participants were maintained on a whole blood trough level of 6 - 10 ng/mL everolimus.

Drug: Tacrolimus (tacrolimus elimination); Drug: Everolimus (tacrolimus elimination); Drug: Corticosteroids

Tacrolimus control

ACTIVE COMPARATOR

Participants were maintained on a whole blood trough level of 6 - 10 ng/mL tacrolimus.

Drug: Tacrolimus (tacrolimus control); Drug: Corticosteroids

Interventions

Tacrolimus (reduced tacrolimus) DRUG

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.

Also known as: FK-506,, fujimycin,, Prograf,, Advagraf,, Protopic

Everolimus + reduced tacrolimus

Everolimus (reduced tacrolimus) DRUG

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.

Also known as: RAD001,, Zortress,, Certican,, Afinitor

Everolimus + reduced tacrolimus

Tacrolimus (tacrolimus elimination) DRUG

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.

Also known as: FK-506,, fujimycin,, Prograf,, Advagraf,, Protopic

Tacrolimus elimination

Everolimus (tacrolimus elimination) DRUG

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.

Also known as: RAD001,, Zortress,, Certican,, Afinitor

Tacrolimus elimination

Tacrolimus (tacrolimus control) DRUG

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.

Also known as: FK-506,, fujimycin,, Prograf,, Advagraf,, Protopic

Tacrolimus control

Corticosteroids DRUG

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.

Everolimus + reduced tacrolimus; Tacrolimus control; Tacrolimus elimination

Eligibility Criteria

• Age: 20 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent
• Ability and willingness to adhere to study regimen
• Completed core study with assigned regimen;

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (57)

Novartis Investigative Site

Washington D.C., District of Columbia, 20007-2197, United States

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Tampa, Florida, 33606, United States

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Lexington, Kentucky, 40536, United States

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Detroit, Michigan, 48202, United States

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Rochester, Minnesota, 55905, United States

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St Louis, Missouri, 63110, United States

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Newark, New Jersey, 07101, United States

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New York, New York, 10016, United States

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New York, New York, 10032, United States

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Chapel Hill, North Carolina, 27599, United States

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Durham, North Carolina, 27710, United States

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Oklahoma City, Oklahoma, 73112, United States

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Charleston, South Carolina, 29425, United States

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Houston, Texas, 77030-2400, United States

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Houston, Texas, 77030, United States

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CABA, Buenos Aires, C1118AAT, Argentina

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San Martín, Buenos Aires, C1107BEA, Argentina

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Camperdown, New South Wales, 2050, Australia

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Bedford Park, South Australia, 5041, Australia

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Heidelberg, Victoria, 3084, Australia

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Ghent, 9000, Belgium

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Leuven, 3000, Belgium

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Liège, 4000, Belgium

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Rio de Janeiro, Rio de Janeiro, 21041-030, Brazil

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Porto Alegre, Rio Grande do Sul, 90020-090, Brazil

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Cali, Valle del Cauca Department, Colombia

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Bogotá, Colombia

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Prague, Czech Republic, 140 21, Czechia

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Bordeaux, 33076, France

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Clichy, 92110, France

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Créteil, 94010, France

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Marseille, 13385, France

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Montpellier, 34295, France

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Villejuif, 94805, France

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Regensburg, Bavaria, 93053, Germany

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Berlin, 13353, Germany

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Essen, 45147, Germany

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Hamburg, 20246, Germany

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Heidelberg, 69120, Germany

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Leipzig, 04103, Germany

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Mainz, 55131, Germany

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Dublin, Ireland

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Milan, MI, 20162, Italy

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Modena, MO, 41124, Italy

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Pisa, PI, 56124, Italy

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Roma, RM, 00161, Italy

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Torino, TO, 10126, Italy

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Rotterdam, 3015 CE, Netherlands

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Moscow, 123182, Russia

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Moscow, 129010, Russia

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L'Hospitalet de Llobregat, Barcelona, 08907, Spain

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Barcelona, Catalonia, 08035, Spain

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Barcelona, Catalonia, 08036, Spain

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Valencia, Valencia, 46026, Spain

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Barakaldo, Vizcaya, 48903, Spain

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Stockholm, 141 86, Sweden

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Edinburgh, EH16 4SA, United Kingdom

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MeSH Terms

Interventions

Tacrolimus; Everolimus; Adrenal Cortex Hormones

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Sirolimus; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2010
• First Posted: June 24, 2010
• Study Start: March 31, 2010
• Primary Completion: May 3, 2013
• Study Completion: May 3, 2013
• Last Updated: November 7, 2018
• Results First Posted: May 30, 2014

Record last verified: 2018-10

Locations

BR (2); US (15); ES (5); CZ (1); NL (1); AR (2); AU (3); RU (2); FR (6); SE (1); IE (1); GB (1); CO (2); DE (7); IT (5); BE (3)