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

Pediatric Kidney Disease Clinical Trial

— Pro-Tac  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06057545
• Other study ID #: Pro-Tac
• Status: Recruiting
• Phase: Phase 3
• Start date: April 25, 2023
• Est. completion date: March 2025

Study information

• Verified date: September 2023
• Source: University Hospital, Essen
• Contact: Julia Grimm
• Phone: +4920172377414
• Email: julia.grimm[@]uk-essen.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: March 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 18 Years

Eligibility

Inclusion Criteria:

1. caucasian paediatric kidney transplant recipients (single-organ recipients)

2. 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®

3. not less than 6 months after transplantation

4. stable kidney function (delta eGFR < 10 ml/min/1.73 m2 (CKID formula) over the last 3 months)

5. women of childbearing potential and women without childbearing potential

6. patient/parents/legal guardian(s) must be capable of understanding purpose and risks of the study

7. signed informed consent obtained by patient and parents/legal guardians

Exclusion Criteria:

1. coefficient of variation of tacrolimus trough levels > 0.35 over the previous 6 months

2. pregnancy/breast feeding

3. instable kidney function

4. hypersensitivity to any of the components of the medications used

5. not eligible for any reason according to the investigator's valuation

6. known positive HIV-1 or HCV test

7. participation in another clinical trial (other investigational drugs or devices at the time of enrolment or within 30 days prior to enrolment)

Related Conditions & MeSH terms

• Kidney Diseases
• Pediatric Kidney Disease

Intervention

Drug:
• Envarsus®
Treatment sequence: 4 weeks prolonged-release tacrolimus (Envarsus®) once daily
• Prograf
Treatment sequence: 4 weeks intermediate-release tacrolimus (Prograf®) twice daily

Locations

Country	Name	City	State
Germany	University Hospital Cologne, Pediatrics	Cologne
Germany	University Hospital of Essen, Pediatrics II	Essen
Germany	University Hospital of Hamburg-Eppendorf	Hamburg
Germany	University Hospital of Heidelberg	Heidelberg

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Essen

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Pharmacogenetic analysis	Number of patients with SNPs in selected genes (CYP3A4, CYP3A5, ABCD1)	4 weeks
Secondary	Tacrolimus trough levels	Tacrolimus trough levels in ng/mL, compared intra- and interindividually.	4 weeks
Secondary	Doses of prolonged-release tacrolimus	Doses of prolonged-release tacrolimus (Envarsus®) in ng/mL.	4 weeks
Secondary	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
Secondary	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
Secondary	eGFR (CKiD formula)	eGFR (CKiD formula) comparing the two study phases	4 weeks
Secondary	Treatment failure rate	composite endpoint: any patient who experienced death, graft failure, BPAR or lost to follow-up	10 weeks
Secondary	limited sampling strategy (LSS)	LSS driven 24h-AUC estimation	4 weeks
Secondary	Taxonomy of the gut microbiome	Taxonomy of the gut microbiome using metagenomic sequencing	10 weeks
Secondary	Gut microbial metabolism	Functional assessment of the gut microbiome using LC-MS based metabolomics	10 weeks