Efficacy and Safety of Everolimus in Liver Transplant Recipients of Living Donor Liver Transplants

NCT01888432 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: CRAD001H23072010-024527-25
• Study Type: interventional
• Target: 285
• Locations: 13 countries
• Sites: 42

Brief Summary

The purpose of this trial was to demonstrate the efficacy and safety of everolimus in combination with reduced tacrolimus, compared to tacrolimus control, in living donor liver transplant recipients.

Conditions

Liver Transplantation

Keywords

liver transplantation; everolimus; tacrolimus; reduced calcineuron inhibitor; renal function; living donor; RAD001H2307; RAD001H

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Composite Efficacy Failure of Treated Biopsy Proven Acute Rejection, Graft Loss or Death in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus

  Rate of composite efficacy failure of treated biopsy proven acute rejection (tBPAR ≥ RAI score 3), graft loss (GL) or death (D) in everolimus with reduced tacrolimus group compared to standard tacrolimus at 12 months

  12 months post transplantation

Secondary Outcomes (15)

• Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization

  From randomization to month 12

• Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization

  From randomziation to month 24

• Number of Participants With Composite of tBPAR, Graft Loss, and Death

  Month 24 post transplantation

• Compare Incidence of tBPAR

  Month 12 and Month 24 post transplantation

• Compare Incidence of BPAR

  Month 12 and Month 24 post transplantation

Study Arms (2)

Everolimus + reduced tacrolimus

EXPERIMENTAL

Everolimus + reduced tacrolimus ± corticosteroids

Drug: Everolimus + reduced tacrolimus

Standard tacrolimus

ACTIVE COMPARATOR

Standard tacrolimus ± corticosteroids

Drug: Standard tacrolimus

Interventions

Everolimus + reduced tacrolimus DRUG

Everolimus was initiated at Week 4 post transplantation. The dose was adjusted to maintain the everolimus trough blood levels between 3-8 ng/mL for the duration of the study. Tacrolimus was reduced to 3-5 ng/mL.

Everolimus + reduced tacrolimus

Standard tacrolimus DRUG

Tacrolimus was initiated as soon as possible after transplantation according to approved labeling recommendations. The trough level should've been 5-15 ng/mL until randomization, 8-12 ng/mL from randomization until month 4 and after month 4 until end of study reduced to 6 -10 ng/mL.

Standard tacrolimus

Eligibility Criteria

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

You may qualify if:

• Written informed consent
• Subject aged ≥18 years of a primary, orthotopic liver allograft, from a living donor
• Subject negative for HIV
• Incusion criteria at Randomization:
• \- Subject was initated on tacrolimus-based immunosuppressive regimen with steroids and other immunosuppression

You may not qualify if:

• Subjects transplanted for acute liver failure
• HCV negativesubjects receiving a transplant from HCV positive donor
• Subjects receiving multiple solid organ (including multiple liver lobes/segments) or islet cell tissue transplants, or have previously received an organ or tissue transplant.
• Subjects receiving an ABO incompatible allograft.
• MELD-score \> 35 within 1 month prior to transplantation.
• Use of immunosuppressive or antibody induction agents not specified in the protocol.
• History of malignancy of any organ system (except hepatocellular carcinoma or localized basal cell carcinoma of the skin)
• Hepatocellular carcinoma with extrahepatic spread or macrovascular invasion
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 2 weeks after the last dose of study medication
• History of hypersensitivity to any of the study drugs or to drugs with similar chemical class, or to any of the excipients
• Any post-transplant history of thrombosis, occlusion or stent placement in any major hepatic arteries, hepatic veins, portal vein or inferior vena cava at any time during the run-in period prior to randomization.
• Subjects with a confirmed spot urine protein/creatinine ratio that indicates ≥ 1.0 g/24 hrs of proteinuria
• Subjects who have severe hypercholesterolemia (\>350 mg/dL; \>9.1 mmol/L) or hypertriglyceridemia (\>500 mg/dL; \>5.6 mmol/L) at randomization.
• Subjects with platelet count \< 30,000/mm3.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (42)

Novartis Investigative Site

Los Angeles, California, 90033, United States

Location

Novartis Investigative Site

San Francisco, California, 94143, United States

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Novartis Investigative Site

Baltimore, Maryland, 21201, United States

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Novartis Investigative Site

Boston, Massachusetts, 02114, United States

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Novartis Investigative Site

Burlington, Massachusetts, 01805, United States

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Novartis Investigative Site

Detroit, Michigan, 48202, United States

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Novartis Investigative Site

Minneapolis, Minnesota, 55455, United States

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Novartis Investigative Site

New York, New York, 10032, United States

Location

Novartis Investigative Site

Charlottesville, Virginia, 22908, United States

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Novartis Investigative Site

Toronto, Ontario, M5G 2N2, Canada

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Novartis Investigative Site

Cairo, Egypt

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Novartis Investigative Site

Regensburg, Bavaria, 93053, Germany

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Novartis Investigative Site

Berlin, 13353, Germany

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Novartis Investigative Site

Jena, 07740, Germany

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Novartis Investigative Site

Kiel, 24105, Germany

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Novartis Investigative Site

Gurgaon, Haryana, 122 001, India

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Novartis Investigative Site

Kochi, Kerala, 682 026, India

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Novartis Investigative Site

Chennai, Tamil Nadu, 600006, India

Location

Novartis Investigative Site

Chennai, Tamil Nadu, 600100, India

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Novartis Investigative Site

Milan, MI, 20162, Italy

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Novartis Investigative Site

Nagoya, Aichi-ken, 466 8560, Japan

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Novartis Investigative Site

Fukuoka, Fukuoka, 812-8582, Japan

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Novartis Investigative Site

Hiroshima, Hiroshima, 734-8551, Japan

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Novartis Investigative Site

Kumamoto, Kumamoto, 860-8556, Japan

Location

Novartis Investigative Site

Sakyo Ku, Kyoto, 606 8507, Japan

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Novartis Investigative Site

Nagasaki, Nagasaki, 852-8501, Japan

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Novartis Investigative Site

Okayama, Okayama-ken, 700-8558, Japan

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Novartis Investigative Site

Bunkyo Ku, Tokyo, 113 8655, Japan

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Novartis Investigative Site

Shinjuku-ku, Tokyo, 160-8582, Japan

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Novartis Investigative Site

Moscow, 123182, Russia

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Novartis Investigative Site

Riyadh, 11211, Saudi Arabia

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Novartis Investigative Site

Singapore, 119260, Singapore

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Novartis Investigative Site

Seoul, Gyeonggi-do, 03080, South Korea

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Novartis Investigative Site

Seoul, Korea, 05505, South Korea

Location

Novartis Investigative Site

Seoul, Korea, 06351, South Korea

Location

Novartis Investigative Site

Seoul, 03722, South Korea

Location

Novartis Investigative Site

Kaohsiung City, 83301, Taiwan

Location

Novartis Investigative Site

Taichung, 40447, Taiwan

Location

Novartis Investigative Site

Taipei, 11217, Taiwan

Location

Novartis Investigative Site

Taoyuan District, 33305, Taiwan

Location

Novartis Investigative Site

Malatya, 44280, Turkey (Türkiye)

Location

Novartis Investigative Site

Mecidiyekoy/Istanbul, 34394, Turkey (Türkiye)

Location

Related Publications (1)

• Jeng LB, Lee SG, Soin AS, Lee WC, Suh KS, Joo DJ, Uemoto S, Joh J, Yoshizumi T, Yang HR, Song GW, Lopez P, Kochuparampil J, Sips C, Kaneko S, Levy G. Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study. Am J Transplant. 2018 Jun;18(6):1435-1446. doi: 10.1111/ajt.14623. Epub 2018 Jan 25.

  PMID: 29237235 DERIVED

MeSH Terms

Interventions

Everolimus

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

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: SINGLE
• Who Masked: CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This was a 24-month, multicenter, open-label, randomized, controlled study. It included the extension to the 24-month, randomized, controlled, open-label CRAD001H2307 study in recipients of living donor liver transplants in Japan.

Study Record Dates

• First Submitted: June 15, 2013
• First Posted: June 27, 2013
• Study Start: September 25, 2013
• Primary Completion: October 19, 2016
• Study Completion: April 21, 2018
• Last Updated: March 18, 2019
• Results First Posted: November 13, 2018

Record last verified: 2019-02

Locations

US (9); KR (4); TW (4); IT (1); TU (2); DE (4); IN (4); RU (1); CA (1); SA (1); SG (1); JP (9); EG (1)