A Twelve-month, Multicenter, Open-label, Randomized Study of the Safety, Tolerability and Efficacy of Everolimus With Basiliximab, Corticosteroids and Two Different Exposure Levels of Tacrolimus in de Novo Renal Transplant Recipients

Study Description

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Brief Summary:

This study is designed to evaluate whether tacrolimus dose reduction in de novo renal recipients receiving everolimus can preserve renal function while maintaining efficacy.

Condition or disease	Intervention/treatment	Phase
Renal Transplantation	Drug: Everolimus (RAD001); Drug: Tacrolimus; Drug: Basiliximab; Drug: Corticosteroids	Phase 4

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	228 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	A Twelve-month, Multicenter, Open-label, Randomized Study of the Safety, Tolerability and Efficacy of Everolimus With IL-2 Receptor Antagonist, Corticosteroids and Two Different Exposure Levels of Tacrolimus in de Novo Renal Transplant Recipients
Study Start Date :	June 2006
Actual Primary Completion Date :	December 2008
Actual Study Completion Date :	December 2008

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Very low dose tacrolimus; The first dose of everolimus was to be administered not later than 24 hours after transplantation with a starting dose of 1.5 mg bis in diem/twice a day (b.i.d.) thereafter adjusted to maintain the trough blood levels between 3 and 8 ng/ml. Tacrolimus was to be initiated within 24 hours after reperfusion of the graft with a starting dose of 0.1 mg/kg/day thereafter adjusted to maintain the trough blood levels between 4 and 7 ng/ml. Up to months three all patients received the same treatment and after three months patients in this arm received tacrolimus to reach a trough blood level between 1.5 and 3 ng/ml. All patients received two doses of 20 mg basiliximab, administered as an intravenous bolus injection. The first dose was given on the day of transplantation, with the second dose being administered on the fourth day post-transplant. Intravenous (i.v.) prednisone (or equivalent) was given pre- or intra-operatively according to center practice.	Drug: Everolimus (RAD001) Drug: Tacrolimus Drug: Basiliximab Drug: Corticosteroids
Active Comparator: Low dose tacrolimus; The first dose of everolimus was to be administered not later than 24 hours after transplantation with a starting dose of 1.5 mg bis in diem/twice a day (b.i.d.) thereafter adjusted to maintain the trough blood levels between 3 and 8 ng/ml. Tacrolimus was to be initiated within 24 hours after reperfusion of the graft with a starting dose of 0.1 mg/kg/day thereafter adjusted to maintain the trough blood levels between 4 and 7 ng/ml. Up to months three all patients received the same treatment and after three months patients in this arm received tacrolimus to reach a trough blood level between 4 and 7 ng/ml. All patients received two doses of 20 mg basiliximab, administered as an intravenous bolus injection. The first dose was given on the day of transplantation, with the second dose being administered on the fourth day post-transplant. Intravenous (i.v.) prednisone (or equivalent) was given pre- or intra-operatively according to center practice.	Drug: Everolimus (RAD001) Drug: Tacrolimus Drug: Basiliximab Drug: Corticosteroids

Outcome Measures

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Primary Outcome Measures :

1. Renal Function Assessed by Calculated Glomerular Filtration Rate (cGFR) [ Time Frame: 12 months post -transplant ]

   Renal function was assessed by calculated glomerular filtration rate (cGFR) using Modification of Diet in Renal Disease (MDRD)formula.

   GFR [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 patient age at sample collection date [years],
   • G=0.742 when gender is female, otherwise G=1,
   • R=1.21 when race is black, otherwise R=1

Secondary Outcome Measures :

1. Number of Participants With Incidence of Biopsy-proven Acute Rejection (BPAR) [ Time Frame: from Month 4 through to Month 12 ]
   Biopsy-proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy (performed by the local pathologist). For all clinically suspected rejection episodes a graft core biopsy must have been performed before or within a 24 hour period from the initiation of anti-rejection therapy.
2. Percentage of Participants With Efficacy Failure [ Time Frame: Month 12 ]
   Efficacy failure was a composite of BPAR, graft loss, death or lost to follow-up. BPAR was defined as a clinically suspected acute rejection confirmed by biopsy (performed by the local pathologist). For all clinically suspected rejection episodes a graft core biopsy must have been performed before or within a 24 hour period from the initiation of anti-rejection therapy. An allograft was presumed to be lost on the day a patient started dialysis and was unable to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, the day of nephrectomy was the day of graft loss.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria

• Male or female of 18-65 years old
• Patient who has received a primary kidney transplant from a cadaveric, living unrelated or non-human leucocyte antigen (HLA) identical living related donor
• Recipient of a kidney with a cold ischemia time (CIT) < 30 hours
• Recipient of a kidney from a donor 10-65 years old
• Patient able to receive the first dose of tacrolimus within 24 hours from graft reperfusion
• Female capable of becoming pregnant must have a negative pregnancy test and is required to practice a medically approved method of birth control for the duration of the study and for a period of three months following discontinuation of investigational drug
• Patient willing and capable of giving written informed consent for study participation and able to participate in the study for 12 months

Exclusion criteria

• Patient who has previously received an organ transplant
• Recipient of multiple organ transplants
• Recipient of a kidney transplant from a non heart-beating donor
• Recipient of donor specific transfusions
• Recipient of A-B-O incompatible transplant or T-cell cross-match positive transplant
• Patient with current Panel Reactive Antibodies (PRA) level ≥ 50%
• Recipient of a kidney from a donor who tests positive for hepatitis B surface antigen or hepatitis C antibodies
• Patient who is human immunodeficiency virus (HIV) positive
• Patient who has a positive hepatitis C serology or who is hepatitis B surface antigen positive with evidence of liver injury as indicated by aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels ≥2.5 times upper limit of normal (UNL). Viral serology results obtained within 6 months prior to the administration of the first dose of Certican™ are acceptable
• Patient with severe hypercholesterolemia (350 mg/dL, 9.1 mmoL/dL) or hypertriglyceridemia ( 500 mg/dL, 5.6 mmoL/L)
• Patient with white blood cell (WBC) count 3,000/mm3 or with platelet count 75,000/mm3
• Patient with any severe allergy requiring acute (within 4 weeks of baseline) or chronic treatment, or with hypersensitivity to drugs similar to Certican (e.g., macrolides)
• Patient who has been treated with an immunosuppressive drug or an investigational drug within 4 weeks prior to the administration of the first dose of Certican
• Patient with uncontrolled infection
• Patient with any surgical or medical condition, other than the current transplant, which in the opinion of the investigator, precludes enrollment in this trial
• Patient with a known malignancy or a history of malignancy within last 5 years other than successfully treated localized basal or squamous cell carcinoma of the skin
• Abnormal physical or laboratory findings of clinical significance within 2 weeks prior to the administration of the first dose of Certican™ which at investigator's discretion would interfere with the objectives of the study
• Breast feeding women
• Patient with symptoms of significant somatic or mental illness or with unresolved history of drug or alcohol abuse
• Patient unable to cooperate or communicate with the investigator

Contacts and Locations

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Locations

Switzerland
Novartis
Basel, Switzerland

Sponsors and Collaborators

Novartis

Investigators

Study Director:	Novartis	Novartis

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Langer RM, Hené R, Vitko S, Christiaans M, Tedesco-Silva H Jr, Ciechanowski K, Cassuto E, Rostaing L, Vilatoba M, Machein U, Ulbricht B, Junge G, Dong G, Pascual J. Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation. Transpl Int. 2012 May;25(5):592-602. doi: 10.1111/j.1432-2277.2012.01465.x. Epub 2012 Mar 26.

Responsible Party:	External Affairs, Novartis Pharmaceticals
ClinicalTrials.gov Identifier:	NCT00369161 History of Changes
Other Study ID Numbers:	CRAD001A2426
First Posted:	August 29, 2006
Results First Posted:	January 19, 2011
Last Update Posted:	March 3, 2017
Last Verified:	February 2017

Additional relevant MeSH terms:

Tacrolimus; Everolimus; Sirolimus; Basiliximab; Antibodies, Monoclonal; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs	Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents