E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult kidney transplant recipients. |
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E.1.1.1 | Medical condition in easily understood language |
Adult patients, who have received a kidney from a another person and need medication to avoid the loss of the organ. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 100000004857 |
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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 |
Evaluate the effect of everolimus with reduced exposure CNI versus MPA with standard exposure CNI on the binary composite of treated biopsy-proven acute rejection (tBPAR) or eGFR < 50
mL/min/1.73m2 (estimated glomerular filtration rate by MDRD4 formula) at Month 12 post-transplantation. |
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E.2.2 | Secondary objectives of the trial |
•composite efficacy failure rate [treated biopsy proven acute rejection(tBPAR), graft loss(GL) or death(D)] at M12
•composite endpoint(cEP)of tBPAR or eGFR<50 mL/min/1.73m2 (MDRD4) M12 among compliers
•cEPof tBPAR or eGFR<50 mL/min/1.73m2 at M24
•cEP of tBPAR (excluding Banff 1A) or eGFR<50 mL/min/1.73m2 at M24
•cEP of tBPAR or eGFR<50 mL/min/1.73m2 at M12 by subgroup
•cEP of tBPAR, GL, D, or loss to follow-up at M12/24
•cEP of tBPAR, GL, D or eGFR<50 mL/min/1.73m2 at M12/24
•individual endpoints of D, GL, tBPAR, BPAR, tAR, AR and humoral rejection at M12/24
•tBPAR by severity and time to event and also excluding excluding Banff 1A
•Tx recipients with eGFR<50 mL/min/1.73m2 at M12/24
•RF and change from M1(eGFR) at M12/24 and over time by slope analysis and by Cystatin C-based and other formulae
•AEs, SAEs and AEs leading to study drug discontinuation
•CMV and BKV, NODM, CKD with associated proteinuria and CNI associated AE
•Urinary protein/albumin excretion |
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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 |
1. Optional Kidney Biopsy-substudy - To explore the development of CAN/IFTA expression by renal protocol biopsy. (Greece will NOT participate in this Sub-Study)
2. Optional Donor Specific Antibody-substudy - To explore the incidence of donor-specific antibody. (Greece WILL participate in this Sub-Study)
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E.3 | Principal inclusion criteria |
1. Written informed consent obtained.
2. Subject randomized within 24 hr of completion of transplant surgery.
3. Recipient of a kidney with a cold ischemia time < 30 hours.
4. Recipient of a primary (or secondary, if first graft is not lost due to immunological reasons) renal transplant from a deceased heart beating, living unrelated, living related non-human leukocyte antigen identical or an expanded criteria donor. |
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E.4 | Principal exclusion criteria |
1. Subject unable to tolerate oral medication at time of randomization.
2. Use of other investigational drugs at the time of enrollment
3. History of hypersensitivity to any of the study drugs or similar chemical classes.
4. multi-organ transplant recipient
5. Recipient of ABO incompatible allograft or complement-dependent lymphocytotoxic (CDC) crossmatch positive transplant
6. high immunological risk by assessment of anti-donor reactivity e.g. high PRA, presence of pre-existing DSA
7. HIV positive
8. HBsAg and/or a HCV positive with evidence of elevated LFTs (ALT/AST levels ≥ 2.5 times ULN)
9. Recipient of a kidney from a donor who tests positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV)
10. BMI greater than 35
11. severe systemic infections
12. Subject requiring systemic anticoagulation
13. History of malignancy
14. severe restrictive or obstructive pulmonary disorders
15. severe hypercholesterolemia or hypertriglyceridemia
16. white blood cell (WBC) count ≤ 2,000 /mm3 or with platelet count ≤ 50,000 /mm3.
17. Pregnant or nursing (lactating) women
18. Women of child-bearing potential |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary analysis will be performed on the Full Analysis Set following the intent-to-treat principle. The primary endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 will be tested at the significance level of 0.05. Event rates will be compared between groups using a 2-stage approach (hierarchical testing strategy). First, noninferiority of EVR plus reduced CNI vs. MPA plus standard CNI will be evaluated using a 10% non-inferiority margin. If this is significant, then superiority will be evaluated. Based on the closed testing principle, no multiplicity adjustment will be made for testing for both non-inferiority and superiority. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At 12-month after transplantation. |
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E.5.2 | Secondary end point(s) |
With respect to the key secondary endpoint - composite efficacy failure of tBPAR, graft loss or death at Month 12, non-inferiority of EVR plus reduced CNI vs. MPA plus standard CNI will be evaluated at the significance level of 0.05 using a 10% non-inferiority margin based on the Full Analysis Set.
To evaluate the binary composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2 (MDRD4) Month 12 among compliant subjects. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 12-month after transplantation. |
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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 | 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 | 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 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 |
Belgium |
Bulgaria |
France |
Japan |
Austria |
Croatia |
Netherlands |
Slovakia |
Argentina |
Australia |
Brazil |
Chile |
Colombia |
Czech Republic |
Egypt |
Germany |
Guatemala |
India |
Indonesia |
Jordan |
Korea, Republic of |
Lebanon |
Malaysia |
Saudi Arabia |
Spain |
Thailand |
Venezuela, Bolivarian Republic of |
Kuwait |
Mexico |
Panama |
Philippines |
Poland |
Russian Federation |
Serbia |
Singapore |
South Africa |
Switzerland |
Taiwan |
Turkey |
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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The study will be completed when LPLV occurs.
The study will be ended after:
- all patients have completed the month 24 visit,
- all data have been cleaned and the database has been locked,
- statistical outputs have been received. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |