| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The rationale for the present study is to assess whether a CNI-free regimen including antibody induction, sirolimus, and mycophenolate mofetil (MMF) results in improved long-term renal function without having a negative impact on safety or immunosuppressive efficacy, and to further examine the potential of sirolimus to reduce the severity and/or progression of Chronic allograft nephropathy (CAN), which could represent a major advance in the field of transplantation. |
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| 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 |
Efficacy: to demonstrate superiority of the sirolimus regimen versus Cyclosporine by intent-to-treat (ITT) analysis of renal function at 52 weeks, measured by mean calculated glomerular filtration rate (GFR).
Safety: to demonstrate non-inferiority at 52 weeks in the composite endpoint of the incidence of the first occurrence of graft loss or death. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Efficacy objectives include:
1. Incidence of the first occurrence of biopsy-confirmed acute rejection (BCAR) at 12, 24, 52, 104, 156 and 208 weeks.
2. Histologic grade of severity of BCAR at 12, 24, 52, 104, 156 and 208 weeks.
3. Mean on-therapy calculated Nankivell GFR at 24, 52, 104, 156 and 208 weeks.
4. Mean Nankivell GFR at 24, 104, 156 and 208 weeks for all randomly assigned subjects in both groups (ITT).
Secondary Safety objectives include:
1. Incidence of patient survival and graft survival at 12, 24, 104, 156 and 208 weeks.
2. Mean systolic and diastolic blood pressure at 52 and 104 weeks.
3. Incidence of infection at 52 and 104 weeks.
4. Incidence of malignancy (including histologically confirmed lymphoproliferative disease) at 52, 104 and 208 weeks.
(See protocol for full list of secondary efficacy and safety objectives). |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Age > 13 years and weight > 40 kg (age > 18 years in some regions per local regulations; see section H of this application form for requested subject age range in the region reviewing the application).
2. Subjects with end-stage renal disease (ESRD) who will receive a primary renal allograft from a deceased donor, a living-unrelated donor, or a human leukocyte antigen (HLA)-mismatched living-related donor.
3. Subjects who receive a primary transplant before the initiation of maintenance dialysis, where the calculated creatinine clearance (CrCl) of the native kidney(s) must be <20 mL/min within 24 hours before transplantation from a deceased donor, a living-unrelated donor, or an HLA-mismatched living-related donor.
4. All female subjects at risk for pregnancy (ie are not surgically sterile or postmenopausal) must have a negative qualitative serum pregnancy test result before randomization, and must agree and commit to the use of a medically acceptable method of contraception throughout the treatment period and for 3 months following discontinuation of study medication. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Any female subject who becomes pregnant during the treatment period must be discontinued from the on-therapy portion of the study.
5. Total white blood cell count greater than or equal to 4.0 x 10 9 /L(> 4,000 cells/mm3) and platelet count greater than or equal to 100.0 x 10 9/L (greater than or equal to 100,000 cells/mm3).
6. Fasting (8 to 12 hours) total cholesterol < 7.8 mmol/L (< 300 mg/dL) and fasting triglycerides < 3.95 mmol/L (< 350 mg/dL).
7. Signed and dated IRB / IEC approved informed consent form before screening and before any protocol-specified tests are performed that are not routinely conducted at the site. A parent or legal representative 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 will also sign an assent form. |
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| E.4 | Principal exclusion criteria |
1. Receipt of a kidney from a donor aged > 60 years; from a living donor aged > 65 years.
2. Receipt of a kidney from a donor aged 50 to 60 years and 2 of the following: terminal creatinine >1.5 mg/dL (132 micromol/L), death secondary to cerebral vascular accident, or known history of hypertension requiring medical treatment.
3. Receipt of a kidney from a living-related, HLA-identical donor.
4. Subjects who have had a previous solid organ transplant.
5. Suspected or confirmed active infection that has the potential to become systemic in the opinion of the primary investigator.
6. Evidence of known infiltrate, cavitation, or consolidation on chest radiograph that has not been repeated and interpreted as normal within the past 2 months.
7. Presence of unstable angina or ongoing use of maintenance therapy for a life-threatening arrhythmia.
8. Known or suspected malignancy within 5 years before enrollment into the study (with the exception of adequately treated basal cell or squamous cell carcinomas of the skin).
9. Use of any investigational drug within 4 weeks before randomization.
10. Prior or current use of sirolimus or any of its derivatives.
11. Known hypersensitivity to CsA, basiliximab, MMF, or corticosteroid formulations.
12. Subjects receiving a kidney-pancreas or other multiple organ transplants.
13. Subjects who are receiving pediatric en bloc transplants, or dual adult kidney transplants.
14. Current use of ketoconazole (except topical), voriconazole, terfenadine, cisapride, astemizole, cimetidine, or pimozide. These agents must be discontinued prior to randomization.
15. Positive past medical history for documented human immunodeficiency virus (HIV) infection.
16. Within 6 months before randomization, subjects receiving a kidney from a deceased donor with the most recent HLA panel-reactive antibodies (PRA) > 20%. If a subject has received a transfusion of a blood product within 6 months before randomization, a PRA less than or equal to 20% must have been documented at least 3 weeks after the transfusion.
17. Receipt of a kidney where the total donor kidney ischemia time was > 30 hours.
18. Receipt of kidneys from nonheart-beating donors.
19. Subjects with a known positive B-cell or T-cell cross-match.
20. Subjects with ABO incompatibility with the allograft.
21. Subjects who have a BMI >30 kg/m 2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is renal function at 52 weeks, measured by mean calculated GFR (Nankivell method), to be analyzed in accordance with the ITT principles. The ITT group is defined as all subjects who are randomly assigned to study therapy and undergo transplantation.
The following secondary efficacy endpoints will also be evaluated:
- The incidence and severity of BCAR at 12, 24, 52, 104, 156 and 208 weeks. The histologic grade of severity of BCAR will also be evaluated at these time points.
- The mean on-therapy calculated Nankivell GFR at 12, 24, 52, 104, 156 and 208 weeks.
- Mean Nankivell GFR at 24, 104, 156 and 208 weeks for all randomly assigned subjects in both groups (ITT).
- Slopes of 1/creatinine versus time at 24, 52, 104, 156 and 208 weeks (on-therapy and ITT).
- Slopes of Nankivell GFR versus time at 24, 52, 104, 156 and 208 weeks (on-therapy and ITT).
- Mean GFR as measured by radionuclide or comparable methodology at 24, 52, and 104 weeks (on-therapy) (at centers that elect to participate).
- Progression of chronic allograft nephropathy at 52 weeks (protocol-mandated biopsies at centers that elect to participate).
- Quality of life outcomes at 24, 52, and 104 weeks. |
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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 | No |
| 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 | Information not present in EudraCT |
| 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 | 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.8.5 | 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
| Date of 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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