Clinical Trials Register

Summary
EudraCT Number:	2018-004043-23
Sponsor's Protocol Code Number:	CoFu-01
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-04-15
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2018-004043-23

A.3

Full title of the trial

Cognitive function after liver transplantation comparing Tacrolimus formulations

Kognitive Funktion nach Lebertransplantation im Vergleich verschiedener Tacrolimus Formulierungen

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Cognitive function after liver transplantation comparing Tacrolimus formulations

Kognitive Funktion nach Lebertransplantation im Vergleich verschiedener Tacrolimus Formulierungen

A.4.1

Sponsor's protocol code number

CoFu-01

A.5.4

Other Identifiers

Name:

DRKS

Number:

DRKS00021108

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Hospital Schleswig-Holstein (UKSH)
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Chiesi GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Schleswig-Holstein (UKSH)
B.5.2	Functional name of contact point	Section ClinicalTransplantation
B.5.3	Address:
B.5.3.1	Street Address	Arnold-Heller-Str. 3
B.5.3.2	Town/ city	Kiel
B.5.3.3	Post code	24105
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4943150020455
B.5.5	Fax number	+4943150020458
B.5.6	E-mail	felix.braun@uksh.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Envarsus 0.75 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi Farmaceutici S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TACROLIMUS
D.3.9.1	CAS number	104987-11-3
D.3.9.4	EV Substance Code	SUB10797MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.75
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TACROLIMUS
D.3.9.1	CAS number	104987-11-3
D.3.9.4	EV Substance Code	SUB10797MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.5 to 5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Envarsus 1 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi Farmaceutici S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TACROLIMUS
D.3.9.1	CAS number	104987-11-3
D.3.9.4	EV Substance Code	SUB10797MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Envarsus 4 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi Farmaceutici S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TACROLIMUS
D.3.9.1	CAS number	104987-11-3
D.3.9.4	EV Substance Code	SUB10797MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Immunosuppression post liver transplantation

Immunsuppression nach Lebertransplantation

E.1.1.1

Medical condition in easily understood language

The immunsystem of patients who received a donor liver must be controlled in order to prevent a rejection reaction against the new liver.

Das Immunsystem von Patienten mit einer Spenderleber muss kontrolliert werden, um Abstoßungsreaktionen gegen die neue Leber zu vermeiden.

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10024716
E.1.2	Term	Liver transplantation
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine whether once-daily formulation of tacrolimus (Envarsus®) improves subjective impression of attention and memory performance compared to twice-daily formulation of tacrolimus [time frame: 6 months].

Ziel ist es, festzustellen, ob die einmal-tägliche Tacrolimus Formulierung (Envarsus®) die Subjective Einschätzung der Aufmerksamkeit und Gedächtnisleistung im Vergleich zur zweimal-täglichen Formulierung verbessert [Zeitpunkt: 6 Monate]

E.2.2

Secondary objectives of the trial

(1) To determine whether once-daily formulation of tacrolimus improves cognitive functions compared to twice-daily formulation [time frame: 6 and 12 months].
(2) To determine whether once-daily formulation of tacrolimus improves quality of life (QoL) compared to twice-daily formulation [time frame: 6 and 12 months].
(3) To determine whether once-daily formulation of tacrolimus improves everyday executive function compared to twice-daily formulation [time frame 6 and 12 months].
(4) To assess the impact on safety-parameters including AEs, clinical significant liver and kidney function.
(5) To investigate whether there is a change in Tacrolimus trough levels over time within the groups.
(6) To assess the correlation between Tacrolimus trough levels and cognitive functions at each time point separated for both study arms.

(1) Festzustellen, ob die einmal-tägliche Tacrolimus Formulierung im Vergleich zur zweimal-täglichen Formulierung die kognitiven Funktionen verbessert [Zeitpunkte 6 und 12 Monate].
(2) Festzustellen, ob die einmal-tägliche Tacrolimus Formulierung im Vergleich zur zweimal-täglichen Formulierung die Lebensqualität verbessert [Zeitpunkte 6 und 12 Monate].
(3) Festzustellen, ob die einmal-tägliche Tacrolimus Formulierung im Vergleich zur zweimal-täglichen Formulierung die Eigenständigkeit verbessert [Zeitpunkte 6 und 12 Monate].
(4) Beurteilung des Einflusses auf Sicherheitsparameter inklusive AEs sowie klinisch signifikanter Leber und Nierenfunktion.
(5) Zu Untersuchen, ob es im Verlauf eine Änderung der Tacrolimus Talspiegel innerhalb der Studienarme gibt.
(6) Festzustellen, ob es zu den jeweiligen Untersuchungszeitpunkten innerhalb der jeweiligen Studienarme eine Korrelation zwischen den Tacrolimus Talspiegeln und den kognitiven Funktionen gibt.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Written informed consent
- Age 20 to 70 years
- After 12 months post liver transplantation
- Immunosuppression with a twice daily formulation of Tacrolimus
- Application of the same active tacrolimus twice daily formulation ≥3 months
- At least mild cognitive impairment (TMT: at least one standard deviation above the age-specific mean for TMT Test B)

- Schriftliche Einwilligung
- Alter zwischen 20 und 70 Jahre
- Mindestens 12 Monate nach Lebertransplantation
- Immunbehandlung mit zweimal-täglicher Tacrolimus Formulierung
- Behandlung mit derselben Tacrolimus-Formulierung seit mindestens 3 Monaten
- Vorhandensein einer leichten kognitive Einschränkung (TMT: mindestens eine Standardabweichung über dem alters-spezifischen Durchschnitt für den TMT Test B)

E.4

Principal exclusion criteria

- Dialysis treatment during the previous 30 days
- Deafness and/or blindness
- Pregnancy/breastfeeding mothers
- Current participation in another study
- Every other aspect that, in the eye of investigator, makes the patient unable to comply with study procedures

- Dialysebehandlung innerhalb der letzten 30 Tage
- Taubheit oder Blindheit
- Schwangerschaft oder stillende Mütter
- Derzeitige Teilnahme in einer weiteren Studie
- Jeder weitere Aspekt, welcher, nach Meinung des Prüfers, eine Teilnahme an der Studie verhindert

E.5 End points

E.5.1

Primary end point(s)

Change in subjective impression of quality of life concerning attention/concentration and memory between screening and visit 4 (6 months) using the FEDA (self-report questionnaire on attention and memory).

Änderung der subjectiven Einschätzung der Lebensqualität im Hinblick auf Aufmerksamkeit / Konzentration und Gedächtnisleistung zwischen Screening und Visite 4 (Monat 6) anhand des FEDA (Fragebogen Erlebter Defizite der Aufmerksamkeit)

E.5.1.1

Timepoint(s) of evaluation of this end point

Change between screening and Visit 4 (month 6)

Veränderung zwischen Screening und Visite 4 (Monat 6)

E.5.2

Secondary end point(s)

- Cognitive function is assessed using the:
1. Trail Making Test – TMT
2. Adaptive Digit Ordering Test – DOT-A
3. Digit Symbol Test – DST
4. Regensburg Stream of Speech Test – RWT
5. Victoria Stroop Test – VST
- Quality of life (QoL) is measured using the SF36
- Everyday executive function is measured by BAFQ

- Kognitive Funktionen werden untersucht anhand von:
1. Trail Making Test – TMT
2. Adaptive Digit Ordering Test – DOT-A
3. Digit Symbol Test – DST
4. Regensburg Stream of Speech Test – RWT
5. Victoria Stroop Test – VST
- Lebensqualität wird anhand des SF36 Fragebogens bestimmt
- Alltägliche exekutive Funktionen werden anhand des BAFQ bestimmt.

E.5.2.1

Timepoint(s) of evaluation of this end point

Cognitive function will be assessed at visit 3 (month 6) and visit 5 (month 12)
Quality of life (QoL) will be assessed at visit 3 (month 6) and visit 5 (month 12)
Everyday executive function is measured at visit 3 (month 6) and visit 5 (month 12)

Kognitive Funktionen werden zu Visite 3 (Monat 6) und Visite 5 (Monat 12) untersucht
Lebensqualität wird zu Visite 3 (Monat 6) und Visite 5 (Monat 12) bestimmt
Alltägliche exekutive Funktionen werden zu Visite 3 (Monat 6) und Visite 5 (Monat 12) bestimmt

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Prüfer (Rater)-verblindet

investigator (rater)-blinded

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

150

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The treatment after the end of a patients' participation will be continued at the discretion of the patient and the physician according to the Standard practice of care.

Die Behandlung nach Beendigung der Teilnahme eines Patienten wird im Ermessen des Patient und des Prüfarztes nach den gültigen Leitlinien fortgeführt.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-07-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-13

P. End of Trial
P.	End of Trial Status	Ongoing

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