E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Renal transplant recipients |
Niertransplantatie ontvangers |
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E.1.1.1 | Medical condition in easily understood language |
For patients with renal failure, renal replacement therapy is needed. One of these therapies is kidney transplantation. Patients receive a kidney from a donor. |
Voor patienten met nierfalen is nierfunctie vervangende therapie levensreddend. Een van deze behandelingen is een niertransplantatie. Zij ontvangen een nier van een donor. |
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E.1.1.2 | Therapeutic area | Not possible to specify |
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 |
The main objective of the trial: To minimize the occurrence of sub-therapeutic and supra-therapeutic C0 of tacrolimus on day 3 after transplantation by basing the starting dose of tacrolimus on a dosing algorithm (34), rather than the standard bodyweight-only-based approach. More specifically, we will investigate whether a tacrolimus starting dose based on the algorithm will lead to a sufficient percentage of patients being within the tacrolimus target C0 (10.0 – 15.0 ng/L) on day 3 after transplantation (i.e. the first steady state concentration). The proportion achieved with the dosing algorithm will be interpreted with regard to the percentage of patients observed in a historic control group of paediatric renal allograft recipients (included in a previous study (11)) who received a standard starting dose of tacrolimus; If the algorithm-based strategy proves successful, a randomised trial might be an option. |
Het verminderen van het voorkomen van sub-therapeutische of supra-therapeutische dalspiegels van tacrolimus op dag 3 na niertransplantatie, door het doseren van tacrolimus op basis van een doserings algoritme in plaats van alleen op gewicht. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are: - The percentage of patients with markedly supra- or sub- therapeutic tacrolimus concentration on day 3 after transplantation; - The percentage of patients with a tacrolimus area under the curve (AUC) within the target range on day 9-14 after transplantation; - The percentage of patients with a sub- and supra-therapeutic tacrolimus AUC on day 9–14 post-transplantation; - The incidence of biopsy-proven acute rejection and other serious adverse events (SAE); - The incidence of viral infections, biopsy-proven tacrolimus nephrotoxicity, and post-transplantation diabetes mellitus; - The role of the human microbiome in intra- and inter-patient variability in tacrolimus pharmacokinetics; - The pharmacokinetics of the once-daily tacrolimus formulation LCP-tacrolimus; And interpret the results with respect to the results observed in the historic control group which could add to the decision to perform an (international) randomised, controlled clinical trial |
- Het percentage patienten met sub- of supra-therapeutische dalspiegel van tacrolimus op dag 3 na niertransplantatie; - Het percentage patienten met een tacrolimus area under the curve (AUC) binnen de streefwaarden op dag 9-14 na niertransplantatie; - Het percentage patienten met sub- of supra-therapeutische AUC van tacrolimus op dag 9-14 na niertransplantatie; - De incidentie van biopt bewezen acute rejectie en andere serious adverse events (SAE); - De incidentie van virale infecties, biopt bewezen tacrolimus nefrotoxiciteit en post-transplantatie diabetes mellitus; - De invloed van het humane microbioom op de intra- en inter-patient variabiliteit in de farmacokinetiek van tacrolimus; - De farmacokinetiek van de éénmaal daags formulering van tacrolimus. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria: - Age 2-18 years old - Patients to be transplanted with a kidney allograft - Patients receiving a kidney from a blood group ABO-compatible donor - Patients who will receive tacrolimus as part of their initial immunosuppressive therapy - Signed written informed consent |
- Leeftijd 2-18 jaar oud; - Ontvanger van een niertransplantatie; - Nier ontvangen van een AB0-bloedgroep compatibele donor; - Tacrolimus als onderdeel van initiele immunosuppresiva na niertransplantatie; - Ondertekend toestemming (informed consent) |
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study: - Recipients of a non-renal organ transplant at the same occasion - Recipients of a blood group ABO-incompatible kidney allograft - Recipients of an HLA-incompatible kidney allograft (positive cross-match) - Recipients receiving tacrolimus as immunosuppressive treatment within the preceding 28 days. - Recipients using medication known to have a pharmacokinetic (drug-drug) interaction with tacrolimus
Extra exclusion criteria for participation in study part B: - Children who are not able to swallow a once-daily tacrolimus capsule - Children with changes in the administration of drugs interacting with tacrolimus around the switch to the once-daily formulation |
- Multi-orgaan transplantatie ontvanger; - Bloedgroep AB0-incompatibel nierdonor; - HLA-incompatibele nierdonor (positieve kruisproef); - Tacrolimus gebruikt in de 28 dagen voor niertransplantatie. - Gebruik van medicatie met bekende interactie met tacrolimus (tabel 1)
Exclusie voor deel B: - Niet mogelijk tot doorslikken van orale medicatie; - Veranderingen in medicatie gebruik (met bekende interactie met tacrolimus) rond de overgang naar de eenmaal daags tacrolimus formulatie. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary study end points is: 1) the percentage of children within the target concentration range of tacrolimus (10-15 ng/mL) on day 3 after kidney transplantation following algorithm-based dosing |
Het percentage kinderen die binnen de streefspiegel van tacrolimus (10-15 ng/mL) vallen op dag 3 na niertransplantatie door gebruik van het dosering algoritme. |
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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) |
The secondary end points are: 1) The percentage of children with tacrolimus concentrations within the target AUC on day 9-14 after kidney transplantation following computerized follow-up dosing; 2) The relationship between the gut microbiome and tacrolimus pharmacokinetics; 3) Description of the pharmacokinetics of the once-daily tacrolimus formulation and exploration of variables that can underlie the expected variability in the pharmacokinetics of the once-daily formulation. |
1) Het percentage kinderen dat een tacrolimus bloedconcentratie heeft binnen de streefwaarden van de AUC, op dag-14 na niertransplantatie, door middel van computer gestuurde doseringen; 2) De relatie tussen het darmmicrobioom en de farmacokinetiek van tacrolimus; 3) Beschrijven van de farmacokinetiek van eenmaal daags formulering tacrolimus en exploratie van de variabelen die de variabiliteit van deze formulering kunnen verklaren. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Day 9-14; 2) 6 weeks; 3) 6 weeks. |
1) Dag 9-14; 2) 6 weken; 3) 6 weken. |
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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 | 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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
open-label, multi-center clinical trial |
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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
| 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 | 2 |
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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LVLS. |
Laatste studievisite van laatste proefpersoon. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |