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Recently, a new prolonged-release tablet version of tacrolimus (Envarsus®) using the so-called MeltDose™ (US Patent No. 7,217,431) drug-delivery technology has been approved as immunosuppressive medication for patients after kidney and liver transplantation in adults but not yet in children. Studies in adults proved that Envarsus® provides the same therapeutic effectiveness as the conventional immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile and reduced peak to trough which might result in reduced tacrolimus dosing and subsequently reduced CNI related toxicity. Furthermore, the once daily formulation might result in improved drug adherence.
The aim of this study is to assess pharmacokinetic profiles of Envarsus® as well as effectiveness and tolerability of this drug in children and adolescents ≥ 8 and ≤ 18 years of age.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A - Envarsus followed by Prograf | Experimental | 4 weeks treatment sequence 1 (Envarsus) followed by 4 weeks treatment sequence 2 (Prograf) |
|
| Group B - Prograf followed by Envarsus | Experimental | 4 weeks treatment sequence 2 (Prograf) followed by 4 weeks treatment sequence 1 (Envarsus) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Envarsus® | Drug | Treatment sequence: 4 weeks prolonged-release tacrolimus (Envarsus®) once daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| Full tacrolimus AUC | full tacrolimus AUC calculated from Tac measures before administration of drug and 1.5, 2, 4, 6, 8, 12, 13.5, 14, 16, 20, 24 hours after administration of drug at the time point of 2 weeks (14±7 days) after end of build-up period for each patient under both treatments within two time periods with each a length of 4 weeks | 4 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacodynamic analysis | Assessment of efficacy in terms of residual expression of NFAT regulated genes, expressed as % of expression at C0 (time point before drug administration set at 100%) at 1.5, 2, 4, 6, 8, 12, 13.5, 14, 16, 20, 24 hours after administration of drug at the time point of 2 weeks (14±7 days) after end of build-up period for each patient under both treatments within two time periods with each a length of 4 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Julia Grimm | Contact | +4920172377414 | julia.grimm@uk-essen.de |
| Name | Affiliation | Role |
|---|---|---|
| Lars Pape, Prof. Dr. | University Hospital of Essen, Pediatrics II | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Cologne, Pediatrics | Recruiting | Cologne | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38444519 | Derived | Karaterzi S, Tonshoff B, Ahlenstiel-Grunow T, Baghai M, Beck B, Buscher A, Eifler L, Giese T, Lezius S, Muller C, Oh J, Zapf A, Weber LT, Pape L. A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial. Front Nephrol. 2024 Feb 20;4:1331510. doi: 10.3389/fneph.2024.1331510. eCollection 2024. |
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| ID | Term |
|---|---|
| D016559 | Tacrolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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Multi-center, prospective, interventional, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b
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| Prograf | Drug | Treatment sequence: 4 weeks intermediate-release tacrolimus (Prograf®) twice daily |
|
| 4 weeks |
| Pharmacogenetic analysis | Number of patients with SNPs in selected genes (CYP3A4, CYP3A5, ABCD1) | 4 weeks |
| Tacrolimus trough levels | Tacrolimus trough levels in ng/mL, compared intra- and interindividually. | 4 weeks |
| Doses of prolonged-release tacrolimus | Doses of prolonged-release tacrolimus (Envarsus®) in ng/mL. | 4 weeks |
| Number of patients with adverse event or toxicity | Cumulative dosage and signs of tacrolimus toxicity and adverse events. Potentially tacrolimus associated adverse events and toxicity are recorded individually and compared with individual tacrolimus AUCs. Special attention is taken e.g. towards metabolic (elevated concentration of blood glucose, fat), hematopoetic (cell counts), neurological (tremor, headache), renal (change in glomerular filtration rate), gastrointestinal (diarrhea, nausea), hepatic (cholestasis, elevated transaminases, blood clotting disorder), elevated blood pressure. | 10 weeks |
| Number of adverse events or toxicity per patient | Special attention is taken e.g. towards metabolic (elevated concentration of blood glucose, fat), hematopoetic (cell counts), neurological (tremor, headache), renal (change in glomerular filtration rate), gastrointestinal (diarrhea, nausea), hepatic (cholestasis, elevated transaminases, blood clotting disorder), elevated blood pressure. | 10 weeks |
| eGFR (CKiD formula) | eGFR (CKiD formula) comparing the two study phases | 4 weeks |
| Treatment failure rate | composite endpoint: any patient who experienced death, graft failure, BPAR or lost to follow-up | 10 weeks |
| limited sampling strategy (LSS) | LSS driven 24h-AUC estimation | 4 weeks |
| Taxonomy of the gut microbiome | Taxonomy of the gut microbiome using metagenomic sequencing | 10 weeks |
| Gut microbial metabolism | Functional assessment of the gut microbiome using LC-MS based metabolomics | 10 weeks |
| University Hospital of Essen, Pediatrics II | Recruiting | Essen | Germany |
|
| University Hospital of Hamburg-Eppendorf | Recruiting | Hamburg | Germany |
|
| University Hospital of Heidelberg | Recruiting | Heidelberg | Germany |
|