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. |
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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 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).
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E.2.2 | Secondary objectives of the trial |
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.
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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. Post text Supplement 1, amendment 1 - PK substudy. 16 Feb 07.
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
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E.3 | Principal 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
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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 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 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 |
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E.5 End points |
E.5.1 | 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.
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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 |
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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 | Yes |
E.8.2.3.1 | Comparator description |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
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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
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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)
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 29 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 29 |