| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prophylaxis of organ rejection in renal allograft recipients |
|
| E.1.1.1 | Medical condition in easily understood language |
| Some patients taking sirolimus may develop protein in urine, which may be sign of kidney damage. Certain blood pressure control medicines like Ramipril may lower amount of protein in urine. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050436 |
| E.1.2 | Term | Prophylaxis against renal transplant rejection |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 determine the efficacy of ramipril in preventing a urinary protein to creatinine ration (U p/c) of 0.5 or greater following conversion to sirolimus from a calcineurin inhibitor (CNI) (either TAC or CsA) in maintaenance renal transplant patients. |
|
| E.2.2 | Secondary objectives of the trial |
| 1) To evaluate the safety of ramipril in maintenance renal transplant patients following sirolimus conversion 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 |
Age equal to or greater than 18 years.
Receiving cyclosporine (CsA) or tacrolimus since the first month post-transplant.
In addition to a calcineurin inhibitor, the subject must be treated with at least one of the following drugs:
• MMF (≥500 mg/day), Mycophenolate sodium (MPS) (≥360 mg/day) or AZA (≥50 mg/day)
• Corticosteroids (2.5 to 15 mg/day for prednisone or prednisolone or 2 to 12 mg/day for methylprednisolone or the alternate day equivalent)
• If subject is on a steroid-free regimen, the subject must be steroid-free for a minimum of 12 weeks before randomization.
Subject is 3 to 60 months after renal transplantation.
Subject is greater than 12 weeks after treatment for any acute rejection.
Blood pressure is equal to or less than 140/90 mm/Hg (determined by the average of three successive readings at the screening visit).
Women of childbearing potential (CBP) with a negative pregnancy test at screening, men, post-menopausal women.
Women of CBP and men with sexual partners of CBP must agree to use a medically acceptable method of contraception throughout the study.
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 the assigned therapy. |
|
| E.4 | Principal exclusion criteria |
- Subjects who, in the opinion of the investigator, are not able to complete the study.
Recipients of multiple organ transplants (i.e. prior or concurrent transplantation of a non-renal allograft).
- Subjects who are currently receiving, or have received within 4 weeks before enrollment, RAAS blockade.
- Subjects with a calculated GFR of less than 40 mL/min (per the Modification of Diet in Renal Disease [MDRD-7] or abbreviated MDRD formula; Attachment 1:Equation for calculating Glomerular Filtration Rates.)
- Subjects with a U p/c of greater than 0.3.
- Subjects with a history of uncontrolled systolic blood pressure defined as those subjects who cannot achieve a sustained systolic blood pressure of equal to or less than 140 mmHg.
- Baseline histology score of equal to or greater than Banff grade II chronic allograft score on any prior renal transplant biopsy according to the updated Banff 1997 criteria as stated in attachment 6 of the protocol.
- Subjects with a history of biopsy-proven acute rejection within 12 weeks of enrollment.
- Any prior exposure to a mammalian target of rapamycin (mTOR) inhibitor.
- Subjects with a history of primary or recurrent FSGS, membranous glomerulonephreitis (MGN) or membranoproloferative glomerulonephritis (MPGN).
- Evidence of any active systemic or localized major infection.
- Evidence of infiltrate, cavitation, or consolidation on chest x-ray obtained within the previous year or a prior history of pulmonary or extra pulmonary tuberculosis.
- Use of any investigational drug or treatment up to 4 weeks before enrollment.
- Known hypersensitivity to sirolimus or its derivatives, macrolide antibiotics, ACEIs, ARBs, corticosteroids, AZA, or inosine monophosphate dehydrogenase (IMPDH) inhibitor.
- Planned use of agents with a known interaction with any of the following: SRL or its derivatives, macrolide antibiotics, ACEIs, ARBs, corticosteroids, AZA, or IMPDH inhibitor.
- Immunosuppressive therapies other than those described in Protocol Section 13.
- Planned systemic treatment with voriconazole, cisapride or ketoconazole that will not be discontinued before randomization.
- Prior treatment with aminoglycosides, amphotericin B, cisplatin, or other drugs associated with renal dysfunction that is not discontinued at least 2 weeks before the screening/baseline visit.
- Subjects with a screening/baseline total white blood cell count (WBC) of equal to or less than 2,000/mm; hemoglobin equal to or less than 10 g per litre; absolute neutrophil count (ANC) of equal to or less than 1000/mm, or platelet count equal to or less than100,000/mm.
- Fasting triglyceride level of equal to or greater than 400 mg/dL (or equal to or greater than 4.5 mmol/L); fasting total cholesterol level of equal to or greater than 300 mg/dL (or equal to or greater than 7.8 mmol/L), or fasting low-density lipoprotein (LDL)-cholesterol level equal to or greater than 160 mg/Dl (or equal to or greater than 4.13 mmol/L) either in the presence or absence of optimal lipid lowering therapy.
- History of malignancy within 3 years before enrollment other than adequately treated basal cell or squamous cell carcinoma of the skin.
- Subjects who are known to be human immunodeficiency virus (HIV) positive.
- Subjects with severe hepatic impairment (defined as Grade C Child-Pugh score).
- Subjects that are either pregnant or lactating at the time of screening.
Exclusion criteria for sirolimus conversion
Subjects with any of the following conditions or characteristics at the post randomization visit immediately prior to the start of sirolimus (SRL) will be excluded from SRL conversion:
- Subjects with a calculated GFR less than 40 mL per min ( per MDRD-7 or abbreviated MDRD formula.
- Subjects with a U p/c of greater than 0.3.
- Blood pressure superior to 140/90 mm Hg ( determined by the average of 3 successive readings)
- Biopsy confirmed acute rejection during the pre-sirolimus conversion phase.
- Less than 10 consecutive days of treatment with ramipril/placebo therapy
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to Losartan therapy initiation |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline, Post-randomization (week 2 and week 4), and Post-conversion (week 3, week 4, week 8, week 12, week 16, week 20, week 24, week 30, week 36, and week 52) |
|
| E.5.2 | Secondary end point(s) |
| (#1) Proportion of patients at week 24 and week 52 with 1) Urine Protein/Creatinine ratio < 0.5, 2) with Urine Albumin/Creatinine ratio < 0.5, and with both Urine Protein/Creatinine ratio AND Urine Albumin/Creatinine ratio < 0.5; GFR at weeks 12, 24, 52 after conversion to sirolimus; (#2) Fraction of Albumin to Protein in urine at baseline and week 24 and week 52 after conversion to sirolimus; (#3) Proportion of patients at week 24 and 52 who discontinue sirolimus; (#4) Change of Urine Protein/Creatinine ratio and Urine Albumin/Creatinine ratio from baseline to week 3, 4, 8, 12, 24, 36, and 52. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| (#1) Proportion of patients at week 24 and week 52 with 1) Urine Protein/Creatinine ratio < 0.5, 2) with Urine Albumin/Creatinine ratio < 0.5, and with both Urine Protein/Creatinine ratio AND Urine Albumin/Creatinine ratio < 0.5; GFR at weeks 12, 24, 52 after conversion to sirolimus; (#2) Fraction of Albumin to Protein in urine at baseline and week 24 and week 52 after conversion to sirolimus; (#3) Proportion of patients at week 24 and 52 who discontinue sirolimus; (#4) Change of Urine Protein/Creatinine ratio and Urine Albumin/Creatinine ratio from baseline to week 3, 4, 8, 12, 24, 36, and 52. |
|
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 7 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Canada |
| France |
| Germany |
| Mexico |
| South Africa |
| United States |
|
| 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
|
| The 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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