Clinical Trials Register

Summary
EudraCT Number:	2013-003564-31
Sponsor's Protocol Code Number:	UNV-TRI-002
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-22
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

2013-003564-31

A.3

Full title of the trial

Multicentre, Retrospective and Prospective Study to Assess Long Term Outcomes of Chelator-Based Treatment With Trientine in Wilson Disease Patients Withdrawn from Therapy With d-Penicillamine

A.3.1

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

A study to review Wilson disease patients who have previously been prescribed d- Penicillamine but were changed to trientine as treatment for their disease, and to follow them for a further 12 months.

A.4.1

Sponsor's protocol code number

UNV-TRI-002

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 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 B.V.
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Univar B.V.
B.5.2	Functional name of contact point	Trientine Enquiries
B.5.3	Address:
B.5.3.1	Street Address	Bramley Road
B.5.3.2	Town/ city	Milton Keynes
B.5.3.3	Post code	MK1 1PT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+440845202 6401
B.5.6	E-mail	trientine@univareurope.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	Trientine dihydrochloride 300mg capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Univar B.V.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/03/172
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	TRIENTINE DIHYDROCHLORIDE
D.3.9.1	CAS number	38260-01-4
D.3.9.4	EV Substance Code	SUB04953MIG
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, also known as hepatolenticular degeneration, a rare automsomal, recessively inherited disorder which results in chronic copper intoxication.

E.1.1.1

Medical condition in easily understood language

Wilson disease, an inherited disease in which the body cannot metabolise copper.

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10047988
E.1.2	Term	Wilson's disease
E.1.2	System Organ Class	100000004850

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

- Assess the clinical course of Cu stores, neurological disease, and hepatic disease following initiation of treatment with trientine following withdrawal of d-Penicillamine. Retrospective data will be collected from visits at 6, 12, 24, 36 and 48 months after initiation of treatment, and at the last available follow up visit. Assessments will be based on the Investigator’s score (unchanged, improved but not normal, improved to normal, asymptomatic over duration, and worsened). Prospective assessments will be performed at Baseline (enrolment) and at 6 months and 12 months following the Baseline visit.
- Assess the safety of trientine treatment based on reported AEs, including AEs leading to discontinuation of treatment with trientine.
- Determine duration of treatment with second line therapy trientine, defined as time to discontinuation of treatment due to AEs and/or inadequate response.

E.2.2

Secondary objectives of the trial

For the prospective part of the study:
- Determine the proportion of patients with stable disease according to the Investigator's score after 12 months of treatment with trientine.
- Assess the course of the hepatic disease.
- Assess the course of disease according to the neurologic subscore of the Unified Wilson Disease Rating Scale (UWDRS).
- Assess serum and urinary parameters of copper metabolism.
- Assess quality of life (QoL).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients aged 1 year to 90 years of age at initiation of treatment with trientine.
- Physician established diagnosis of Wilson disease based on a Ferenci score > 3 at the date of diagnosis.
- Documented treatment with d-Penicillamine, withdrawal of treatment with d- Penicillamine, followed by treatment with trientine for at least 6 months at date of informed consent.
- Able/willing to provide written informed consent.

For enrolment in the prospective part:
- Enrolment in the retrospective part of the study.
- On-going treatment with trientine.
- Negative pregnancy test.
- Able/willing to provide written informed consent.

E.4

Principal exclusion criteria

- Incomplete history of medication use for trientine from initial diagnosis to latest follow up.
- Unavailable outcome data for hepatic and neurological course of disease at initiation of treatment with trientine and at least 1 time point post-initiation of treatment with trientine.

For enrolment in the prospective part:
- Hypersensitivity to trientine
- Severe anaemia.

E.5 End points

E.5.1

Primary end point(s)

- The clinical course of hepatic disease at 6, 12, 24, 36, and 48 months and at the last available time point while taking second line trientine, based on the Investigator’s score and based on hepatic status at the time of initiating trientine.
- The clinical course of neurological disease at 6, 12, 24, 36, and 48 months and at the last available time point while taking second line trientine, based on the Investigator’s score and based on neurological status at the time of initiating trientine.
- Cu storage and metabolism, measured at 6, 12, 24, 36, and 48 months and at the last available time point after initiation of treatment with trientine, by available tests, for example,
*24 hour urinary Cu excretion
*Serum CPN
*Serum Cu
compared to Cu storage values at the time of initiation of treatment with trientine.

- Time to discontinuation of trientine due to AEs
- Time to discontinuation of trientine due to inadequate response measured by poor clinical outcome
- Time to discontinuation of trientine due to AEs and/or inadequate response measured by poor clinical outcome
- Patient treatment status at last available timepoint

For the prospective part - The clinical course of neurological and hepatic disease will be scored (Investigator's score) based on status at 6 and 12 months after Baseline. A patient will be counted as a responder if they have a rating of 1-4 at the 12 month visit for both neurological and hepatic Investigator's score. They will be counted as a non-responder if they have a rating of 5 for one or both scores at the 12 month visit or if they were discontinued from the study for any reason prior to the 12 month visit.

E.5.1.1

Timepoint(s) of evaluation of this end point

The time point available after initiation of treatment (6, 12, 24, 36 and 48 months), and at the last available time point while taking second line trientine. For the prospective part, this will be the 12 month visit.

E.5.2

Secondary end point(s)

For the prospective part:-
- The clinical course of hepatic disease at 6 and 12 months while taking second line trientine, based on the Investigator’s score and based on hepatic status at the time of enrolment into prospective part in terms of:
*AST to Platelet Ratio Index (APRI) based on AST, gender, and platelet count
*Child-Pugh Score based on INR, total bilirubin, albumin, hepatic encephalopathy, and esophageal varices
*FIB4 based on age, ALT, AST, and platelets
*Model for End-Stage Liver Disease (MELD) based on INR, total bilirubin, creatinine, and sodium
*Modified Nazer Score based on albumin, AST, total bilirubin, INR, and leukocytes
*Fibroscan.
- The clinical course of neurological disease at 6 and 12 months while taking second line trientine, based on the Investigator’s score and based on neurological status at the time of enrolment into prospective part.
- The neurologic subscore of the UWDRS at Baseline, 6 and 12 months.
- Cu storage and metabolism, measured at 6 and 12 months after initiating second line trientine therapy, by available tests, e.g., 24-hour urinary Cu excretion, serum CPN, and Serum Cu, compared to Cu storage values at the time of enrolment into prospective part.
- Quality of life questionnaires will be completed for each time point and data will be compared to baseline (prospective part) after 6 and 12 months.

E.5.2.1

Timepoint(s) of evaluation of this end point

The 6 month and 12 month visits.

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

A m/c study with retrospective review of patients' medical records and an optional prospective part

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

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

For patient in the retrospective part - The timepoint by when all data from eligible patients who consent to participate in the study have been collected.
For the prospective part - 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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2013-10-22.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

It is possible that children and adolescents below the age of 18 may be included in this retrospective study.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Throughout the study and afterwards, patients will continue to be cared for under their routine treatment plan.

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

2014-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-26

P. End of Trial
P.	End of Trial Status	Completed

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