Pharmacokinetics, Effectiveness and Tolerability of Prolonged-release Tacrolimus After Paediatric Kidney Transplantation (Pro-Tac)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Pediatric Kidney Disease
• Intervention / Treatment: Drug: Envarsus®; Drug: Prograf

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Julia Grimm; Phone Number: +4920172377414; Email: julia.grimm@uk-essen.de

Study Locations

• Germany
  • Cologne, Germany
    • Recruiting
    • University Hospital Cologne, Pediatrics
    • Contact: Lutz Weber, Prof. Dr.
  • Essen, Germany
    • Recruiting
    • University Hospital of Essen, Pediatrics II
    • Contact: Lars Pape, Prof. Dr.
  • Hamburg, Germany
    • Recruiting
    • University Hospital of Hamburg-Eppendorf
    • Contact: Jun Oh, Prof. Dr.
  • Heidelberg, Germany
    • Recruiting
    • University Hospital of Heidelberg
    • Contact: Burkhard Tönshoff, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Essen
• Investigators: Principal Investigator: Lars Pape, Prof. Dr., University Hospital of Essen, Pediatrics II

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: April 24, 2023
• First Submitted That Met QC Criteria: September 26, 2023
• First Posted (Actual): September 28, 2023

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 26, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: Pro-Tac

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No