Clinical Trials Register

Summary
EudraCT Number:	2020-004604-33
Sponsor's Protocol Code Number:	TR-004
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:	2020-12-17
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

2020-004604-33

A.3

Full title of the trial

Open label, Multicenter, Prospective Study to Characterize the Pharmacokinetics and Pharmacodynamics of Cufence (Trientine Dihydrochloride) and to Investigate the Efficacy and Safety in Wilson’s Disease Patients

Offene, multizentrische, prospektive Studie zur Charakterisierung der Pharmakokinetik und Pharmakodynamik von Cufence (Trientindihydrochlorid) und zur Untersuchung der Wirksamkeit und Sicherheit bei Patienten mit Morbus Wilson

A.3.1

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

Multicentre, open-label study to investigate the effects Cufence has, the effects the body has on Cufence and the continued safety and efficacy on patients with Wilson Disease

Multizentrische, offene Studie zur Untersuchung der Auswirkungen von Cufence, der Auswirkungen des Körpers auf Cufence und der anhaltenden Sicherheit und Wirksamkeit bei Patienten mit Wilson-Krankheit

A.3.2

Name or abbreviated title of the trial where available

TR-004 UNITED Study

A.4.1

Sponsor's protocol code number

TR-004

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	Univar Solutions, B.V.
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Univar Solutions, B.V
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	QPS Austria
B.5.2	Functional name of contact point	Karin Flicker
B.5.3	Address:
B.5.3.1	Street Address	Parkring 12
B.5.3.2	Town/ city	Grambach
B.5.3.3	Post code	8074
B.5.3.4	Country	Austria
B.5.4	Telephone number	0043316258111100
B.5.5	Fax number	0043316258111300
B.5.6	E-mail	karin.flicker@qps.com

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	Cufence (trientine dihydrochloride)
D.2.1.1.2	Name of the Marketing Authorisation holder	Univar Solutions, B.V.
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.3.1	Product name	Cufence (trientine dihydrochloride)
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	Triethylenetetramine dihydrochloride
D.3.9.1	CAS number	38260-01-4
D.3.9.2	Current sponsor code	TR-004
D.3.9.3	Other descriptive name	Cufence
D.3.9.4	EV Substance Code	AS1
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	300
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

Wilson Disease

Morbus Wilson

E.1.1.1

Medical condition in easily understood language

Wilson's disease is a rare inherited disorder that causes copper to accumulate in the liver, brain and other vital organs. If left untreated this can lead to significant damage and even death.

Morbus Wilson ist eine seltene Erbkrankheit, bei der sich Kupfer in Leber, Gehirn und anderen lebenswichtigen Organen ansammelt. Unbehandelt kann dies zu erheblichen Schäden und sogar zum Tod führen.

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.1
E.1.2	Level	PT
E.1.2	Classification code	10019819
E.1.2	Term	Hepato-lenticular degeneration
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To characterize the Cufence dose – exposure – copper markers (24-h urinary copper excretion (UCE), total serum copper, ceruloplasmin bound copper, non-ceruloplasmin
bound copper (NCC)) relationships through population pharmacokineticpharmacodynamic
(PKPD) modelling in Wilson’s disease (WD) patients and to evaluate the influence of patient characteristics on relevant model parameters, such as apparent clearance, apparent volume of distribution and drug potency.

E.2.2

Secondary objectives of the trial

• To investigate the contribution of trientine, N(1)-acetyltriethylenetetramine (MAT) and
N(1),N(10)-diacetyltriethylenetetramine (DAT) to the exposure and copper markers (exposure-response) in patients with Wilson’s disease.
• To investigate the relationship between Cufence exposure (systemic trientine, MAT and DAT) and clinical efficacy measures (changes in neurological disease, changes in psychiatric symptoms and changes in hepatic disease) in patients with Wilson’s disease.
• To investigate the relationships between copper markers (24-h UCE, total serum Cu, ceruloplasmin bound copper, NCC and clinical efficacy measures (changes in neurological disease, changes in psychiatric symptoms and changes in hepatic disease) in patients with
Wilson’s disease.
• To investigate the safety and tolerability of Cufence in patients with Wilson’s disease.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient (or a representative) must provide written, informed consent before the start of any study procedures.
2. Male and female patient aged ≥ 5 years at time of consent.
3. Diagnosis of WD previously determined by the physician based on a Leipzig score ≥ 4.
4. Patient (≥ 18 years) has previously been treated with D-penicillamine for WD.
5. Patient (< 18 years) has previously been treated with D-penicillamine or zinc for WD.
6. For female patients of childbearing potential, a negative pregnancy test at the Screening visit and the Baseline visit is required. In addition, a highly effective method (failure
rate <1%) of birth control must be used during the study which includes (but is not limited to) the following:
- vasectomized partner (at least 6 months prior to dosing);
- oral, patch, or injected contraceptives, or vaginal hormonal device (i.e. NuvaRing®), in use for at least 3 consecutive months prior to study dosing and throughout the study duration;
- implanted or intrauterine contraceptives in use for at least 6 consecutive months prior to study dosing and throughout the study duration;
- abstinence (must agree to use a highly effective method if they become sexually active during the study).
7. Patient is considered to be able to complete study requirements and attend the study visits, in the opinion of the investigator.

Alle Patienten, für die eine Teilnahme an der Studie erwogen wird, müssen die folgenden Kriterien erfüllen:
1. Der Patient (oder der/die Sorgeberechtigte[n]) muss/müssen vor der Durchführung studienbedingter Maßnahmen nach erfolgter Aufklärung schriftlich in die Teilnahme einwilligen und/oder der Teilnahme zustimmen
2. Männliche und weibliche Patienten im Alter von ≥ 5 Jahren zum Zeitpunkt der Einwilligung
3. Die Diagnose Morbus Wilson muss zuvor von einem Arzt basierend auf einem Leipzig-Score von ≥ 4 gestellt worden sein.
4. Patienten (≥ 18 Jahre) müssen zuvor für Morbus Wilson eine Behandlung mit D-Penicillamin erhalten haben.
5. Patienten (< 18 Jahre) müssen zuvor für Morbus Wilson eine Behandlung mit D-Penicillamin oder Zink erhalten haben.
6. Für Patientinnen im gebärfähigen Alter ist ein negativer Schwangerschaftstest beim Screening-Besuch und beim Baseline-Besuch erforderlich. Darüber hinaus muss eine hochwirksame Methode (failure rate <1%) während der Studie angewendet werden, die folgendes umfasst (aber nicht darauf beschränkt ist):
- vasektomierter Partner (mindestens 6 Monate vor der Dosierung);
- orale, Patch- oder injizierte Kontrazeptiva oder vaginale Hormonvorrichtungen (d. H. NuvaRing®), die mindestens 3 aufeinanderfolgende Monate vor der Dosierung der Studie und während der gesamten Studiendauer angewendet werden;
- implantierte oder intrauterine Kontrazeptiva, die mindestens 6 aufeinanderfolgende Monate vor der Dosierung der Studie und während der gesamten Studiendauer angewendet werden;
- Abstinenz (Patientin muss zustimmen, eine hochwirksame Methode anzuwenden, wenn sie während der Studie sexuell aktiv wird).
7. Der Prüfarzt geht davon aus, dass der Patient in der Lage ist, die Studienanforderungen zu erfüllen und die Besuchstermine wahrzunehmen.

E.4

Principal exclusion criteria

1. Patient has evidence of uncontrolled liver disease, including but not limited to:
a. New Wilson index (Dhawan Index) > 10
b. Alanine aminotransferase (ALT) > 5x upper limit of normal (ULN)
c. Aspartate aminotransferase (AST) > 5x ULN
d. MELD score > 13 (only applicable for patients that are ≥ 12 years of age)
e. Acute liver failure
f. Hepatic malignancy
2. Uncontrolled neurological disease according to the judgement of the physician.
3. Patient has severe anaemia defined as hemoglobin of < 9 g/dL.
4. Patient has a known intolerance, allergy or sensitivity to trientine dihydrochloride, including any component of the study medication.
5. Female patient is pregnant or lactating.
6. Any patients who lack the capacity to consent including the parent(s) of a paediatric patient.

Patienten werden ausgeschlossen, wenn sie eines der folgenden Kriterien erfüllen:
1. Der Patient leidet nachweislich an einer unkontrollierte Lebererkrankung einschließlich unter anderem:
a. New Wilson-Index (Dhawan-Index) > 10
b. Alanin-Aminotransferase (ALT) > 5 x obere Normgrenze (ONG)
c. Aspartat-Aminotransferase (AST) > 5 x ONG
d. Score des Modells für terminale Leberinsuffizienz (Model for End-Stage Liver Disease, MELD) > 13 (gilt nur für Patienten ab ≥ 12 Jahren)
e. Akutes Leberversagen
f. Hepatisches Malignom
2. Unkontrollierte neurologische Erkrankung laut Urteil des Arztes
3. Patient leidet unter einer schweren Anämie, definiert als Hämoglobin < 9 g/dl
4. Der Patient hat eine bekannte Unverträglichkeit, Allergie oder Empfindlichkeit gegenüber Trientinhydrochlorid einschließlich aller Bestandteile des Prüfpräparats.
5. Patientin ist schwanger oder stillend.
6. Alle erwachsenen Patienten, die nicht einwilligungsfähig sind, einschließlich der Eltern eines pädiatrischen Patienten.

E.5 End points

E.5.1

Primary end point(s)

• Concentration of trientine in plasma
• Trientine clearance (CL/F) and volume(s) of distribution (V/F)
• 24-h UCE (copper marker)
• NCC* (copper marker)
• Serum copper (copper marker)
• Serum ceruloplasmin (copper marker)
• Patient characteristics for covariates

• Konzentration von Trientin im Plasma
• Trientin Clearance (CL/F) und Verteilungsvolumina (V/F)
• 24-Std.-UCE (Kupfer-Marker)
• NCC* (Kupfer-Marker)
• Serumkupfer (Kupfer-Marker)
• Serum-Coeruloplasmin (Kupfer-Marker)
• Patientenmerkmale im Hinblick auf Kovariaten

E.5.1.1

Timepoint(s) of evaluation of this end point

• Concentration of trientine in plasma at Visit 2- Visit 10
• Trientine clearance (CL/F) and volume(s) of distribution (V/F) at Visit 2- Visit 10 except Visit 5
• 24-h UCE (copper marker)at Visit 2- Visit 10 except Visit 5
• NCC* (copper marker) at Visit 2- Visit 10 except Visit 5
Serum copper (copper marker)- Visit 2- Visit 10 except Visit 5

• Konzentration von Trientin im Plasma bei Besuch 2 - Besuch 10
• Trientin-Clearance (CL / F) und Verteilungsvolumen (V / F) bei Besuch 2 - Besuch 10 außer Besuch 5
• 24-Stunden-UCE (Kupfermarker) bei Besuch 2 - Besuch 10 außer Besuch 5
• NCC * (Kupfermarker) bei Besuch 2 - Besuch 10 außer Besuch 5
Serumkupfer (Kupfermarker) - Besuch 2 - Besuch 10 außer Besuch 5

E.5.2

Secondary end point(s)

• Concentration of MAT in plasma
• Concentration of DAT in plasma
• AUC0-t, Cmax and Ctrough for trientine and metabolites. (As secondary endpoint, pre-dose concentrations are reported and summarized using NCA. While the pre-dose PK samples
are collected shortly prior to the next dose, the pre-dose concentration is assumed to approximate the Ctrough.)
• Number of AEs including number of AEs leading to discontinuation of treatment with
Cufence
• Changes in neurological disease status (Unified Wilson’s Disease Rating Scale (UWDRS))
• Changes in psychiatric symptoms (SCID-5, MMSE, EQ-5D-3L, PHQ-9, PHQ-9-A, CBCL)
• Changes in hepatic disease (full liver panel to determine the APRI, the Child-Pugh score, the FIB4 index and the New Wilson Index (Dhawan Index), and Fibroscan)

• Konzentration von MAT im Plasma
• Konzentration von DAT im Plasma
• AUC0-t, Cmax und CTal für Trientin und die Metaboliten (Als ein sekundärer Endpunkt werden die Konzentrationen vor der Dosisgabe berichtet und anhand einer nichtkompartimentellen Analyse zusammengefasst. Da die Prä-PK-Proben kurz vor der nächsten Dosis entnommen werden, wird davon ausgegangen, dass sich die Konzentration vor Dosisgabe CTal annähert.)
• Anzahl von UEs einschließlich UEs, die zum Absetzen von Cufence führen
• Veränderungen beim neurologischen Krankheitsstatus (UWDRS)
• Veränderungen bei den psychiatrischen Symptomen (SCID-5, MMSE, EQ-5D-3L, PHQ-9, PHQ-9-A, CBCL)
• Veränderungen bei der hepatischen Erkrankung (vollständiges Leber-Panel zur Ermittlung von APRI, Child-Pugh-Score, FIB4-Index und New Wilson-Index [Dhawan-Index] und FibroScan)

E.5.2.1

Timepoint(s) of evaluation of this end point

• Concentration of MAT in plasma at Visit 2- Visit 10
• Concentration of DAT in plasma at Visit 2- Visit 10
• AUC0-tau, Cmax and Cmin for trientine and metabolites (by NCA) at Visit 2- Visit 10 except Visit 5
• Number of AEs including number of AEs leading to discontinuation of treatment with Cufence at all visits
• Changes in neurological disease status (Unified Wilson’s Disease Rating Scale (UWDRS)) at Visit 2,4 and Visit 6-10
• Changes in psychiatric symptoms (SCID-5, MMSE,
EQ-5D-3L, PHQ-9, PHQ-9-A, CBCL)-various timepoint for each assessment
• Changes in hepatic disease (full liver panel to determine the APRI, the Child-Pugh score, the FIB4 index and the New Wilson Index (Dhawan Index), and Fibroscan)

• Konzentration von MAT im Plasma bei Besuch 2 - Besuch 10
• Konzentration von DAT im Plasma bei Besuch 2 - Besuch 10
• AUC0-Tau, Cmax und Cmin für Trientin und Metaboliten (von NCA) bei Besuch 2 - Besuch 10 außer Besuch 5
• Anzahl der Nebenwirkungen, die bei allen Besuchen zum Abbruch der Behandlung mit Cufence führen
• Änderungen des neurolog Krankheitsstatus (Unified Wilson's Disease Rating Scale (UWDRS)) bei Besuch 2,4 und Besuch 6-10
• Veränderungen der psychiatri Symptome (SCID-5, MMSE,
EQ-5D-3L, PHQ-9, PHQ-9-A, CBCL) - versch Zeitpunkte für jede Bewertung
• Veränderungen der Lebererkrankung (APRI, Child-Pugh-Scores, des FIB4-Index und des New Wilson-Index (Dhawan-Index) sowie von Fibroscan)

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Cufence (Trientine Dihydrochloride)- fixed dose as per SmPc

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Follow up call 28 days after LVLS.

Follow-up-Anruf 28 Tage nach 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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1