E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cardiac transplant recipients with mild to moderate renal insufficiency. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10050432 |
E.1.2 | Term | Prophylaxis against heart transplant rejection |
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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 |
To demonstrate the superiority of converting from CNI therapy to sirolimus therapy to continuing CNI therapy with respect to renal function in cardiac transplant recipients with mild to moderate renal dysfunction. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of conversion from CNI therapy to sirolimus therapy in this patient population. To explore the effect of conversion from CNI therapy to sirolimus therapy on surrogate markers of cardiovascular risk. |
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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 |
Iothalamate Clearance Substudy. A substudy will be performed at designated centers using measured creatinine clearance (as measured by iothalamate clearance) to validate creatinine clearance calculations in cardiac transplant recipients. |
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E.3 | Principal inclusion criteria |
1. Cardiac transplant recipients aged ≥ 18 years. 2. Receiving CsA or TAC as part of the maintenance immunosuppressive regimen since the time of transplantation. 3. ≥ 12 Months after cardiac transplantation but ≤ 96 months after transplantation at the time of screening. 4. GFR > 40 mL/min but < 90 mL/min/1.73m2 (calculated by the Cockcroft-Gault equation and adjusted for body surface area [BSA] using the Mosteller formula) with stable renal function (as defined by no decrease in > 20% of GFR) over the previous 3 months. 5. Left ventricular ejection fraction by echocardiogram (ECHO) ≥ 40%. 6. Women of childbearing potential (CBP) must have a negative urine pregnancy test before randomization. 7. Women of CBP and men with sexual partners of CBP must agree to use a medically acceptable method of contraception throughout the treatment period. 8. Women of CBP and men with sexual partners of CBP must agree to use a medically acceptable method of contraception for 3 months after discontinuation of assigned treatment. |
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E.4 | Principal exclusion criteria |
1. Secondary cardiac transplant recipients (subjects who have lost 1 or more previous cardiac transplant). 2. Multiple-organ transplant recipients (such as heart-lung, heart-kidney, or heart-after-kidney transplant recipients). 3. Treatment of acute rejection within 3 months. 4. Evidence of active systemic or localized major infection at the time of randomization. 5. Evidence of infiltrate, cavitation or consolidation on chest x-ray film obtained within 3 months before or at the time of the screening evaluation. 6. Use of any investigational drug or treatment up to 4 weeks before random assignment. 7. Spot urine protein-to-creatinine ratio > 0.5 or proteinuria > 500 mg/day. 8. Subjects maintained on CNI monotherapy. 9. Prior or current use of mammalian target of rapamycin (mTOR) inhibitors unless administration was part of a "CNI holiday" (a planned temporary switch from a CNI to an mTOR inhibitor to limit exposure to CNIs) lasting no more than 10 days. 10. Known hypersensitivity to sirolimus or its derivatives or macrolide antibiotics. 11. Treatment with voriconazole, cisapride, or ketoconazole, which are all known to interact with sirolimus, that is not discontinued before randomization. 12. Treatment with aminoglycosides, amphotericin B, cisplatin, or other drugs associated with renal dysfunction that is not discontinued before randomization. 13. Subjects with screening baseline white blood cell (WBC) count < 3000/mm3, platelet count < 100,000/mm3, fasting triglyceride level > 400 mg/dL (4.5 mmol/L), or total cholesterol level > 300 mg/dL (7.6 mmol/L). 14. History of malignancy within 3 years before enrollment (except for adequately treated basal-cell or squamous-ell carcinoma of the skin). 15. Planned used of agents with a known major interaction with sirolimus or CNIs. 16. Subjects who are known to be positive for human immunodeficiency virus (HIV). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline calculated creatinine clearance (using the Cockcroft-Gault equation and adjusted for BSA using the Mosteller formula) at 52 weeks. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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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The last follow-up visit for safety of the last randomised subject. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |