A 12-month open-label, randomized, multicenter, sequential cohort, dose finding study to evaluate the efficacy, safety and tolerability of oral AEB071 versus tacrolimus® in combination with myfortic®, Simulect® and corticosteroids in de novo adult renal transplant recipient

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-004128-35-GB
• Date of registration: 29/03/2007
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A 12-month open-label, randomized, multicenter, sequential cohort, dose finding study to evaluate the efficacy, safety and tolerability of oral AEB071 versus tacrolimus® in combination with myfortic®, Simulect® and corticosteroids in de novo adult renal transplant recipient
• Scientific title: A 12-month open-label, randomized, multicenter, sequential cohort, dose finding study to evaluate the efficacy, safety and tolerability of oral AEB071 versus tacrolimus® in combination with myfortic®, Simulect® and corticosteroids in de novo adult renal transplant recipient
• Date of first enrolment: 25/06/2007
• Target sample size: 279
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-004128-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: yes Other trial design description: sequential cohort If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: myfortic + tacrolimus

Countries of recruitment

Belgium, Germany, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
• Male and female patients of any race = 18 years old
• Recipients of a primary kidney transplant from a deceased, living unrelated or non-HLA identical living related donor
• Recipients of a kidney with a cold ischemic time (CIT) < 24 hours
• Recipients of a kidney from a donor 10-65 years old
• Patients expected to be able to take oral medication within 24 hours after graft reperfusion
• Patients willing and capable of giving written informed consent for study participation and able to participate in the study for 12 months

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
• Multi-organ transplant recipients or if the patient previously received an organ transplant
• Recipients of an organ from a non-heart beating donor
• Patients who are recipients of A-B-O incompatible transplants, all CDC crossmatch positive transplants
• Patients without functional graft 24 hours after graft reperfusion; functional graft being defined as urine output of more than 250 mL/12 hours for patients without residual urinary output from native kidneys, or a decrease in serum creatinine by at least 20% from pre-transplant
• Patients with an absolute neutrophil count of < 1,500/mm3, or absolute leukocytes count < 2,500/mm3 or platelet count < 100,000/mm3 at screening.
• Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4 at screening and can not discontinue this treatment (see Appendix 3)
• Patients with long QT-syndrome, or QTc at baseline exceeding 500 msec, or who are treated with drugs inducing QT prolongation at screening (see appendix 3), and can not discontinue this treatment
• Patients requiring antiarrhythmic drugs with QT-prolonging properties (such as amiodarone, sotalol, dofetilide, quinidine, procainamide, disopyramide)
• Patients a family history of long QT syndrome or of sudden unexplained death
• Patients with a family history of long QT syndrome or of sudden unexplained death
• Patients with left branch bundle block (LBBB) or who experienced, during the previous 6 months, hospitalization for heart failure of cardiac etiology, or left-ventricular dysfunction (LVEF <40%)
• Patients with a history, in the preceding 3 months, of significant and persistent
arrhythmias such as ventricular fibrillation or tachycardia, atrial fibrillation or
flutter.
• Patients with symptomatic coronary artery disease.
• Use of other investigational drugs or a non-protocol immunosuppressant, including induction agents other than Simulect, at randomization, or within 30 days or 5 half-lives prior to randomization, whichever is longer
• History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures
• Patients who are anti-HIV-positive, or HBsAg-positive or anti-HCV-positive except patients with negative PCR-result. Laboratory results obtained more than 6 months prior to study entry should be repeated within the first week after randomization. Patients who test positive for any of the viral indicators after randomization will be discontinued from study treatment.
• Recipients of a kidney from a donor who tests positive for HIV, HBsAg or anti-HCV
• Sensitized patients (most recent anti-HLA Class I Panel Reactive Antibodies > 20% by a CDC-based assay or > 50% by a Flow cytometry or ELISA-based assay) or patients identified otherwise to be at high immunological risk
• History of malignancy of any organ system, treated or untreated, within the past 5 years regardless of evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin (excised = 2 years prior to randomization)
• Patients with severe systemic infections, current or within the 2 weeks prior to randomization.
• Patients with any history of significant coagulopathy or medical condition requiring long-term systemic anticoagulation after transplantation, which would interfere with obtaining biopsies. Low-dose Aspirin treatment (up tp 200mg/day) is allowed. Plavix is not allowed.
• Evidence of severe liver disease, including abnormal liver profile (aspartate

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Evaluation of the efficacy and safety of AEB071 in de novo CNI free regimen for prevention of rejection in solid organ transplantation. Combination of AEB071 with a well established, effective adjunct regimen to provide a safe entry into the transplant indication. Determination of the appropriate AEB071 dose(s) or target range for therapeutic drug monitoring on fixed or concentration controlled approach in de novo renal transplant patients.

Intervention(s)

Product Name: AEB071
Product Code: AEB071A
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: n/a
CAS Number: 425637-18-9
Current Sponsor code: AEB071
Concentration unit: mg/g milligram(s)/gram
Concentration type: equal
Concentration number: 100-

Trade Name: Prograf 0.5mg hard capsules
Product Name: Tacrolimus
Product Code: FK506
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: tacrolimus
CAS Number: 104987-11-3
Current Sponsor code: Prograf
Other descriptive name: FK-506
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Prograf 1 mg hard capsules
Product Name: Tacrolimus
Product Code: FK506
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: tacrolimus
CAS Number: 104987-11-3
Current Sponsor code: Prograf
Other descriptive name: FK-506
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.0-

Trade Name: Prograf 5 mg hard capsules
Product Name: Tacrolimus
Product Code: FK506
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: tacrolimus
CAS Number: 104987-11-3
Current Sponsor code: Prograf
Other descriptive name: FK-506
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: Prograf 5 mg/ml concentrate for solution for infusion
Product Name: Tacrolimus
Product Code: FK506
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: tacrolimus
CAS Number: 104987-11-3
Current Sponsor code: Prograf
Other descriptive name: FK-506
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Main Objective: The primary objective of the study is to compare, in stage 1, the efficacy of AEB071 to tacrolimus, both in combination with myfortic®, Simulect®, and steroids, at 3 months after transplantation. Efficacy will be defined using a composite efficacy failure end point (treated biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up).

Secondary Objective: The main secondary opbjectives are to compare the composite efficacy failure end point (treated BPAR, graft loss, death or loss to follow-up) of the additional AEB071 treatment regimens in stage 2 with the control regimen (myfortic® + tacrolimus) at Month 3 post transplant and for all AEB071 regimens at Month 12 months post transplant.

To compare renal function in the AEB071 treatment arms with the control arm at Month 3 and Month 12 post-transplant with calculated GFR using the MDRD formula.

Primary end point(s): The primary efficacy variable is the occurrence of efficacy failure, defined as treated biopsy-proven acute rejection (BPAR) of grade 1A or higher, graft loss, death or loss to follow-up.

Secondary ID(s)

CAEB071A2207

2006-004128-35-SE