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

Primary Purpose

Pediatric Kidney Disease

Status
Recruiting
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
Envarsus®
Prograf
Sponsored by
University Hospital, Essen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pediatric Kidney Disease

Eligibility Criteria

8 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • University Hospital Cologne, PediatricsRecruiting
  • University Hospital of Essen, Pediatrics IIRecruiting
  • University Hospital of Hamburg-EppendorfRecruiting
  • University Hospital of HeidelbergRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group A - Envarsus followed by Prograf

Group B - Prograf followed by Envarsus

Arm Description

4 weeks treatment sequence 1 (Envarsus) followed by 4 weeks treatment sequence 2 (Prograf)

4 weeks treatment sequence 2 (Prograf) followed by 4 weeks treatment sequence 1 (Envarsus)

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
April 24, 2023
Last Updated
September 26, 2023
Sponsor
University Hospital, Essen
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1. Study Identification

Unique Protocol Identification Number
NCT06057545
Brief Title
Pharmacokinetics, Effectiveness and Tolerability of Prolonged-release Tacrolimus After Paediatric Kidney Transplantation
Acronym
Pro-Tac
Official Title
A Multi-center Interventional Study to Assess Pharmacokinetics, Effectiveness and Tolerability of Prolonged-release Tacrolimus After Paediatric Kidney Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 25, 2023 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Essen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pediatric Kidney Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Model Description
Multi-center, prospective, interventional, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group A - Envarsus followed by Prograf
Arm Type
Experimental
Arm Description
4 weeks treatment sequence 1 (Envarsus) followed by 4 weeks treatment sequence 2 (Prograf)
Arm Title
Group B - Prograf followed by Envarsus
Arm Type
Experimental
Arm Description
4 weeks treatment sequence 2 (Prograf) followed by 4 weeks treatment sequence 1 (Envarsus)
Intervention Type
Drug
Intervention Name(s)
Envarsus®
Intervention Description
Treatment sequence: 4 weeks prolonged-release tacrolimus (Envarsus®) once daily
Intervention Type
Drug
Intervention Name(s)
Prograf
Intervention Description
Treatment sequence: 4 weeks intermediate-release tacrolimus (Prograf®) twice daily
Primary Outcome Measure Information:
Title
Full tacrolimus AUC
Description
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
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Pharmacodynamic analysis
Description
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
Time Frame
4 weeks
Title
Pharmacogenetic analysis
Description
Number of patients with SNPs in selected genes (CYP3A4, CYP3A5, ABCD1)
Time Frame
4 weeks
Title
Tacrolimus trough levels
Description
Tacrolimus trough levels in ng/mL, compared intra- and interindividually.
Time Frame
4 weeks
Title
Doses of prolonged-release tacrolimus
Description
Doses of prolonged-release tacrolimus (Envarsus®) in ng/mL.
Time Frame
4 weeks
Title
Number of patients with adverse event or toxicity
Description
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.
Time Frame
10 weeks
Title
Number of adverse events or toxicity per patient
Description
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.
Time Frame
10 weeks
Title
eGFR (CKiD formula)
Description
eGFR (CKiD formula) comparing the two study phases
Time Frame
4 weeks
Title
Treatment failure rate
Description
composite endpoint: any patient who experienced death, graft failure, BPAR or lost to follow-up
Time Frame
10 weeks
Title
limited sampling strategy (LSS)
Description
LSS driven 24h-AUC estimation
Time Frame
4 weeks
Title
Taxonomy of the gut microbiome
Description
Taxonomy of the gut microbiome using metagenomic sequencing
Time Frame
10 weeks
Title
Gut microbial metabolism
Description
Functional assessment of the gut microbiome using LC-MS based metabolomics
Time Frame
10 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
8 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Julia Grimm
Phone
+4920172377414
Email
julia.grimm@uk-essen.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lars Pape, Prof. Dr.
Organizational Affiliation
University Hospital of Essen, Pediatrics II
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Cologne, Pediatrics
City
Cologne
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lutz Weber, Prof. Dr.
Facility Name
University Hospital of Essen, Pediatrics II
City
Essen
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lars Pape, Prof. Dr.
Facility Name
University Hospital of Hamburg-Eppendorf
City
Hamburg
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jun Oh, Prof. Dr.
Facility Name
University Hospital of Heidelberg
City
Heidelberg
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Burkhard Tönshoff, Prof. Dr.

12. IPD Sharing Statement

Learn more about this trial

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

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