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    Summary
    EudraCT Number:2013-003564-31
    Sponsor's Protocol Code Number:UNV-TRI-002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-04-26
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-003564-31
    A.3Full title of the trial
    Multicentre, Retrospective Study to Assess Long-Term Outcomes of Chelator-Based Treatment With Trientine in Wilson Disease Patients Withdrawn from Therapy With
    Studio retrospettivo multicentrico per valutare i risultati a lungo termine di terapia chelante con trientina in pazienti affetti da malattia di Wilson precedentemente sottoposti a terapia con d-penicillamina
    A.3.1Title 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.
    Studio per esaminare pazienti affetti dalla malattia di Wilson che sono stati in precedenza
    trattati d- Penicillamine ma sono passati al trattamento con Trientine e che verrano seguiti per ulteriori 12 mesi.
    A.3.2Name or abbreviated title of the trial where available
    N/A
    N/A
    A.4.1Sponsor's protocol code numberUNV-TRI-002
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02426905
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    A.5.4Other Identifiers
    Name:N/ANumber:N/A
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUNIVAR LTD
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUnivar B.V
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUnivar B.V.
    B.5.2Functional name of contact pointTrientine Enquiries
    B.5.3 Address:
    B.5.3.1Street AddressBramley Road
    B.5.3.2Town/ cityMilton Keynes
    B.5.3.3Post codeMK1 1PT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4408452026401
    B.5.5Fax number0
    B.5.6E-mailtrientine@univareurope.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Trientine dihydrochloride 300mg capsules
    D.2.1.1.2Name of the Marketing Authorisation holderUnivar B.V.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/03/172
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Wilson disease, also known as hepatolenticular degeneration, a rare automsomal, recessively inherited disorder which results in chronic copper intoxication.
    Malattia di Wilson, nota anche come degenerazione epatolenticolare, malattia rara autosomica, recessiva ereditaria, disturbo che si traduce in intossicazione cronicada rame
    E.1.1.1Medical condition in easily understood language
    Wilson disease, an inherited disease in which the body cannot metabolise copper
    Malattia di Wilson, una malattia ereditaria in cui il corpo non può metabolizzare il rame
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10019819
    E.1.2Term Hepato-lenticular degeneration
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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, and at the last available follow up and will be based on the Investigator's score (unchanged, improved but not normal, improved to normal, asymptomatic over duration, and worsened).
    Valutare l'andamento clinico degli accumuli di rame (Cu), il disturbo neurologico e il disturbo epatico in seguito all'inizio del trattamento con trientina dopo la sospensione di d-penicillamina. Saranno eseguite valutazioni a intervalli di circa 6, 12, 24, 36 e 48 mesi, nonché all'ultimo follow-up disponibile, e ci si baserà sulla valutazione eseguita dal ricercatore (invariato, migliorato ma non normale, migliorato fino a normale, asintomatico per tutta la durata e peggiorato).
    E.2.2Secondary objectives of the trial
    - Assess the safety of trientine treatment based on reported adverse events (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.

    This study aims to show that trientine is likely to be better tolerated without compromising effective treatment management of Wilson disease when given 2nd line to d-Penicillamine.
    - Valutare la sicurezza del trattamento con trientina sulla base degli eventi avversi (AE) registrati, inclusi AE che comportino un'interruzione del trattamento con trientina
    - Definire la durata del trattamento con trientina per trattamento di seconda linea, definito come intervallo fino all'interruzione del trattamento dovuta a AE e/o risposta inadeguata.

    Lo studio mira a dimostrare che è probabile che la trientina venga tollerata meglio, senza compromettere l'efficacia della gestione del trattamento della malattia di Wilson, se somministrata come seconda linea dopo la d-penicillamina.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients aged 1 year to 90 years of age
    2. Physician-established diagnosis of Wilson disease based on a Ferenci score ≥ 3
    3. 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
    4. Able/willing to provide written informed consent.
    1. Pazienti di età compresa tra 1 e 90 anni
    2. Diagnosi effettuata da un medico della malattia di Wilson basata su uno score diagnostico di Ferenci ≥ 3
    3. Trattamento documentato con d-penicillamina, sospensione del trattamento con d-penicillamina seguita da trattamento con trientina per almeno 6 mesi alla data del consenso informato
    4. Capace/disponibile a fornire un consenso informato scritto.
    E.4Principal exclusion criteria
    1. Incomplete history of medication use for trientine from initial diagnosis to last follow-up
    2. Unavailable outcome data for hepatic and neurological course of disease at all assessment time points
    3. Patients with acute liver failure and fulminant hepatic disease with fatal outcome.
    1. Storia incompleta dell'uso del farmaco per la trientina dalla diagnosi iniziale all'ultimo follow-up
    2. Dati sugli esiti clinici del decorso epatico e neurologico della malattia non disponibili per tutte le date di valutazione
    3. Pazienti con insufficienza epatica acuta ed epatite fulminante con esiti fatali.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy Endpoints: The clinical course of neurological and hepatic disease for each 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) will be scored (Investigator’s score) based on the status at the time of initiating trientine as: 1 = Unchanged 2 = Improved but not normal 3 = Improved to normal 4 = Asymptomatic over duration of therapy 5 = Worsened.  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 initiating second line trientine therapy, by available tests, eg, 24-hour urinary Cu excretion, serum ceruloplasmin (CPN), and Serum Cu, compared to Cu storage values at the time of initiating trientine. Overall duration of treatment, defined as time to discontinuation of treatment due to AEs and/or inadequate response, will be assessed after initiation of trientine.  Time to discontinuation of trientine due to AEs  Time to discontinuation of trientine due to inadequate response measured by poor clinical outcome (failure to stabilise or reverse signs and symptoms) where: o Inadequate hepatic response is defined by:  Progression to liver transplant  Increase of at least 2 of 3 liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyltranspeptidase [GGT]) ≥ 2 x normal or ≥ 2 x baseline  Increase of 24-hour urinary Cu excretion when collected in 2 consecutive measurements o Inadequate neurological response is defined by neurological deterioration (physician’s decision).  Patient treatment status at the last available time point: o Treatment status o If trientine stopped:  Reason for discontinuing  When trientine discontinued o What new treatment prescribed. Safety Endpoint:  Adverse events related to trientine treatment and AEs leading to discontinuation of trientine will be assessed at each available study time point.
    Endpoint di efficacia. L'andamento clinico dei disturbi neurologici ed epatici per ogni data disponibile dopo l'inizio del trattamento (a 6, 12, 24, 36 e 48 mesi e all'ultima data disponibile durante l'assunzione di trientina di seconda linea) sarà valutato (valutazione del ricercatore) sulla base dello stato al momento dell'inizio del trattamento con trientina come: 1 = invariato 2 = migliorato ma non normale 3 = migliorato fino a normale 4 = asintomatico per tutta la durata del trattamento 5 = peggiorato. - L'andamento clinico del disturbo epatico a 6, 12, 24, 36 e 48 mesi e all'ultima data disponibile durante l'assunzione di trientina di seconda linea, sulla base della valutazione del ricercatore e dello stato epatico al momento dell'inizio della somministrazione di trientina - L'andamento clinico del disturbo neurologico a 6, 12, 24, 36 e 48 mesi e all'ultima data disponibile durante l'assunzione di trientina di seconda linea, sulla base della valutazione del ricercatore e dello stato neurologico al momento dell'inizio della somministrazione di trientina - Il metabolismo e l'accumulo di Cu, misurato a 6, 12, 24, 36 e 48 mesi e all'ultima data disponibile dopo l'inizio della somministrazione di trientina di seconda linea, con i test disponibili, per es. escrezione urinaria di Cu nell'arco di 24 ore, ceruloplasmina nel siero (CPN) e Cu nel siero rispetto ai valori di accumulo di Cu al momento dell'inizio della somministrazione di trientina. La durata complessiva del trattamento, definita come l'intervallo fino all'interruzione del trattamento dovuta a AE e/o risposta inadeguata, verrà valutata dopo l'inizio della somministrazione di trientina. - Intervallo fino all'interruzione della trientina dovuta a AE - Intervallo fino all'interruzione della trientina dovuta a risposta inadeguta, misurata come esito clinico poco soddisfacente (mancata stabilizzazione o segni e sintomi opposti), dove: - una risposta epatica inadeguata è definita da - progressione fino al trapianto di fegato - aumento di almeno 2 di 3 enzimi epatici (aspartato aminotransferasi [AST], alanina aminotransferasi [ALT], gamma-glutamil-transpeptidasi [GGT] ≥ 2 volte il valore normale o ≥ 2 volte la baseline - aumento dell'escrezione urinaria di Cu nell'arco di 24 ore rilevato in 2 misure consecutive - una risposta neurologica inadeguata è definita da un peggioramento neurologico (decisione del medico). - Stato del paziente durante il trattamento all'ultima data disponibile - Stato durante il trattamento - Se la somministrazione di trientina è stata interrotta: - ragione dell'interruzione - quando è stata interrotta la trientina - Quale nuovo trattamento è stato prescritto. Endpoint di sicurezza: - Eventi avversi collegati al trattamento con trientina ed eventi avversi che causano l'interruzione della somministrazione di trientina vengono valutati ad ogni data disponibile dello studio.
    E.5.1.1Timepoint(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.
    il timepoint disponibile dall'inizio del trattamento (6, 12, 24, 36 e 48 mesi), e all'ultimo timepoint disponibile durante la seconda assunzione di trientine.
    E.5.2Secondary end point(s)
    N/A
    N/A
    E.5.2.1Timepoint(s) of evaluation of this end point
    N/A
    N/A
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Studio multicentrico con revisione retrospettiva delle cartelle cliniche dei pazienti
    A m/c study with retrospective review of patients' medical records
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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
    The time point when all data from eligible patients who consent to participate in the study have been collected.
    La data in cui saranno stati raccolti tutti i dati dei pazienti idonei che hanno dato il loro consenso alla partecipazione allo studio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 1
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 23
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women 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 2018-04-26. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women Yes
    F.3.3.4Nursing women Yes
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details 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.
    E' possible che vengano coinvolti nello studio bambini e adolescenti minori d i18 anni.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state26
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 90
    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.
    Durante lo studio e successivamente ad esso, i pazienti continueranno ad essere trattati con la loro terapia standard.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-06-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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