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    Summary
    EudraCT Number:2016-000630-22
    Sponsor's Protocol Code Number:TV50717-CNS-30047
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-05-21
    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 ConcernedSpain - AEMPS
    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
    Estudio abierto de seguridad a largo plazo que incluye un período de retirada aleatorizado, doble ciego y controlado con placebo de TEV-50717 (deutetrabenacina) para el tratamiento del síndrome de Tourette en niños y adolescentes
    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).
    Ensayo Clínico en niños y adolescents con Síndrome de Tourette para investigar la seguridad de TEV-50717 (medicamento experimental)
    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)
    Tics asociados al Síndrome de Tourette (ST)
    E.1.1.1Medical condition in easily understood language
    Tics associated with Tourette Syndrome(TS)
    Tics asociados al Síndrome de Tourette (ST)
    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.
    El objetivo principal de este estudio es evaluar la seguridad y la tolerabilidad del tratamiento a largo plazo 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
    Los objetivos secundarios de este estudio son los siguientes:
    • Evaluar la eficacia del tratamiento a largo plazo con TEV-50717 en la reducción de la intensidad de los tics del ST
    • Confirmar el mantenimiento del efecto a largo plazo durante un período doble ciego, controlado con placebo, de retirada aleatorizada del fármaco después de 28 semanas de tratamiento abierto
    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.
    a. El paciente tiene menos de 18 años de edad en el día 1
    b. El paciente pesa como mínimo 20 kg en el día 1
    c. El paciente es capaz de tragarse el PEI entero
    d. El paciente y el cuidador o un adulto están dispuestos a cumplir la pauta del PEI y todos los procedimientos del estudio
    e. El paciente tiene una buena salud general, según indica su historia clínica y psiquiátrica así como la exploración física y neurológica
    f. En opinión del investigador, el paciente y el cuidador o un adulto tienen capacidad para entender la naturaleza del estudio y sus procedimientos y se espera que el paciente complete el estudio conforme a lo diseñado.
    g. El paciente y el cuidador o un adulto otorgan su consentimiento informado/asentimiento por escrito, según la edad del niño, si procede, conforme a la normativa local
    h. Mujeres posmenárquicas o ≥ 12 años de edad solo pueden incluirse si obtienen un resultado negativo en la prueba de la fracción beta de la gonadotropina coriónica humana (β-HCG) en el día 1 o son estériles.
    i. Las mujeres posmenárquicas o ≥ 12 años de edad, cuyas parejas masculinas son potencialmente fértiles (es decir, no están vasectomizados) tienen que usar métodos anticonceptivos altamente efectivos durante todo el estudio (es decir, comenzando en la selección) y durante 30 días o 5 semividas del fármaco, lo que más tiempo dure, después de la última dosis de PEI.
    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).
    a. l paciente tiene ≥18 años
    b. El paciente padece trastorno neurológico distinto al ST que podría confundir la evaluación de tics
    c. El trastorno de movimientos predominante del paciente es estereotipia (movimientos coordinados repetidos de forma continua e idéntica) relacionados con el espectro del autismo
    d. El paciente está diagnosticado de trastorno bipolar, esquizofrenia u otro trastorno psicótico
    e. El paciente tiene depresión en la selección o el día 1
    Nota: los pacientes tratados con antidepresivos podrán inscribirse si toman una dosis estable al menos durante las 6 semanas previas a la selección
    f. El paciente tiene antecedentes de intento de suicidio o conductas relacionadas en los 2 años anteriores a la selección:
    -Intento previo de poner en práctica ideas suicidas con un plan específico, independientemente del nivel de ambivalencia, en el momento de los pensamientos suicidas
    -Actos preparatorios o conducta de suicidios anteriores
    g. El paciente tiene antecedentes de intento de suicidio real, interrumpido o frustrado
    h. El paciente tiene un familiar de primer grado que se ha suicidado
    i. El paciente tiene un TOC clínicamente importante en el día 1 que, según el investigador, es la principal causa del deterioro
    j. El paciente ha tenido una intervención conductual exhaustiva para los tics del ST o un tto. conductual cognitivo para el TOC en las 4 semanas anteriores a la selección
    k. El paciente ha recibido cualquiera de los siguientes medicamentos concomitantes para los tics dentro de los tiempos de exclusión de la selección:
    - En los 3 meses anteriores: neurolépticos depot, toxina botulínica o tetrabenacina
    - En los 21 días anteriores: reserpina
    - En los 14 días anteriores: neurolépticos (orales), antipsicóticos típicos y atípicos (véase Anexo A, Tabla 7), metoclopramida, levodopa y agonistas de la dopamina
    Nota: está permitido el uso de benzodiacepinas si su uso principal no es para tratar los tics y la administración ha sido estable durante al menos las 4 semanas anteriores a la selección
    Nota: está permitido el uso del topiramato (máximo 200mg/día) si la administración ha sido estable durante al menos las 4 semanas anteriores a la selección
    Nota: está permitido el uso de la guanfacina o clonidina si la administración ha sido estable durante al menos las 4 semanas anteriores a la selección
    l. El paciente ha recibido tratamiento con estimulación cerebral profunda, estimulación transmagnética o estimulación de corriente directa transcraneal para la reducción de tics las 4 semanas anteriores a la selección.
    m. El paciente padece una enfermedad inestable o grave en el momento de la selección o en el día 1.
    n. El paciente tiene un intervalo QT corregido de la frecuencia cardiaca usando el valor del intervalo de la fórmula de Frederica (QTcF) > 450ms (hombres) o > 460ms (mujeres) o > 480ms (con bloqueo de rama derecha) en el ECG de 12 derivaciones en la selección. El paciente requiere tratamiento con fármacos que prolongan el intervalo QT
    o. Paciente con antecedentes de «torsade de pointes», síndrome de QT largo congénito, bradiarrítmias o insuficiencia cardiaca no compensada
    p. Paciente con signos de insuficiencia hepática por:
    -Aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT) >2,5 × el límite superior de normalidad (LSN) en la selección
    - Fosfatasa alcalina (ALP) o bilirrubina total (Tbil) >2 × LSN en la selección
    Nota: los pacientes con síndrome de Gilbert son aptos para participar con aprobación del monitor médico
    Nota: los pacientes con valores anormales en ≥2 de los siguientes parámetros analíticos clínicos deben tener aprobación del monitor médico: AST, ALT, ALP y Tbil
    q. El paciente tiene signos de insuficiencia renal clínicamente importante, indicado por un valor de la creatinina sérica >1,5 × LSN en la selección
    r. El paciente ha recibido un inhibidor de la monoaminooxidasa en los 14 días anteriores a la visita inicial
    s. El paciente tiene alergia diagnosticada a cualquier componente del PEI
    t. El paciente ha participado en un estudio con un fármaco o dispositivo en investigación (salvo los estudios SD-809-C-17, TV50717-CNS 30046 o TV50717-CNS 30060) y recibió el PEI o fue intervenido en los 30 días anteriores
    u. la paciente está embarazada, en período de lactancia o tiene previsto quedarse embarazada durante el estudio
    v. El paciente tiene antecedentes o admite un trastorno relacionado con el alcohol en los 12 meses anteriores, según DSM-5™.
    w. El paciente tiene resultado positivo en la prueba de orina o es incapaz de abandonar la adicción de la sustancia en el transcurso del estudio
    x. El paciente tiene diagnosticado DSM-5™ basado en los módulos MINI Kid realizados en la selección que, según el investigador, hacen que el paciente no sea apto para el estudio (para pacientes procedentes de los estudios TV50717-CNS 30046/ TV50717-CNS 30060, estos datos se recogerán en la visita de selección del estudio original).
    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
    Mediciones de seguridad Parte A:
    •Incidencia de acontecimientos adversos
    •Valores y cambios observados desde el día 1 en las constantes vitales
    •Valors y cambios observados desde el día 1 en el Inventario de depresión infantil, 2.ª edición, versiones para padres y de autoinforme (CDI 2)
    •Valores observados en la Escala de puntuación de la intensidad de intención suicida infantil de Columbia (C-SSRS)
    •Valores observados en los parámetros del electrocardiograma (ECG) y desviaciones respecto al inicio del estudio para la detección de resultados anormales clínicamente significativos
    •Valores y cambios observados desde el día 1 en cuanto a los parámetros analíticos (hematología, bioquímica y análisis de orina)

    En la parte B se evaluarán los siguientes criterios de valoración de la seguridad (período doble ciego, de retirada aleatorizada del fármaco y ajuste de la dosis después de la retirada del fármaco):
    • Incidencia de acontecimientos adversos
    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: desde el Inicio a la semana 54
    Parte B: de la semana 28 a la semana 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
    Criterios de valoración de la eficacia:
    Parte A (Day 1, Ajuste de la dosis y mantenimiento):
    • cambio en la puntuación total de tics (TTS, por sus siglas en inglés) de la Escala de Yale de gravedad global de tics (YGTSS, Yale Global Tic Severity Scale) desde el día 1 hasta cada una de las visitas en las que se administra la escala
    • cambio en la puntuación de la Impresión clínica global-Síndrome de Tourette (TS-CGI) desde el día 1 hasta cada una de las visitas en las que se administra la escala
    • cambio en la puntuación de la Impresión global del paciente-Síndrome de Tourette (TS-PGII) desde el día 1 hasta cada una de las visitas en las que se administra la escala
    • cambio en la puntuación de la subescala de actividades de la vida diaria (AVD) de Calidad de vida-Síndrome de Gilles de la Tourette en niños y adolescentes (C&A-GTS-QOL, por sus siglas en inglés) desde el día 1 hasta cada una de las visitas en las que se administra la escala
    Parte B (período ciego, de retirada aleatorizada del fármaco y ajuste de la dosis después de la retirada del fármaco):
    • Cambio en la TTS de la YGTSS desde la semana 28 a la semana 30
    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
    Valoración de la Eficacia:
    Parte A: del día 1 a cada visita en la que se administra la escala
    Parte B: de la semana 28 a la semana 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
    Incluye un período doble ciego, controlado con placebo, de retirada aleatorizada las semana 28-30
    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
    El final del estudio se define como la fecha de la visita de la semana 56 del último participante
    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: 260
    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: 115
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 145
    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.
    Los pacientes en este estudio tienen entre 6 y 16 años, en caso de que los niños más pequeños no puedan dar su consentimiento legal, los padres o el tutor legal firmarán el formulario de consentimiento informado.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 87
    F.4.2.2In the whole clinical trial 260
    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).
    Los pacientes tendrán un contacto telefónico de seguimiento para evaluar la seguridad una semana después del final del período de lavado (2 semanas después de su última dosis de 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 Decision2018-08-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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