E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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. |
|
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to compare, in stage 1, the efficacy of the first dose 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).
|
|
E.2.2 | Secondary objectives of the trial |
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 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.
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
CAEB071A2207: 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 recipients - PK substudy- T cell-sub study
1- All objectives in this sub-study are exploratory. These are to: • Measure the abbreviated PK-profiles of AEB071, its major metabolite AEE800, tacrolimus and MPA in blood samples of de novo renal transplant patients in corresponding treatment arms • Explore dose-exposure relationship with the chosen fixed dose of AEB071 in the AEB071 treatment arms • Explore exposure-effect relationship with regard to clinical efficacy and safety parameters. Details of this T-cell sub-study are described in Post-text Supplement 1.
2- The frequencies of primed alloreactive and CMV-IE-1 T cells before and after transplantation in the different treatment arms will be determined at selected trial sites with the required expertise and technical facilities in consenting patients... Blood samples (20 mL citrate blood) will be collected prior to starting immunosuppressive medication, and at 4 weeks and 3 months post-transplant. Responder cells (Peripherial blood mononuclear cells = PBMNC) will be isolated with Ficoll gradient centrifugation, and stored in liquid nitrogen until shipment and later usage as responder cells in the Elispot assay. An aliquot of the citrate blood will be cryopreserved for determination of CMV viral load. Details of this T-cell sub-study are described in Post-text Supplement 2.
|
|
E.3 | Principal inclusion 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 WITH FUNCTIONAL GRAFT WITHIN 24 HOURS AFTER GRAFT REPERFUSION; FUNCTIONAL GRAFT BEING DEFINED AS ONE OF THE FOLLOWING:
• FOR PATIENTS WITHOUT RESIDUAL URINARY OUTPUT FROM THE NATIVE KIDNEYS, URINE OUTPUT OF MORE THAN 250ML/12 HOURS
OR • FOR PATIENTS WITH RESIDUAL URINARY OUTPUT FROM THE NATIVE KIDNEYS EITHER OF THE FOLLOWING CONDITIONS MUST BE MET:
• A DECREASE FROM PRETRANSPLANT IN SERUM CREATININE BY AT LEAST 20%
OR • MUST BE A RECIPIENT OF AN UNCOMPLICATED LIVE-DONOR TRANSPLANT THAT IN THE OPINION OF THE INVESTIGATOR IS NOT LIKELY TO RESULT IN DELAYED GRAFT FUNCTION (E.G. PROLONGED WARM ISCHEMIC TIME, OR EXCESSIVELY LONG PERIOD OF INCREASED INTRAPERITONEAL PRESSURE DURING LAPAROSCOPIC NEPHRECTOMY)
• 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
|
|
E.4 | Principal 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 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 antiarrhytmic 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 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 arrythmias 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. Anti-HCV-positive patients are excluded, exceot 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 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 to 200 mg/day) is allowed. Plavix® is not allowed. • 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]) at screening. • Patients with a severe digestive system disorder (including functional disorders) at screening. • Patients with any condition which is expected to prohibit full-dose myfortic® therapy or tacrolimus therapy • 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 (details and definitions see below)
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point of the study is the occurrence of composite efficacy failure end point defined as treated biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up within 3 months of the initial dose of study drug in de novo adult renal transplant patients.
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Patients must be discontinued from the study if any of the following occur: -Withdrawal of consent* -Lost to follow-up -Death -Administration reasons (as defined by Novartis) * A 2nd consent will be asked to allow for minimal data collection (survival status of patient, graft loss, rejection episodes)
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 29 |