Pharmacokinetics, Effectiveness and Tolerability of Prolonged-release Tacrolimus After Paediatric Kidney Transplantation

Study Overview
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Brief Summary
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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.

Official Title
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A Multi-center Interventional Study to Assess Pharmacokinetics, Effectiveness and Tolerability of Prolonged-release Tacrolimus After Paediatric Kidney Transplantation

Conditions
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Pediatric Kidney Disease

Intervention / Treatment
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* Drug: Envarsus®
* Drug: Prograf


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: caucasian paediatric kidney transplant recipients (single-organ recipients) aged ≥ 8 years but ≤ 18 years who are under tacrolimus (Prograf®) therapy and who are able to swallow tablets with a minimum dose of 0.75 mg / day Envarsus® not less than 6 months after transplantation stable kidney function (delta eGFR < 10 ml/min/1.73 m2 (CKID formula) over the last 3 months) women of childbearing potential and women without childbearing potential patient/parents/legal guardian(s) must be capable of understanding purpose and risks of the study signed informed consent obtained by patient and parents/legal guardians Exclusion Criteria: coefficient of variation of tacrolimus trough levels > 0.35 over the previous 6 months pregnancy/breast feeding instable kidney function hypersensitivity to any of the components of the medications used not eligible for any reason according to the investigator's valuation known positive HIV-1 or HCV test participation in another clinical trial (other investigational drugs or devices at the time of enrolment or within 30 days prior to enrolment)

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Multi-center, prospective, interventional, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A - Envarsus followed by Prograf<br>4 weeks treatment sequence 1 (Envarsus) followed by 4 weeks treatment sequence 2 (Prograf) | Drug: Envarsus®<br>* Treatment sequence: 4 weeks prolonged-release tacrolimus (Envarsus®) once daily<br>Drug: Prograf<br>* Treatment sequence: 4 weeks intermediate-release tacrolimus (Prograf®) twice daily<br>|
| Experimental: Group B - Prograf followed by Envarsus<br>4 weeks treatment sequence 2 (Prograf) followed by 4 weeks treatment sequence 1 (Envarsus) | Drug: Envarsus®<br>* Treatment sequence: 4 weeks prolonged-release tacrolimus (Envarsus®) once daily<br>Drug: Prograf<br>* Treatment sequence: 4 weeks intermediate-release tacrolimus (Prograf®) twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 |