E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prophylaxis of rejection in kidney allograft recipients (by immunosuppression) |
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E.1.1.1 | Medical condition in easily understood language |
After transplantation all patients need to use immunosuppression to prevent rejection. |
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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 | 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 |
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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 |
The cumulative incidence of NODAT (new onset of diabetes after transplantation) 12 months after transplantation as defined by the ADA-criteria (2012).
Arm A. Steroid-free low-TAC arm:
Thymoglobuline® induction (2,5 mg/kg, pre-/peroperatively day 0, 2,5 mg/kg day 1)
+ Advagraf® (conc.: 5-10 ng/ml, after 3 months 4-7, started postop. day 1)
+ MMF 1gx2 (controlled by a single AUC measurement day 7 with a target AUC between 40 and 60 mg.h/L)
+ steroids day 0 (250 mg methylprednisolon iv. before start of Thymoglobuline infusion and day 1 50 mg methylprednisolon iv. before start of Thymoglobuline infusion)
Arm B. Standard low-TAC arm:
Simulect® induction 20mg (day 0 and day 4)
+ Advagraf® (conc.: 5-10 ng/ml, after 3 months 4-7ng/ml, started per hospital practice)
+ MMF 1gx2 (controlled by AUC measurements to 40-60 mg.h/L)
+ steroids according to hospital practice but not less than 5 mg prednisolone daily after 6 months. |
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E.2.2 | Secondary objectives of the trial |
•The cumulative incidence of NODAT
•Use of antidiabetic medication
•The composite measure of freedom from acute rejection (AR), graft survival, and patient survival.
•The incidence of antibody-mediated rejection
•Renal function
•The incidence of chronic changes, analyzed by protocol biopsies
•Incidence of hypertension
•Number of antihypertensive drugs
•Number of lipid lowering
•Incidence of cardiovascular complications and events
•Incidence of malignancy
•Safety and tolerability |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients receiving a first or second single kidney transplant from a deceased or a living donor.
2. Female or male aged above 18 years
3. Patients considered for a standard immunosuppressive protocol.
4. Patients capable of giving written informed consent for participation in the study for 24 months
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E.4 | Principal exclusion criteria |
1. Patients with known diabetes mellitus or plasma glucose >11.1 mmol/l at admission
2. Recipients of multiorgan transplants, and or previously transplanted with any other organ than kidney
3. Patients with CDC-PRA > 25 % in most recent test or for any other reason considered to be of a high risk for rejection which requires an enhanced immunosuppression.
4. Patients receiving a renal transplant from a HLA-identical sibling
5. Patients with hypersensitivity to, or other reasons to not be able to take the immunosuppressive drugs used in the study
6. Patients who are recipients of ABO-incompatible transplants
7. Patients who are unlikely to comply with the study requirements
8. Patients, and/or those receiving organs from donors, who are positive for HIV, Hepatitis B surface antigen or Hepatitis C virus.
9. Females of childbearing potential, who are, or are planning to be, pregnant, and/or are unwilling to use effective means of contraception. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is the incidence of New Onset Diabetes Mellitus defined as:
The cumulative incidence of NODAT (new onset of diabetes after transplantation) 12 months after transplantation as defined by the ADA-criteria (2012).
Cumulative incidence of one of the following:
1. ≥2 FPG ≥7, 0 mmol/l ≥ 30 consecutive days apart
2. 2-h Plasma Glucose ≥11,1 mmol/l in the OGTT≥ 30 consecutive days apart
3. Oral hypoglycemic ≥30 consecutive days
4. Insulin ≥30 consecutive days |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The cumulative incidence of NODAT (new onset of diabetes after transplantation) 12 months after transplantation |
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E.5.2 | Secondary end point(s) |
- The cumulative incidence of NODAT (new onset of diabetes after transplantation) 3, 6 and 24 months after transplantation.
- OGTT will be performed 3 and 12 months after transplantation
- Use of antidiabetic medication at 6, 12 and 24 months.
- Acute rejection at 6, 12 and 24 months
- The composite measure of freedom from acute rejection (AR), graft survival, and patient survival at 12 and 24 months after transplantation.
- Renal function at 12 and 24 months
- Incidence of chronic allograft nephropathy (CAN) at 12 months
- Incidence of patients with hypertension at 12 and 24 months.
- Number of antihypertensive drugs at 12 and 24 months
- Number of lipid lowering drugs at 12 and 24 months
- Incidence of cardiovascular complications and events
- Incidence of malignancy
- Safety and tolerability |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please see above, different timepoints for different endpoints. |
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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
| 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 | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 end of study is defined as the last subject's last protocol-defined assessment (performance of End of Study Visit or follow-up visit in the case of a withdrawn subject). |
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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 | 5 |
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 | 5 |
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 |