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    Summary
    EudraCT Number:2016-000630-22
    Sponsor's Protocol Code Number:TV50717-CNS-30047
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2018-10-19
    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 number2016-000630-22
    A.3Full title of the trial
    An Open-Label, Long-Term Safety Study Including a Double-Blind, Placebo-Controlled, Randomized Withdrawal Period of TEV-50717 (deutetrabenazine) for the Treatment of Tourette Syndrome in Children and Adolescents
    Studio di sicurezza in aperto, a lungo termine comprendente un periodo di sospensione randomizzata in doppio cieco, controllato con placebo, di TEV-50717(deutetrabenazina) per il trattamento della sindrome di Tourette in bambini e adolescenti
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study in children and adolescents with Tourette Syndrome to investigate the safety of TEV-50717 (experimental drug).
    Studio clinico su bambini e adolescenti affetti da syndrome di Tourette per indagare la sicurezza di TEV-50717 (farmaco sperimentale).
    A.4.1Sponsor's protocol code numberTV50717-CNS-30047
    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 SponsorTeva Branded Pharmaceutical Products R&D, Inc.
    B.1.3.4CountryUnited States
    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 supportNuvelution TS Pharma, INC.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNuvelution TS Pharma, INC.
    B.5.2Functional name of contact pointDr Betsy Garofalo
    B.5.3 Address:
    B.5.3.1Street Address601 Gateway Boulevard Suite 1270
    B.5.3.2Town/ citySouth San Francisco, California
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number16505031551
    B.5.5Fax number16506480552
    B.5.6E-mailinfo@nvtpharma.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code TEV-50717
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDeutetrabenazine
    D.3.9.1CAS number 1392826-25 3
    D.3.9.2Current sponsor codeTEV-50717
    D.3.9.3Other descriptive nameDEUTETRABENAZINE
    D.3.9.4EV Substance CodeSUB179485
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.IMP: 2
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code TEV-50717
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDeuterabenazine
    D.3.9.1CAS number 1392826-25 3
    D.3.9.2Current sponsor codeTEV-50717
    D.3.9.3Other descriptive nameDEUTETRABENAZINE
    D.3.9.4EV Substance CodeSUB179485
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number9
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.IMP: 3
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code TEV-50717
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDeuterabenazine
    D.3.9.1CAS number 1392826-25 3
    D.3.9.2Current sponsor codeTEV-50717
    D.3.9.3Other descriptive nameDEUTETRABENAZINE
    D.3.9.4EV Substance CodeSUB179485
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.IMP: 4
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code TEV-50717
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDeuterabenazine
    D.3.9.1CAS number 1392826-25 3
    D.3.9.2Current sponsor codeTEV-50717
    D.3.9.3Other descriptive nameDEUTETRABENAZINE
    D.3.9.4EV Substance CodeSUB179485
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.IMP: 5
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code TEV-50717
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDeuterabenazine
    D.3.9.1CAS number 1392826-25 3
    D.3.9.2Current sponsor codeTEV-50717
    D.3.9.3Other descriptive nameDEUTETRABENAZINE
    D.3.9.4EV Substance CodeSUB179485
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number18
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 5
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Tics associated with Tourette Syndrome(TS)
    Tic associati alla sindrome di Tourette
    E.1.1.1Medical condition in easily understood language
    Tics associated with Tourette Syndrome(TS)
    Tic associati alla sindrome di Tourette
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate the safety and tolerability of long-term therapy with TEV-50717.
    L’obiettivo primario dello studio è valutare la sicurezza e la tollerabilità della terapia a lungo termine con TEV-50717.
    E.2.2Secondary objectives of the trial
    The secondary objective of this study are:
    •to evaluate the efficacy of long-term therapy with TEV-50717 in reducing the severity of TS tics
    •to confirm long-term maintenance of effect by means of a double-blind, placebo-controlled, randomized drug withdrawal period after 28 weeks of open-label treatment
    Gli obiettivi secondari di questo studio sono i seguenti:
    • valutare l’efficacia della terapia a lungo termine con TEV-50717 nel ridurre la gravità dei tic associati alla TS
    • confermare il mantenimento a lungo termine degli effetti mediante un periodo di sospensione randomizzata del farmaco, controllato con placebo, in doppio cieco, dopo 28 settimane di trattamento in aperto.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a.Patient is younger than 18 years of age on day 1.
    b.Patient weighs at least 44 pounds (20 kg) on day 1.
    c.Patient is able to swallow IMP whole.
    d.Patient and caregiver/adult are willing to adhere to IMP regimen and comply with all study procedures.
    e.Patient is in good general health, as indicated by medical and psychiatric history as well as physical and neurological examination.
    f.In the investigator’s opinion, the patient and caregiver/adult have the ability to understand the nature of the study and its procedures, and the patient is expected to complete the study as designed.
    g.Patient and caregiver/adult provide written informed consent according to local regulations (eg, the patient has provided written assent and/or co-consent for patients 14 years of age and older, as appropriate).
    h.Females who are postmenarchal or ≥12 years of age may be included only if they have a negative β-human chorionic gonadotropin test on day 1 or are sterile.
    i.Females who are postmenarchal or ≥12 years of age whose male partners are potentially fertile (ie, no vasectomy) must use highly effective birth control methods for the duration of the study (ie, starting at screening) and for 30 days or 5 drug half lives, whichever is longer after last dose of IMP.
    I pazienti che abbiano completato lo Studio TV50717-CNS-30046 o lo Studio TV50717-CNS-30060 sono già in linea con i criteri indicati di seguito.
    Inoltre, i pazienti che abbiano completato lo Studio SD-809-C-17 possono essere inclusi nello studio se, durante lo screening, sono in linea con i seguenti criteri:
    a. Il paziente ha meno di 18 anni in corrispondenza del giorno 1.
    b. Il paziente pesa almeno 20 kg in corrispondenza del giorno 1.
    c. Il paziente è in grado di deglutire l’IMP per intero.
    d. Il paziente e l’adulto/tutore sono disposti ad aderire al regime dell’IMP e a rispettare tutte le procedure dello studio.
    e. Il paziente è in buona salute generale, come indicato dall’anamnesi medica e psichiatrica, nonché dall’esame obiettivo e neurologico.
    f. In base all’opinione dello sperimentatore, il paziente e l’adulto/il tutore devono avere la capacità di comprendere la natura dello studio e le sue procedure e ci si può aspettare che il paziente completi lo studio per come progettato.
    g. Il paziente e l’adulto/il utore devono fornire il proprio assenso/consenso scritto informato, in funzione dell’età del bambino, in base alle normative locali.
    h. I soggetti di sesso femminile che hanno già avuto il menarca o con un’età superiore ai 12 anni di età possono essere inclusi solo se presentano un test negativo della beta-gonadotropina corionica umana (β-HCG) in corrispondenza del giorno 1 o sono sterili. Le definizioni di sterile sono fornite nell’appendice L.
    i. I soggetti di sesso femminile che hanno già avuto il menarca o con età superiore ai 12 anni, i cui partner maschili siano potenzialmente fertili (ovvero non abbiano subito vasectomia) devono utilizzare metodi di contraccezione estremamente efficaci per la durata dello studio (ovvero a partire dallo screening) e per 30 giorni o 5 emivite di farmaci, a seconda di quale periodo sia il più lungo, dopo l’ultima dose di IMP. Ulteriori dettagli sono inclusi nell’Appendice L.
    E.4Principal exclusion criteria
    a.Patient is 18 years of age or older.
    b.Patient has a neurologic disorder other than TS that could obscure the evaluation of tics.
    c.The patient’s predominant movement disorder is stereotypy (coordinated movements that repeat continually and identically) associated with autism spectrum disorder.
    d.Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder.
    e.Patient has clinically significant depression at screening or day 1.
    Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose for at least 6 weeks before screening.
    f.Patient has a history of suicidal intent or related behaviors within 2 years of screening, defined as:
    -Previous intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence, at the time of suicidal thought.
    -Previous suicidal preparatory acts or behavior
    g.Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
    h.Patient has a first-degree relative who has completed suicide.
    i.Patient has clinically significant obsessive-compulsive disorder (OCD) on day 1 that, in the opinion of the investigator, is the primary cause of impairment.
    j.Patient has received comprehensive behavioral intervention for tics for TS or cognitive behavioral therapy for OCD within 4 weeks of screening.
    k.Patient has received any of the following concomitant medications for tics within the specified exclusionary windows of screening:
    -Within 3 months: depot neuroleptics, botulinum toxin, or tetrabenazine
    -Within 21 days: reserpine
    -Within 14 days: neuroleptics (oral), typical and atypical antipsychotics (see Appendix A, Table 7), metoclopramide, levodopa, and dopamine agonists
    Note: Use of benzodiazepines is allowed if the primary use is not for tics, and dosing has been stable for at least 4 weeks before screening.
    Note: Use of topiramate (up to 200 mg/day) is allowed if the dosing has been stable for at least 4 weeks before screening.
    Note: Use of guanfacine or clonidine is allowed if the dosing has been stable for at least 4 weeks before screening.
    l.Patient has received treatment with deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation for reduction of tics within 4 weeks of the screening visit.
    m.Patient has an unstable or serious medical illness at screening or day 1.
    n.Patient has a QT interval corrected for heart rate using Frederica’s formula (QTcF) interval value >450 msec (males) or >460 msec (females), or >480 msec (with right bundle branch block) on 12-lead ECG at screening. Patient requires treatment with drugs known to prolong the QT interval
    o.Patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure.
    p.Patient has evidence of hepatic impairment, as indicated by:
    -Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit of the normal range (ULN) at screening
    -Alkaline phosphatase (ALP) or total bilirubin (Tbil) >2 × ULN at screening
    Note: Patients with Gilbert’s Syndrome are eligible to participate if approved by the medical monitor.
    Note: Patients with abnormalities in 2 or more of the following clinical laboratory parameters must be approved for enrollment by the medical monitor: AST, ALT, ALP, and Tbil.
    q.Patient has evidence of clinically significant renal impairment, indicated by a serum creatinine >1.5 × ULN at screening.
    r.Patient has received a monoamine oxidase inhibitor within 14 days of the day 1 visit.
    s.Patient has a known allergy to any of the components of the IMP.
    t.Patient has participated in an investigational drug or device study (with the exception of Study SD 809 C 17, Study TV50717-CNS-30046, or Study TV50717-CNS-30060) and received IMP/intervention within 30 days or 5 drug half-lives of day 1, whichever is longer.
    u.The patient is a pregnant or lactating female, or plans to become pregnant during the study.
    v.Patient has a history of, or acknowledges, alcohol-related disorder in the previous 12 months, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
    w.Patient has a positive urine drug screen test result or is unable to refrain from substance abuse throughout the study.
    x.Patient has a DSM diagnosis based on the MINI Kid modules performed at screening that, in the opinion of the investigator, makes the patient unsuitable for the study (for patients rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, these data will be obtained from the screening visit of the parent study).
    I pazienti non saranno arruolati nello studio se sono in linea con uno qualsiasi dei seguenti criteri:
    Dei pazienti che hanno completato lo Studio TV50717-CNS-30046 o lo Studio TV50717-CNS-30060 è stato già confermato che non rientrano in alcuno dei criteri riportati di seguito.
    Inoltre, i pazienti che hanno completato lo Studio SD-809-C-17 non saranno arruolati se, durante lo screening, sono in linea con uno qualsiasi dei seguenti criteri:
    a.Il paziente ha un’età di almeno 18 anni.
    b.Il paziente presenta un disturbo neurologico diverso dalla TS, che può rendere impossibile la valutazione dei tic.
    c.Il disturbo del movimento predominante del paziente è stereotipato (movimenti coordinati che si ripetono in modo continuo e identico) associati a disturbi dello spettro autistico.
    d.Il paziente presenta una diagnosi confermata di disturbo bipolare, schizofrenia o altro disturbo psicotico.
    e.Il paziente presenta depressione clinicamente significativa allo screening o al giorno 1. Nota: I pazienti che ricevono terapia antidepressiva saranno arruolati se hanno assunto una dose stabile per almeno 6 w prima dello screening.
    f.Il paziente presenta un’anamnesi di pensieri suicidi o comportamenti correlati entro 2 anni dallo screening, definita come:
    - precedente intenzione di mettere in atto un suicidio con un piano specifico, indipendentemente dal livello di ambivalenza, al momento dell’intenzione suicida
    - precedenti azioni suicide preparatorie o relativi comportamenti
    g.Il paziente presenta una storia di precedenti tentativi di suicidio effettivi, interrotti o non portati a termine.
    h.Il paziente presenta un parente di primo grado morto suicida.
    i.Il paziente presenta significativi disturbi ossessivo-compulsivi in corrispondenza del giorno 1 che, in base all’opinione dello sperimentatore, rappresenta la causa principale del disturbo.
    j.Il paziente ha ricevuto intervento comportamentale completo per i tic per quanto riguarda la TS o terapia cognitivo-comportamentale per i disturbi OCD entro 4 W dallo screening.
    k.Il paziente ha ricevuto uno dei seguenti farmaci concomitanti per i tic entro la finestra temporale di esclusione specificata dello screening:
    - entro 3 mesi: neurolettici ,tossina botulinica o tetrabenazina
    - entro 21 giorni: reserpina
    - entro 14 giorni: neurolettici (orale), antipsicotici tipici e atipici,metoclopramide, levodopa e agonisti della dopamine. Nota: L’uso di benzodiazepine è consentito se l’uso principale non è per i tic e il dosaggio è rimasto stabile per almeno 4 settimane prima dello screening.
    Nota: L’uso di topiramato (fino a 200 mg/die) è consentito se il dosaggio è stato stabile per almeno 4W prima dello screening.
    Nota: L’uso di guanfacina o clonidina è consentito se il dosaggio è rimasto stabile per almeno 4 settimane prima dello screening.
    l.Il paziente presenta patologia media instabile o grave allo screening o in corrispondenza del giorno 1.
    m.Il paziente presenta un intervallo QTcF >450 msec (maschi) o >460 msec (femmine), oppure >480 msec (con blocco di branca destro) sull’ECG a 12 derivazioni allo screening. Il paziente richiede il trattamento con farmaci di cui è noto che prolungano l’intervallo QT.
    n.I pazienti con pregressa torsione di punta, sindrome congenita del QT lungo, bradiaritmie o insufficienza cardiaca non compensata.
    o.l paziente presenta evidenza di compromissione epatica, come indicato da:
    - AST o ALT >2,5 x ULN allo screening
    - ALP o bilirubina totale >2 x ULN allo screening
    Nota: I pazienti con sindrome di Gilbert sono idonei a partecipare se approvati dal medical monitor.
    Nota: I pazienti con anomalie relative a 2 o più dei seguenti parametri clinici di laboratorio devono essere approvati per l’arruolamento dal medical monitor: AST, ALT, ALP e Tbil.
    p.Il paziente presenta evidenza di insufficienza renale significativa, indicata da creatinina sierica>1,5 x ULN allo screening.
    q.Il paziente ha ricevuto un inibitore della monoaminoossidasi entro 14 g. dalla visita del giorno 1.
    r.Il paziente presenta allergia nota a uno dei componenti dell’IMP.
    s.Il paziente ha partecipato a uno studio sperimentale o a uno studio relativo a un dispositivo (con l’eccezione dello Studio SD-809-C-17, dello Studio TV50717-CNS-30046 o dello Studio TV50717-CNS-30060) e hanno ricevuto l’IMP/intervento entro 30 giorni.
    t.Il paziente è in stato di gravidanza o allattamento o hanno in programma l’allattamento durante lo studio.
    u.Il paziente presenta disturbi pregressi relativi all’uso di alcol, o riconosce di averne avuti, nei precedenti 12 mesi.
    v.Il paziente presenta un test antidroga delle urine positivo o è incapace di non fare uso di sostanze nel corso dello studio.
    w.Il paziente presenta una diagnosi di DSM-5™ in base ai moduli MINI Kid eseguiti in corrispondenza dello screening che, secondo l’opinione dello sperimentatore, rende il paziente non idoneo per lo studio.
    E.5 End points
    E.5.1Primary end point(s)
    Safety endpoints Part A:
    •incidence of adverse events
    •observed values and changes from day 1 in vital signs
    •observed values and changes from day 1 in the Children’s Depression Inventory, Second Edition (CDI 2; Parent and Self-report versions)
    •observed values in the Children’s Columbia-Suicide Severity Rating Scale (C-SSRS)
    •observed values in electrocardiogram (ECG) parameters and shifts from day 1 for clinically significant abnormal findings
    •observed values and changes from day 1 in clinical laboratory parameters (hematology, serum chemistry, and urinalysis)

    The following safety endpoints will be assessed in Part B (Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug Withdrawal):
    •incidence of adverse events
    I seguenti endpoint di sicurezza saranno valutati nella Parte A:
    • incidenza degli eventi avversi
    • valori osservati e variazioni dal giorno 1 dei parametri vitali
    • valori osservati e variazioni dal giorno 1 nel questionario sulla depressione nei bambini (Children’s Depression Inventory, Seconda Edizione, Profili genitore e soggetto stesso, CDI-2)
    • valori osservati nella scala della Columbia University per la valutazione della gravità del rischio di suicidio (Children’s Columbia-Suicide Severity Rating Scale, C-SSRS)
    • valori osservati nei parametri dell’elettrocardiogramma (ECG) e variazioni dal basale dello studio principale (per i pazienti provenienti dallo Studio TV50717-CNS-30046 o dallo Studio TV50717-CNS-30060) o dal giorno 1 (per i pazienti provenienti dallo Studio SD-809-C-17) per quanto riguarda i risultati anomali clinicamente significativi
    • valori osservati e variazioni dal giorno 1 in relazione ai parametri clinici di laboratorio (ematologia, chimica sierica, analisi delle urine)

    I seguenti endpoint di sicurezza saranno valutati nella Parte B:
    • incidenza degli eventi avversi
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A: Baseline to Week 54
    Part B: week 28 to Week 30
    Parte A: dal basale alla settimana 54
    Parte B. Dalla settimana 28 alla settimana 30
    E.5.2Secondary end point(s)
    Efficacy Endpoints:
    Part A (Day 1, Titration, and Maintenance):
    •change in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) from day 1 to each visit in which the scale is administered
    •change in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score from day 1 to each visit in which the scale is administered
    •change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from day 1 to each visit in which the scale is administered
    •change in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life (C&A-GTS QOL) activities of daily living (ADL) subscale score from day 1 to each visit in which the scale is administered

    Part B (Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug Withdrawal):
    •change in the TTS of the YGTSS from week 28 to week 30
    I seguenti endpoint di efficacia saranno valutati nella Parte A:
    • variazione del punteggio totale dei tic (Total Tic Score, TTS) della scala globale sulla gravità dei tic di Yale (Yale Global Tic Severity Scale, YGTSS) dal giorno 1 a ciascuna visita nella quale viene somministrata la scala
    • variazione del punteggio di impressione clinica globale della sindrome di Tourette (Tourette Syndrome-Clinical Global Impression, TS-CGI) dal giorno 1 a ciascuna visita nella quale viene somministrata la scala
    • variazione del punteggio di impressione globale del paziente dell’impatto della sindrome di Tourette (TS-PGII, Tourette Syndrome-Patient Global Impression of Impact) dal giorno 1 a ciascuna visita in cui viene somministrato il questionario
    • variazione del punteggio della sottoscala delle attività quotidiane (activities of daily living, ADL) della scala sulla qualità della vita nei bambini e negli adolescenti affetti da sindrome di Tourette (Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life, C&A-GTS-QOL) dal giorno 1 a ciascuna visita in cui viene somministrata la scala

    I seguenti endpoint di efficacia saranno valutati nella Parte B:
    • variazione del TTS della YGTSS dalla settimana 28 alla settimana 30, con le analisi primarie e i test di sensibilità eseguiti come descritto nella sezione
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy endpoints
    Part A: day 1 to each visit in which the scale is administered
    Part B: week 28 to week 30
    Parte A: giorno 1 di ogni ciclo in cui viene somministrata la scala
    Parte B. salla settimana 28 alla settimana 30
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Periodo di sospensione random. dell'IMP, in doppio cieco, VS placebo tra la W28 e la W30
    Study Includes a Double-Blind, Placebo-Controlled, Randomized Withdrawal Period between week 28-30
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA56
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Bulgaria
    Canada
    Denmark
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Netherlands
    Poland
    Romania
    Russian Federation
    Serbia
    Spain
    Sweden
    Ukraine
    United States
    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 end of study is defined as the date of the week 56 visit of the last participant
    La fine dello studio è definita come la data della visita della settimana 56 dell’ultimo partecipante.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months30
    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: 354
    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: 156
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 198
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    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
    Patients in this study are between 6-16 years old, in case younger children are not able to give a legal consent, parents or legal guardian will sign the informed consent form.
    I pazienti in questo studio hanno un'età compresa tra 6 e 16 anni, nel caso in cui i bambini più piccoli non siano in grado di dare un consenso legale, i genitori o il tutore legale firmeranno il modulo di consenso informato.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 87
    F.4.2.2In the whole clinical trial 354
    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)
    Patients will have a follow-up telephone contact to evaluate safety 1 week after the end of the washout period (2 weeks after their last dose of IMP).
    I pazienti avranno un contatto telefonico di follow-up per valutare la sicurezza 1 settimana dopo la fine del periodo di washout (2 settimana dopo la loro ultima dose di IMP).
    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 Decision2018-10-31
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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