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

NCT00622869 | Completed Phase 3 Results

• 2 other identifiers: CRAD001H23042007-001821-85
• Study Type: interventional
• Target: 719
• Locations: 19 countries
• Sites: 91

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.

Conditions

Liver Transplantation

Keywords

Liver transplantation; everolimus; calcineurin inhibitors; tacrolimus; renal function; MDRD formula; progression of fibrosis

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (3)

• Incidence Rate of Composite Efficacy Failure From Randomization to Month 24

  Randomization to Month 24

• Incidence Rate of Treated Biopsy Proven Acute Rejection (tBPAR) at Months 12 and 24

  Randomization to Month 24

• Change in Renal Function From Randomization to Months 12 and 24

  Randomization to Month 24

Study Arms (3)

Everolimus + reduced tacrolimus

EXPERIMENTAL

Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.

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

Tacrolimus elimination

EXPERIMENTAL

Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.

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

Tacrolimus control

ACTIVE COMPARATOR

Control dose tacrolimus + corticosteroids.

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

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

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

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: RAD-001, Zortress, Certican, Afinitor

Everolimus + reduced tacrolimus

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: RAD-001, Zortress, Certican, Afinitor

Tacrolimus elimination

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.

Everolimus + reduced tacrolimus; Tacrolimus control; Tacrolimus elimination

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (91)

Novartis Investigative Site

Los Angeles, California, 90033, United States

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Los Angeles, California, 90048, United States

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Los Angeles, California, 90095, United States

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Novartis Investigative Site

San Francisco, California, 94143, United States

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Aurora, Colorado, 80045, United States

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

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Tampa, Florida, 33606, United States

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Atlanta, Georgia, 30309, United States

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Novartis Investigative Site

Chicago, Illinois, 60637, United States

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Lexington, Kentucky, 40536-0293, United States

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Detroit, Michigan, 48202-2689, 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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Cleveland, Ohio, 44195, United States

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Oklahoma City, Oklahoma, 73112, United States

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Portland, Oregon, 97201-3098, United States

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Philadelphia, Pennsylvania, 19107, United States

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Charleston, South Carolina, 29425, United States

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Nashville, Tennessee, 37232, United States

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Dallas, Texas, 75208-2312, United States

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Dallas, Texas, 75246, United States

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Houston, Texas, 77030-2400, United States

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Novartis Investigative Site

Houston, Texas, 77030, United States

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Buenos Aires, Buenos Aires, C1118AAT, Argentina

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Buenos Aires, Buenos Aires, C1181ACH, Argentina

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Buenos Aires, Buenos Aires, W3400ABH, Argentina

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San Martín, Buenos Aires, C1107BEA, Argentina

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Rosario, Santa Fe Province, C2000DSR, Argentina

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Camperdown, New South Wales, 2050, Australia

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Bedford Park, South Australia, 5042, Australia

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Heidelberg, Victoria, 3084, Australia

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Nedlands, Western Australia, 6009, 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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Blumenau, Santa Catarina, 89010-500, Brazil

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Ribeirão Preto, São Paulo, 14048-900, Brazil

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São Paulo, São Paulo, 01323-900, Brazil

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Edmonton, Alberta, T6G 2B7, Canada

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Vancouver, British Columbia, V5Z 1M9, Canada

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London, Ontario, N6A 5A5, Canada

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Toronto, Ontario, M5G 2C4, Canada

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Bogotá, Colombia

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Cali, Colombia

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Medellín, 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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Lille, 59000, 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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Berlin, Germany, 13353, Germany

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Mainz, Germany, 55131, 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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Jena, 07740, Germany

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Leipzig, 04103, Germany

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Regensburg, 93053, Germany

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Budapest, 1082, Hungary

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Dublin, Ireland, Ireland

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Jerusalem, 91120, Israel

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Tel Aviv, 64239, Israel

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Pisa, Italy, 56124, Italy

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Milan, MI, 20162, Italy

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Modena, MO, 41100, 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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Novartis Investigative Site

Moscow, 129010, Russia

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Novartis Investigative Site

Barakaldo, Basque Country, 48903, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

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Barcelona, Catalonia, 08036, Spain

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Novartis Investigative Site

L'Hospitalet de Llobregat, Catalonia, 08907, Spain

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Novartis Investigative Site

Madrid, Madrid, 28007, Spain

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Majadanonda, Madrid, 28222, Spain

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Pamplona, Navarre, 31002, Spain

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Valencia, Valencia, 46026, Spain

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Stockholm, 141 86, Sweden

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Edinburgh, ED16 4SA, United Kingdom

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Novartis Investigative Site

London, SE5 9RS, United Kingdom

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Related Publications (3)

• 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.

  PMID: 28817434 DERIVED

• 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.

  PMID: 26151607 DERIVED

• 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.

  PMID: 23714399 DERIVED

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: February 13, 2008
• First Posted: February 25, 2008
• Study Start: January 1, 2008
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: May 27, 2013
• Results First Posted: May 20, 2013

Record last verified: 2013-05

Locations

BR (5); FR (7); US (28); CA (4); SE (1); ES (8); RU (2); IT (5); CZ (1); AU (4); AR (5); DE (8); GB (2); BE (3); HU (1); IE (1); IL (2); NL (1); CO (3)