| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 that of Neoral, both in combination with Certican, Simulect, and steroids, at 3 months after transplantation. Efficacy will be defined using a composite efficacy failure end point (treated BPAR, graft loss, death or loss to follow-up). |
|
| E.2.2 | Secondary objectives of the trial |
Main secondary efficacy objective:
• compare the composite efficacy failure end point (treated BPAR, graft loss, death or loss to follow-up) of the additional AEB071 treatment regimen in Stage 2 with the control regimen (Certican + Neoral)
Main safety objective:
• 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.
Other secondary objectives:
• Determine the target range for AEB071 trough levels to be used in phase III
• Determine the dose or concentration of AEB071 with the best benefit/risk profile.
• Compare the incidence of various additional efficacy endpoints
• Compare the incidence of CAN
• Compare the safety and tolerability
• Compare the incidence of BK-polyoma viremia
• Determine the efficacy of the added regimen in Stage 2 at 3 months post transplantation.
• Determine the efficacy of all regimens at 12 months post transplantation. |
|
| 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 |
Protocol post-text supplement: 1
A 12-month open-label, randomized, multicenter, sequential cohort, dose finding study to evaluate the efficacy, safety and tolerability of oral AEB071 versus
Neoral® in combination with Certican®, Simulect® and corticosteroids in de novo adult renal transplant recipients
15 March 2007, Original version
Objectives:
• Measure the abbreviated PK-profiles of AEB071, its major metabolite AEE800, everolimus (Certican®), and Neoral® (cyclosporin) in blood samples of de novo renal transplant patients in corresponding treatment arms.
• Explore dose-exposure relationship with the chosen fixed doses of AEB071 in the
AEB071 treatment arms.
• Explore exposure-effect relationship with regard to clinical efficacy and safety parameters.
Protocol post-text supplement: 2
Exploratory Biomarker Study for CAEB071A2206, 14 March 2007, original version,
Objectives:
This search for biomarkers will involve determination of levels of the candidate proteins in urine, and in parallel, the determination of the urinary creatinine levels. Urinary protein levels will be normalized to urinary creatinine concentrations.
Serum creatinine is determined at the same timepoints as part of the core study protocol procedures. |
|
| E.3 | Principal inclusion criteria |
• Male and female patients ≥ 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 CIT < 24h.
• Recipients of a kidney from a donor 10-65 years old.
• Patients expected to be able to take oral medication within 24h 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 cross-match positive transplants.
• Patients without functional graft 24h after graft reperfusion (functional graft being defined as urine output of more than 250 mL/12h for patients without residual urinary output from native kidneys, or as a decrease in serum creatinine by at least 20% from pre-transplant).
• Patients with a platelet count < 100,000/mm3 at screening.
• Patients with an absolute neutrophil count of < 1,500/mm³ at baseline before surgery or WBC count of < 2,500/mm³.
• Patients who are treated with drugs that are strong inducers or inhibitors of CYP3A4 at screening and who can not discontinue this treatment (see Appendix 3).
• Patients with QTc > 500 ms, long QT syndrome (own or with a family history) or with a family history of sudden unexplained death.
• Patients with LBBB or who experienced, during the previous 6 months, hospitalisation for heart failure of cardiac etiology, or significant and persistant left-ventricular dysfunction (LVEF < 40%).
• Patients with a history, in the preceeding 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, sotalol, dofetilide, quinidine, procainamide, disopyramide).
• 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, 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 (PRA) > 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 (AST, ALT or total bilirubin > 3 times ULN) at screening.
• Patients with BMI > 30.
• Patients who have severe hypercholesterolemia (> 350 mg/dL; > 9 mmol/L) or hypertriglyceridemia (> 500 mg/dL; > 8.5 mmol/L). Patients with controlled hyperlipidemia are acceptable.
• Patients with any condition which is expected to prohibit full-dose Certican or Neoral therapy, as per current product labels.
• 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 composite efficacy failure end point treated BPAR, graft loss, death or loss to follow-up. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| kidney safety biomarker study |
|
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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
|
|
| 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 | 34 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 34 |
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