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

NCT ID: NCT00622869

Last Updated: 2013-05-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 719 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-01-31
• Study Completion Date: 2012-04-30

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.

Detailed 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.

Conditions

Liver Transplantation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Everolimus + reduced tacrolimus

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

Group Type: EXPERIMENTAL

Tacrolimus (reduced tacrolimus)

Intervention Type: 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.

Everolimus (reduced tacrolimus)

Intervention Type: 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.

Corticosteroids

Intervention Type: 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.

Tacrolimus elimination

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

Group Type: EXPERIMENTAL

Tacrolimus (tacrolimus elimination)

Intervention Type: 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.

Everolimus (tacrolimus elimination)

Intervention Type: 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.

Corticosteroids

Intervention Type: 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.

Tacrolimus control

Control dose tacrolimus + corticosteroids.

Group Type: ACTIVE_COMPARATOR

Tacrolimus (tacrolimus control)

Intervention Type: 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.

Corticosteroids

Intervention Type: 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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Other Intervention Names

FK-506; fujimycin; Prograf; Advagraf; Protopic; FK-506; fujimycin; Prograf; Advagraf; Protopic; FK-506; fujimycin; Prograf; Advagraf; Protopic; RAD-001; Zortress; Certican; Afinitor; RAD-001; Zortress; Certican; Afinitor

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

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Los Angeles, California, United States

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Los Angeles, California, United States

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San Francisco, California, United States

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Washington D.C., District of Columbia, United States

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Ghent, , Belgium

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Prague, Czech Republic, Czechia

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Bordeaux, , France

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References

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.

Reference Type: DERIVED

PMID: 28817434 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26151607 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23714399 (View on PubMed)

Other Identifiers

2007-001821-85

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CRAD001H2304

Identifier Type: -

Identifier Source: org_study_id