E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Development of renal interstitial fibrosis in renal transplant recipients |
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E.1.1.1 | Medical condition in easily understood language |
Development of kidney toxicity in renal transplant recipients |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023438 |
E.1.2 | Term | Kidney transplant |
E.1.2 | System Organ Class | 100000004865 |
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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 primary objective is to compare the degree of renal interstitial fibrosis in renal transplant recipients with low, medium and high intrarenal Tac concentrations 3-5 years after transplantation. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to compare the degree of renal interstitial fibrosis in renal transplant recipients with low, medium and high intrarenal Tac metabolite concentrations, to investigate associations between intrarenal concentration of Tac and metabolites and renal protein expression of drug transporters and drug metabolizing enzymes, to compare intrarenal concentration of Tac and metabolites with concentrations in whole blood and PBMC, to investigate associations between intrarenal concentration of Tac and metabolites and donor/recipient polymorphisms in genes relevant for drug metabolism and transport, to investigate associations between urinary markers for kidney fibrosis and kidney histology scoring of fibrosis, and to develop improved methods for molecular PK-PD measurements by investigating the relationship between molecular pharmacodynamic responses, intracellular tacrolimus, drug targets, and cell number-reflecting biomarkers in lymphocyte populations. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Renal transplant recipients transplanted 3-5 years ago Continuously treated with tacrolimus as part of their immunosuppressive therapy since transplantation (clinical decision not influenced by this study). Protocol biopsy obtained at both 8 weeks and 1 year after transplantation Recipients of kidney from deceased or living adult donor Female and males Standard immunological risk. Measured GFR (iohexol) ≥30 mL/min 1 year after transplantation Must be at least 18 years of age. Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations. |
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E.4 | Principal exclusion criteria |
Known pre-transplant DSA, PRA, ABO-incompatibility or previous heart, lung, liver or pancreas transplanted Cold ischemia time >24 hours Receiving antithrombotic treatment (with the exception of acetylsalicylic acid) Contraindication for renal biopsy at time of inclusion Estimated GFR <30 mL/min at follow-up biopsying Experienced biopsy verified acute rejection episodes after 8 weeks post engraftment Pre-transplantation diabetes Focal segmental glomerulosclerosis Polyoma virus allograft nephropathy infection |
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E.5 End points |
E.5.1 | Primary end point(s) |
Difference in degree of renal interstitial fibrosis in renal transplant recipients with low, medium and high intrarenal Tac concentrations 3-5 years after transplantation. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
3-5 years after transplantation |
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E.5.2 | Secondary end point(s) |
1. Difference in degree of renal interstitial fibrosis in renal transplant recipients with low, medium and high intrarenal Tac metabolite concentrations 3-5 years after transplantation 2. Associations between intrarenal concentration of Tac and metabolites and: -renal protein expression of drug transporters and drug metabolizing enzymes -concentrations of Tac and metabolites in whole blood and PBMC -donor/recipient polymorphisms in genes relevant for drug metabolism and transport 3. Association between urinary markers of fibrosis and kidney histological scoring of fibrosis 4. Improvement of molecular PK-PD measurements: -Association between ex vivo cytokine responses upon mitogenic stimulation and the intracellular tacrolimus concentrations in PBMC and T cells. -Association between ex vivo cytokine responses upon mitogenic stimulation and tacrolimus target proteins (including FKBP1A and calcineurin). -Correlation between cell count, total protein and lipid molecules. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3-5 years 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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Comparison of renal fibrosis in patients with low/high renal Tac concentration 3-5 years post tx |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |