E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
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 |
To determine the effect of conversion from calcineurin inhibitor (CI)- to sirolimus (SRL)-based therapy on renal function 52 weeks after randomization, as indicated by the change from baseline calculated glomerular filtration rate (GFR) (Nankivell method), and to demonstrate:
a)superiority of the SRL conversion versus CI continuation regimens in subjects with baseline Nankivell GFRs greater than (>) 40 milliliter per minute (mL/min). OR
b)noninferiority of the SRL conversion versus CI continuation regimens in subjects with baseline Nankivell GFRs of 20 to 40 mL/min, and to establish superiority in this group if the results are consistent with this conclusion.
To assess equivalence 52 weeks after randomization between treatment groups in the composite endpoint of the incidence of the first occurrence of biopsy-confirmed acute rejection, graft loss, or death. |
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E.2.2 | Secondary objectives of the trial |
Change from baseline in the on-therapy Nankivell GFR at 24, 52, 104, 156 and 208 weeks. The least squares slopes of 1/creatinine vs time at 24, 52, 104, 156 and 208 weeks. The least squares slopes of the plot of Nankivell GFR vs time at 24, 52, 104, 156 and 208 weeks. The change from baseline in GFR as measured by radionuclide or comparable techniques at 52, 104 and 208 weeks (at selected centers). The incidence and severity of biopsy-confirmed acute rejection at 24, 52, 104,156 and 208 weeks. Patient and graft survival at 24, 52, 104, 156 and 208 weeks. The incidence of treatment failure, defined as the occurrence of acute rejection or premature withdrawal from study medication for any reason by weeks 52, 104, 156 and 208. The change from baseline in mean systolic and diastolic blood pressure and mean calculated arterial pressure . Quality of life outcomes . The change from baseline in the severity and progression of biopsy-confirmed chronic allograft nephropathy (CAN). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age greater than equal to (≥) 13 years.
2. Treatment with corticosteroids (dosage range 2.5 to 15 milligrams / day (mg/day) for prednisone or prednisolone (2 to 12 mg/day for methylprednisolone) or the alternate day equivalent) and either mycophenolate mofetil (MMF) (≥500 mg/day) or azathioprine (AZA) (≥50 mg/day) for a minimum of 12 weeks before randomization.
3. Receiving either cyclosporin A (CsA) or tacrolimus from the time of transplantation or within 2 weeks thereafter.
4. Subjects with a functioning allograft and a Nankivell glomerular filtration rate (GFR) ≥ 40 milliliter/ minute (mL/min), within 2 weeks before randomization.
5. Six to 120 months after renal transplantation.
6. Greater than 12 weeks after treatment for any acute rejection.
7. Renal biopsy within 16 weeks before randomization.
8. All female Subjects at risk for pregnancy must have a negative serum pregnancy test before randomization. Female Subjects at risk for pregnancy must agree to use a medically acceptable method of contraception throughout the treatment period and for 12 weeks after discontinuation of study medication.
9. Total white blood cell count greater than (>) 3000/mm 3 [>3.0 * 109/Liter (L)], platelet count >100,000/mm 3(>100 * 109/L), fasting triglycerides <350 mg/dL [<3.95 millimoles/liter (mmol/L)], fasting cholesterol less than (<) 300 milligrams/ deciliter (mg/dL) (<7.8 mmol/L).
10. Signed and dated independent ethics committee (IEC)- approved informed consent before screening and before any protocol specified tests. A parent or legal guardian must provide written consent for Subjects younger than the age of majority as defined by state and local laws. Subjects younger than the age of majority may also sign an assent form.
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E.4 | Principal exclusion criteria |
1.Clinically diagnosed or biopsy-confirmed acute rejection, as diagnosed by the Banff 97 classification within 12 weeks before randomization, that was determined to require anti-rejection treatment.
2.Serum creatinine at the time of screening that has increased by >30 percent (%) above the last value obtained at least 12 weeks earlier.
3.Subjects in whom kidney-pancreas or other multiple organ transplants have been performed.
4.Evidence of systemic infection at the time of randomization.
5.Presence of unstable angina or use of ongoing maintenance therapy for a life-threatening arrhythmia.
6.Known or suspected malignancy (with the exception of adequately treated basal cell or squamous cell carcinomas of the skin) less than equal to (≤5) years before randomization or any history of posttransplant lymphoproliferative disease (PTLD).
7.Prior or current use of SRL or any of its derivatives.
8.Use of investigational agents ≤4 weeks before randomization.
9.Use of immunosuppressive agents (at the time of randomization)
10.Current use of terfenadine, cisapride, astemizole, pimozide, or cimetidine; these drugs must be discontinued before randomization. Cimetidine must be discontinued before the screening examination.
11.Positive past medical history for documented human immunodeficiency virus (HIV)infection.
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E.5 End points |
E.5.1 | Primary end point(s) |
Nankivell Glomerular Filtration Rate (GFR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
First Occurrence of Biopsy-confirmed Acute Rejection, Graft Loss, or Death |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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) | 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.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
Czech Republic |
Denmark |
France |
Germany |
Italy |
Mexico |
Poland |
Portugal |
Saudi Arabia |
South Africa |
Spain |
Sweden |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 17 |