| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prophilaxyas of organ rejection in renal allograft recipients |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048870 |
| E.1.2 | Term | Prophylaxis against transplant rejection |
|
| 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 determine the efficacy of ramipril in preventing a urinary protein to creatinine ratio (U p/c) ≥0.5 following conversion to sirolimus from a calcineurin inhibitor (CNI) (either TAC or CsA) in maintenance renal transplant patients. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to 1) to evaluate the safety of ramipril in maintenance renal transplant patients following sirolimus conversion and 2) to evaluate the effect of losartan in maintenance renal transplant patients where ramipril or placebo is ineffective in controlling proteinuria. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1.Age ≥ 18 years at the time of screening. 2.Treatment with corticosteroids at a dosage range of 2.5 to 15 mg/day for prednisone or prednisolone (2 to 12 mg/day for methylprednisolone), the alternate day equivalent, or a steroid-free regimen, for a minimum of 12 weeks before randomization. Subjects may be treated with either MMF (>500mg/day), Mycophenolate sodium (MPS) (>360 mg/day) or AZA (>50 mg/day) and must be on a minimum of two immunosuppressive drugs if on a steroid-free regimen. 3.Receiving cyclosporine (CsA) or tacrolimus since the first month post-transplant 4.Subject is 6 to 60 months after renal transplantation. 5.Subject is greater than 12 weeks after treatment for any acute rejection. 6.Blood pressure is < 140/90 mm/Hg taken as defined below (average of 3 readings at the screening visit). 7.Men, post-menopausal women or women of childbearing potential (CBP) with a negative pregnancy test at screening. 8.Women of CBP and men with sexual partners of CBP must agree to use a medically acceptable method of contraception throughout the study. 9.Women of CBP and men with sexual partners of CBP must agree to use a medically acceptable method of contraception for 3 months following discontinuation of assigned treatment. |
|
| E.4 | Principal exclusion criteria |
| 1. Subjects who, in the opinion of the investigator, are not able to complete the study. 2. Recipients of multiple organ transplants (i.e., prior or concurrent transplantation of a non-renal allograft). 3. Subjects who are currently receiving, or have received within 8 weeks before enrollment, RAAS blockade. 4. Subjects with a calculated glomerular filtration rate (GFR) < 40 mL/min (per the Modification of Diet in Renal Disease [MDRD-7] or abbreviated MDRD formula). 5. Subjects with a Up/c, or a U alb/c of >0.3 collected as defined below. 6. Subjects with a history of uncontrolled systolic blood pressure defined as those subjects who cannot achieve a sustained systolic blood pressure of < 140 mm Hg. 7. Baseline histology score ≥ Banff grade II chronic allograft score on any prior renal transplant biopsy. 8. Subjects with a history of biopsy-proven acute rejection within 12 weeks before enrollment. 9. Any prior exposure to a mammalian target of rapamycin (mTOR) inhibitor 10. Subjects with primary or recurrent focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MGN), or membranoproliferative glomerulonephritis (MPGN). 11. Evidence of any active systemic or localized major infection. 12. Evidence of infiltrate, cavitation, or consolidation on any prior chest x-ray obtained within the previous year or a prior history of pulmonary or extra pulmonary tuberculosis. 13. Use of any investigational drug or treatment up to 4 weeks prior to enrollment. 14. Known hypersensitivity to sirolimus or its derivatives, macrolide antibiotics, ACEIs, ARBs, corticosteroids, AZA, or inosine monophosphate dehydrogenase (IMPDH) inhibitor. 15. Planned use of agents with a known interaction with any of the following: sirolimus or its derivatives, macrolide antibiotics, ACEIs, ARBs, corticosteroids, AZA, or IMPDH inhibitor. 16. Immunosuppressive therapies other than CsA, TAC, AZA, MMF, MPS, and corticosteroids. 17.Planned treatment with voriconazole, cisapride, or ketoconazole that will not be discontinued prior to randomization. 18. Prior treatment with aminoglycosides, amphotericin B, cisplatin, or other drugs associated with renal dysfunction that is not discontinued at least 2 weeks prior to the screening/baseline visit. 19. Subjects with a screening/baseline total white blood cell count ≤ 2,000/mm3, absolute neutrophil count (ANC) ≤ 1000/mm3 or platelet count ≤ 100,000/mm3. 20. Fasting triglyceride level ≥ 400 mg/dL (≥ 4.5 mmol/L), fasting total cholesterol level ≥ 300 mg/dL (≥ 7.8 mmol/L), or fasting low-density lipoprotein (LDL)-cholesterol level 160 mg/dL (4.13 mmol/L) despite the use of optimal lipid-lowering therapy. 21. History of malignancy within 3 years before enrollment other than adequately treated basal cell or squamous cell carcinoma of the skin. 22.Subjects who are known to be human immunodeficiency virus (HIV) positive. Exclusion Criteria for Sirolimus Conversion The presence of any of these at the week 4 post randomization visit, while on ramipril or placebo, will preclude SRL conversion: 1.Subjects with a calculated GFR < 40mL/min (per MDRD-7 or abbreviated MDRD formula). 2.Subjects with a U p/c or U alb/c of >0.3. 3.Blood pressure >140/90 mmHg on 3 successive determinations 4.Biopsy-confirmed acute rejection during the 4 weeks following enrollment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to losartan therapy initiation |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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.8.6 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 | No |
| 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
|
Ultima visita di F-UP per gli AEs dell' ultimo paziente randomizzato
(Last follow up visit for safety of last randomised subject) |
|
| 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 | 2 |
| 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 | 2 |
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