12-month open label, randomized, multicenter study evaluating efficacy, safety and tolerability of oral AEB071 plus tacrolimus (converted to myfortic after 3 months), vs. myfortic plus tacrolimus in de novo renal transplant recipients

• Register: EUCTR
• Last refreshed on: 18 April 2012
• Main ID: EUCTR2005-003494-25-GB
• Date of registration: 24/05/2006
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: 12-month open label, randomized, multicenter study evaluating efficacy, safety and tolerability of oral AEB071 plus tacrolimus (converted to myfortic after 3 months), vs. myfortic plus tacrolimus in de novo renal transplant recipients
• Scientific title: 12-month open label, randomized, multicenter study evaluating efficacy, safety and tolerability of oral AEB071 plus tacrolimus (converted to myfortic after 3 months), vs. myfortic plus tacrolimus in de novo renal transplant recipients
• Date of first enrolment: 30/08/2006
• Target sample size: 195
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-003494-25
• 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: conversion design If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: combination of myfortic and tacrolimus

Countries of recruitment

Germany, Italy, Spain, 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) < 30 hours
•Recipients of a kidney from a donor 10-65 years old
•Recipients of a functional graft i.e producing a urinary output of = 250 mL/12h (applicable only in patients with no residual urinary output from native kidneys) or a decrease in serum creatinine. Functionality must be achieved no later than 36h aftr transplantation.
•Patients able to swallow the first dose of oral study drug within 36 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

Pregnancy has to be excluded in any female study participant below age 60 by a negative hCG laboratory test in serum (=10 IU/L) at study start, with results available within 2 days past randomisation.
All women physiologically capable of becoming pregnant and receiving tacrolimus,
should receive reproductive counseling as per local standards for patients on tacrolimus. Counseling needs to address the potential drug-drug interaction between tacrolimus and hormonal contraceptives which may decrease the effectiveness of hormonal contraception. For women on an AEB071 study arm, non-hormonal contraception is mandatory until finishing the conversion from tacrolimus to myfortic. Reliable nonhormonal contraception consists of any form of intra-uterine devices (without hormones) or of other double-barrier methods. Barrier method includes essure, condom, diaphragm, shield, cap, sponge and spermicides. Acceptable methods of contraception may also include methods with a Pearl index of <1 at the discretion of the investigator. In women receiving AEB071 but not tacrolimus, hormonal contraception can be used. Counseling should include the potential drug-drug interaction between AEB071 and hormonal contraceptives which may moderately increase the exposure to hormonalcontraceptives and thereby decrease their tolerability.

Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Postmenopausal women (defined as 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >100 IU/L) can participate without contraception.
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
•Recipients of an organ from a non-heart beating donor
•Patients who are recipients of A-B-O incompatible transplants, all crossmatch positive transplants
•Use of other investigational drugs or a non-protocol immunosuppressant, including induction agents other than Simulect®, at the time of enrollment, or within 30 days or 5 half-lives prior to enrollment, 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. Anti-HCV-positive patients are excluded, except patients with spontaneously negative PCR-result (patients who cleared the virus under treatment remain excluded). Laboratory results obtained more than 6 months prior to study entry should be repeated within the first week after randomization. Patients who test positve 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 QTc >500msec, long QT-syndrome (own or with a family history) or with a family history of sudden unexplained death
•Patients with left branch bundle block (LBBB) or who experienced, during the previous 6 months, hospitalisation for heart failure of cardiac etiology, or significant and persistent 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, or atrial fibrillation or flutter.
•Patients requiring antiarrhythmic drugs with QT-prolonging properties (such as amiodarone, stalol, dofetilide, quinidine, procainamide, disopyramide)
•Patients with Symptomatic coronary artery disease.
•Patients with any history of significant coagulopathy or medical condition requiring long-term systemic anticoagulation after transplantation, which would interfere with obtaining biopsies. Aspirin treatment is allowed
•Patients with an absolute neutrophil count of < 1,500/mm3, or absolute leukocytes count < 2,500/mm3.
•Evidence of severe liver disease, including abnormal liver profile (aspartate aminotransferase [AST], alanine aminotransferase [ALT] or total bilirubin > 3 times upper limit of normal [ULN]).
•Patients with a severe digestive system disorder (including functional disorders).
•Patients with any condition which is expected to prohibit full-dose myfortic therapy, or tacrolimus withdrawal in the maintenance period.
•Patients with any surgical or medical condition, which in the opinion of the investigator, precludes enrollment in this trial
•Patients who are unlikely to comply with the study requirements or unable to cooperate or communicate with the investigator
•Pregnant or nursing (lactating) women, and women who might become pregnant during the study




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

Health Condition(s) or Problem(s) studied

First evaluation of the efficacy and safety of AEB071 in its target indication: prevention of rejection in solid organ tranplantation. The study population will consist of a representative group of male and female de novo renal transplant patients.

Intervention(s)

Product Name: AEB071
Product Code: AEB071A
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: not established
CAS Number: n/a
Current Sponsor code: AEB071 drug substance, mono acetate
Other descriptive name: CAS
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Myfortic 180mg film-coated gastro-resistant tablet
Product Name: Myfortic
Product Code: ERL080
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: mycophenolic acid
Current Sponsor code: ERL080
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 180-

Trade Name: Prograf 0.5mg capsules
Product Name: Prograf
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: tacrolimus
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Myfortic 360mg film-coated gastro-resistant tablets
Product Name: Myfortic
Product Code: ERL080
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: mycophenolic acid
Current Sponsor code: ERL080
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 360-

Trade Name: Prograf 1mg capsules
Product Name: Prograf
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: tacrolimus
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.0-

Trade Name: Prograf 5mg capsules
Product Name: Prograf
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: tacrolimus
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5.0-

Trade Name: Prograf 5mg/ml concentrate for infusion
Product Name: Prograf
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: tacrolimus
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5.0-

Primary Outcome(s)

Secondary Objective: •Evaluate the AEB071 regimens in comparison to the control arm with respect to primary efficacy failure at Month 3 post-transplant
•Compare renal function in the AEB071 treatment arms with the control arm at Month 6 post-transplant (MDRD formula for GFR).
•Compare the AEB071 treatment arms to the control arm with respect to various efficacy endpoints at Month 3, 6 and 12, using treated BPAR, treated AR, death, graft loss, loss to follow-up and combinations thereof.
•Compare the changes in renal function (GFR) in the AEB071 treatment arms from Month 3 (before conversion to myfortic®) to Month 6 with the change in the control arm.
•Compare renal function in the AEB071 treatment arms to the control arm at various time points using the Cockroft-Gault formula (creatinine clearance) and the Filler formula (GFR).
•Compare the safety and tolerability, including GI-tolerability, in the AEB071 treatment arms and the control arm

Main Objective: The primary objective of the study is to demonstrate that in de novo renal transplant patients, at least one of the AEB071 treatment regimens is not inferior to the control treatment (myfortic® + tacrolimus) within 6 months of the initial dose of study drug with respect to primary efficacy failure, defined as a composite efficacy endpoint of treated BPAR, graft loss, death or loss to follow-up.

Primary end point(s): The primary objective of the study is to demonstrate that in de novo renal transplant patients, non inferior rates of efficacy failure, defined as the first occurrence of treated biopsy-proven acute rejection of grade =1A, graft loss, death, or loss to follow-up, are achieved with at least one AEB071 regimen compared to the control regimen within 6 months of the initial dose of study medication (Simulect® and steroids will be administered in all treatment arms).
Based on the available data [Stefoni et al (2005)] [Vincenti et al (2005)], the rate of efficacy failure was assumed to be 10% in each treatment arm. The non-inferiority margin was defined as 15%. This margin is somewhat higher than that used in pivotal trials in renal transplantation (10%), but may be justified for a Phase IIa trial.
Based on these assumptions, a sample size of 65 patients in each treatment regimen will have 81% power to demonstrate that an AEB071 regimen is not more than 15% worse than the control regimen (one-sided test, a=0.025).
The analysis will be based on the ITT population. The primary objective will be evaluated by testing the following null hypothesis:
H0 : ?T - ?C = 0.15: the proportion of patients experiencing efficacy failure with an AEB071 regimen (?T) is higher than that with the control regimen (?C) by 15% or more at 6 months.
The alternative hypothesis is:
HA : ?T - ?C < 0.15: the proportion of patients experiencing efficacy failure with an AEB071 regimen is less than 15% higher than that seen with the control regimen at 6 months.
To evaluate the null hypothesis, a Z-test based two-sided 95% confidence interval (CI) for the difference in efficacy failure rates for each AEB071 regimen – control regimen will be computed. If the confidence interval yields an upper bound less than 0.15, then that AEB071 regimen will be declared non inferior to the control regimen. Since this is a Phase IIa study, there will be no adjustments for multiplicity. The two-sided 95% CI of treatment regimen difference will be computed as follows:
(?Ti - ?C) ± Z 0.025 *SED
where ?Ti = Kaplan-Meier estimate for the probability of efficacy failure in an AEB071 arm (i=1,2) at 6 months
?C = Kaplan-Meier estimate for the probability of efficacy failure in the control arm at 6 months
SED= square root of SETi2 + SEC2 for AEB regimen i, i=1, 2
SETi= estimated standard error for the AEB regimen i using Greenwood’s formula, i=1, 2
SEC= estimated standard error for the control arm using Greenwood’s formula
Similar methods will be applied to other efficacy measures: treated biopsy proven acute rejection of grade = 1A; treated biopsy proven acute rejection of grade = 1A, death, or graft loss; death, graft loss, or lost to follow-up; treated acute rejections; treated acute rejections, graft loss, death, loss to follow up.

Secondary ID(s)

CAEB071A2203