A multi-center interventional study to assess pharmacokinetics, effectiveness and tolerability of prolonged-release Tacrolimus after Paediatric Kidney Transplantation (Pro-Tac)

Start 23 Feb 2022 · End 8 Jan 2026 · Status Ended · 1 EU/EEA countries · 4 sites · Protocol Pro-Tac

Overview

Sponsor-declared trial summary

Phase Phase II and Phase III (Integrated)

Status Ended

Participants planned 30

Countries 1

Sites 4

Caucasian paediatric kidney transplant recipients

To assess, whether the tacrolimus full-area under the curve concentration with blood samples drawn before and 1.5, 2, 4, 6, 8, 12, 13.5, 14, 16, 20, 24 hrs after administration in compliant patients without any major protocol deviations is bioequivalent between immediate-release tacrolimus (Prograf®) therapy and prolon…

Key facts

Sponsor: Universitaetsklinikum Essen AöR
Participant type: Pediatric, Patients
Age range: 0-17 years
Gender: Male and Female
Therapeutic area: Not possible to specify
Trial duration: 23 Feb 2022 → 8 Jan 2026
Decision date (initial): 2024-10-21
Transition trial: Yes
Low-intervention: No
Rare-disease indication: No
Vulnerable population: Yes

External identifiers

EU CT number: 2024-516608-40-00
EudraCT number: 2019-003710-13

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy

Secondary objectives 1

To assess efficacy in terms of residual expression of NFAT regulated genes (pharmacodynamics), potential influence of pharmacogenetics, trough levels and doses of prolonged-release tacrolimus (Envarsus®), the level of adherence, cumulative dosage and signs of tacrolimus toxicity and adverse events, biopsy proven rejections as well as a decrease in eGFR >10% (CKiD formula) of baseline and DSAs are determined.

Conditions and MedDRA coding

Caucasian paediatric kidney transplant recipients

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

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 witha 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 •who is practicing true abstinence from sexual intercourse(periodic abstinence and withdrawal are not acceptable) or •who has sexual relationship with female partners only and/orwith sterile male partners; or women of childbearing potential and sexually active withfertile male partner: • who have a negative pregnancy test during screening and • who agree to use reliable methods of contraception from thetime of screening, during the study and for a period of fourweeks following the last administration of study medication(for details please refer to chapter 6.2); or women without childbearing potential defined asfollows: • females before menarche or • at least 6 weeks after surgical sterilization by bilateral tuballigation or bilateral oophorectomy or • hysterectomy or uterine agenesis
patient/parents/legal guardian(s)1 must be capable ofunderstanding purpose and risks of the study
signed informed consent obtained by patient andparents/legal guardians

Exclusion criteria 7

coefficient of variation of tacrolimus trough levels > 0.35over the previous 6 months
pregnancy/breast feeding
instable kidney function
hypersensitivity to any of the components of themedications used
not eligible for any reason according to the investigator’svaluation
known positive HIV-1 or HCV test
participation in another clinical trial (other investigationaldrugs or devices at the time of enrolment or within 30 daysprior to enrolment)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

Full AUCs will be described by median, minimum and maximum, geometric mean, arithmetic mean, standard deviation and coefficient of variation and analysed using an ANOVA model on the log transformed AUC values comparing Envarsus® and Prograf® with sequence, subject within sequence and period as further fixed factors. The resulting 90% confidence interval must lie within the acceptance boundaries of 0.8 and 1.25.

Secondary endpoints 1

The secondary pharmacokinetic and pharmacodynamic endpoints will be analysed analogous to the primary endpoint or assessed using descriptive statistics (such as absolute and relative frequencies, median and interquartile range, geometric mean, arithmetic mean and standard deviation, minimum and maximum and coefficients of variation) to compare both phases. The suitability of LSS for 24h-AUC calculation will be judged using Pearson’s correlation coefficients.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Envarsus 1 mg prolonged-release tablets

PRD1609561 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 1 mg milligram(s)
Max total dose: 28 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/004
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Envarsus 0.75 mg prolonged-release tablets

PRD1609515 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 0.75 mg milligram(s)
Max total dose: 21 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/002
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Envarsus 0.75 mg prolonged-release tablets

PRD1609514 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 0.75 mg milligram(s)
Max total dose: 21 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/001
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Envarsus 4 mg prolonged-release tablets

PRD1609571 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 4 mg milligram(s)
Max total dose: 112 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/009
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Envarsus 1 mg prolonged-release tablets

PRD1609563 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 1 mg milligram(s)
Max total dose: 28 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/006
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Envarsus 1 mg prolonged-release tablets

PRD1609562 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 1 mg milligram(s)
Max total dose: 28 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/005
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Envarsus 0.75 mg prolonged-release tablets

PRD1609516 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 0.75 mg milligram(s)
Max total dose: 21 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/003
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Envarsus 4 mg prolonged-release tablets

PRD1609570 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 4 mg milligram(s)
Max total dose: 112 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/008
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Envarsus 4 mg prolonged-release tablets

PRD1609569 · Product

Active substance: Tacrolimus
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL
Max daily dose: 4 mg milligram(s)
Max total dose: 112 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: EU/1/14/935/007
MA holder: CHIESI FARMACEUTICI S.P.A.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Comparator 3

Prograf 0,5 mg Hartkapseln

PRD335096 · Product

Active substance: Tacrolimus
Pharmaceutical form: CAPSULE, HARD
Route of administration: ORAL
Max daily dose: 1 mg milligram(s)
Max total dose: 28 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: 41954.00.00
MA holder: ASTELLAS PHARMA GMBH
MA country: Germany
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Prograf 1 mg Hartkapseln

PRD361965 · Product

Active substance: Tacrolimus
Pharmaceutical form: CAPSULE, HARD
Route of administration: ORAL
Max daily dose: 2 mg milligram(s)
Max total dose: 56 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: 41954.01.00
MA holder: ASTELLAS PHARMA GMBH
MA country: Germany
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Prograf 5 mg Hartkapseln

PRD344604 · Product

Active substance: Tacrolimus
Pharmaceutical form: CAPSULE, HARD
Route of administration: ORAL
Max daily dose: 10 mg milligram(s)
Max total dose: 280 mg milligram(s)
Max treatment duration: 4 Week(s)
Authorisation status: Authorised
ATC code: L04AD02 — -
Marketing authorisation: 41954.02.00
MA holder: ASTELLAS PHARMA GMBH
MA country: Germany
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Essen AöR

Sponsor organisation: Universitaetsklinikum Essen AöR
Address: Hufelandstrasse 55, Holsterhausen Holsterhausen
City: Essen
Postcode: 45147
Country: Germany

Scientific contact point

Organisation: Universitaetsklinikum Essen AöR
Contact name: Prof. Dr. Lars Pape

Public contact point

Organisation: Universitaetsklinikum Essen AöR
Contact name: Universitätsmedizin Essen-Studienzentrum GmbH

Locations

1 EU/EEA country · 4 investigational sites

By country

Country	MS status	Planned subjects	Sites
Germany	Ended	30	4
Rest of world	—	0	—

Investigational sites

Germany

4 sites · Ended

University Medical Center Hamburg-Eppendorf

KfH Nierenzentrum für Kinder und Jugendliche, Martinistrasse 52, Eppendorf, Hamburg

Universitaetsklinikum Essen AöR

Klinik für Kinderheilkunde II, Hufelandstrasse 55, Holsterhausen, Essen

University Hospital Cologne AöR

Klinik und Poliklinik für Kinder- und Jugendmedizin, Kerpener Strasse 62, Lindenthal, Cologne

Universitaetsklinikum Heidelberg AöR

Klinik Kinderheildkunde I, Im Neuenheimer Feld 430, Neuenheim, Heidelberg

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Country	Trial start	Trial end	Recruitment start	Recruitment end	Early termination
Germany	2022-02-23	2026-01-08	2023-04-25	2025-12-02

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Type	Title	Version
Protocol (for publication)	D1_Protocol_2024-516608-40-00_redacted	V3.0
Recruitment arrangements (for publication)	K1_Recruitment arrangements_Placeholder	1
Subject information and informed consent form (for publication)	L1_Informed consent form_ 8-11 years_ Germany	2.0
Subject information and informed consent form (for publication)	L1_Informed consent form_12-17 years_Germany	2.0
Subject information and informed consent form (for publication)	L1_Informed consent form_parents_Germany_redacted	2.0
Subject information and informed consent form (for publication)	L2_Participation Fee_Reimbursement of travel expenses_redacted	1.0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmPc _Envarsus	2
Summary of Product Characteristics (SmPC) (for publication)	G2_SmPc_Prograf	2

Application history

3 submissions — initial application plus substantial / non-substantial modifications

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2024-10-07	Germany	Acceptable 2024-10-18	2024-10-21
2	NON SUBSTANTIAL MODIFICATION	NSM-1	2025-12-08	Germany	Acceptable 2024-10-18	2025-12-08
3	NON SUBSTANTIAL MODIFICATION	NSM-2	2026-01-06	Germany	Acceptable 2024-10-18	2026-01-06