Clinical Trials Register

Summary
EudraCT Number:	2019-001807-19
Sponsor's Protocol Code Number:	TV50717-CNS-30081
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-10-21
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2019-001807-19

A.3

Full title of the trial

An Open-Label, Long-Term Safety, Tolerability, and Efficacy Study of TEV-50717 (Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in Children and Adolescents (Open RECLAIM-DCP)

Estudio sin enmascaramiento de seguridad, tolerabilidad y eficacia a largo plazo de TEV-50717 (deutetrabenazina) para el tratamiento de la discinesia en la parálisis cerebral en niños y adolescentes (RECLAIM-DCP abierto)

A.3.1

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

A Study to Test if TEV-50717 is Safe and Effective in Relieving Abnormal Involuntary Movements in Cerebral Palsy

Estudio para evaluar si TEV-50717 resulta seguro y eficaz a la hora de aliviar los movimientos involuntarios anormales en la parálisis cerebral

A.3.2

Name or abbreviated title of the trial where available

Open RECLAIM-DCP

RECLAIM-DCP abierto

A.4.1

Sponsor's protocol code number

TV50717-CNS-30081

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Teva Branded Pharmaceutical Products R&D, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Teva Branded Pharmaceutical Products R&D, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Teva Branded Pharmaceutical Products R&D, Inc.
B.5.2	Functional name of contact point	Clinical Trial Manager
B.5.3	Address:
B.5.3.1	Street Address	41 Moores Road
B.5.3.2	Town/ city	Frazer, Pennsylvania
B.5.3.3	Post code	19355
B.5.3.4	Country	United States
B.5.4	Telephone number	+197298361100
B.5.6	E-mail	laure.voisin@tevafrance.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Austedo
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Branded Pharmaceuticals Products R&D, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TEV-50717 (deutetrabenazine)
D.3.2	Product code	TEV-50717
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	deutetrabenazine
D.3.9.1	CAS number	1392826-25-3
D.3.9.2	Current sponsor code	TEV-50717
D.3.9.3	Other descriptive name	DEUTETRABENAZINE
D.3.9.4	EV Substance Code	SUB179485
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Austedo
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Branded Pharmaceuticals Products R&D, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TEV-50717 (deutetrabenazine)
D.3.2	Product code	TEV-50717
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	deutetrabenazine
D.3.9.1	CAS number	1392826-25-3
D.3.9.2	Current sponsor code	TEV-50717
D.3.9.3	Other descriptive name	DEUTETRABENAZINE
D.3.9.4	EV Substance Code	SUB179485
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	9
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Austedo
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Branded Pharmaceuticals Products R&D, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TEV-50717 (deutetrabenazine)
D.3.2	Product code	TEV-50717
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	deutetrabenazine
D.3.9.1	CAS number	1392826-25-3
D.3.9.2	Current sponsor code	TEV-50717
D.3.9.3	Other descriptive name	DEUTETRABENAZINE
D.3.9.4	EV Substance Code	SUB179485
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	12
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Dyskinesia in cerebral palsy (DCP)

Discinesia en la parálisis cerebral (DPC)

E.1.1.1

Medical condition in easily understood language

Dyskinesia in cerebral palsy (DCP)

Discinesia en la parálisis cerebral (DPC)

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10068804
E.1.2	Term	Athetoid cerebral palsy
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate the safety and tolerability of long-term therapy with TEV-50717 in children and adolescents with DCP.

El objetivo principal de este estudio es evaluar la seguridad y tolerabilidad del tratamiento a largo plazo con TEV-50717 en niños y adolescentes con DPC.

E.2.2

Secondary objectives of the trial

The secondary objective of this study is to evaluate the efficacy of long-term therapy with TEV-50717 in reducing the severity of DCP.

El objetivo secundario de este estudio es evaluar la eficacia del tratamiento a largo plazo con TEV-50717 a la hora de reducir la gravedad de la CPD.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients who have completed Study TV50717-CNS-30080 have already met the criteria below:
1. Patient is of an eligible age from parent Study TV50717-CNS-30080.
2. Patient weighs at least 12 kg (26 lb) on day 1 of this study.
3. Patient is able to swallow TEV-50717 tablet whole.
4. Patient and caregiver/adult are willing to adhere to TEV-50717 regimen and comply with all study procedures.
5. Patient is in good general health, as indicated by medical and psychiatric history and physical and neurological examination.
6. 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.
7. Patient and caregiver/adult provide written informed consent/assent, depending on the child’s age, as appropriate, according to local regulations.
8. Females who are postmenarchal or ≥12 years of age may be included only if they have a negative β-HCG test on day 1 or are sterile.
9. 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 day 1) and for 30 days after last dose of TEV-50717.

Los pacientes que han finalizado el estudio TV50717-CNS-30080 ya cumplen los criterios que figuran a continuación:
1.El paciente cumple los requisitos de edad del estudio original TV50717-CNS-30080
2.El paciente pesa al menos 12 kg el día 1 de este estudio.
3.El paciente es capaz de tragar el TEV-50717 entero.
4.El paciente y el cuidador/adulto están dispuestos a seguir la pauta de administración de TEV-50717 y a cumplir con todos los procedimientos del estudio.
5.El paciente tiene buena salud general, según indican los antecedentes médicos y psiquiátricos y las exploraciones física y neurológica
6.En opinión del investigador, el paciente y el cuidador/adulto tienen la capacidad de comprender la naturaleza del estudio y sus procedimientos y se prevé que el paciente finalice el estudio según lo diseñado
7.El paciente y el cuidador/adulto proporcionan el consentimiento/asentimiento informado por escrito, según corresponda dependiendo de la edad del niño, de acuerdo con la normativa local.
8.Las mujeres posmenárquicas o ≥12 años podrán participar solo si obtienen un resultado negativo en una prueba de β-HCG el día 1 o son estériles.
9.Las mujeres posmenárquicas o ≥12 años cuyas parejas sean potencialmente fértiles (es decir, sin vasectomía) deberán usar un método anticonceptivo de gran eficacia durante el estudio (es decir, a partir del día 1) y durante 30 días tras la última dosis de TEV-50717.

E.4

Principal exclusion criteria

Patients will not be randomized/enrolled in this study if they meet any of the following criteria:
1. Patient has a predominant movement disorder other than dyskinesia.
2. Patient’s predominant motor symptoms are dystonic.
3. Patient’s predominant motor symptoms are spastic.
4. Patient has another movement disorder that could impair the motor assessment in the MD-CRS part II.
5. Patient has clinically significant depression at day 1 of this study. Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose.
6. Patient has a history of suicidal intent or related behaviors: (a) previous intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence, at the time of suicidal thought; (b) previous suicidal preparatory acts or behaviour.
7. Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
8. Patient has a first-degree relative who has completed suicide.
9. Patient who is currently receiving or who has received botulinum neurotoxin (BoNT) in an investigational clinical trial.
Note: Patients may be included in the study if they have at least 2 treatments of Food and Drug Administration-approved BoNT at a regular interval (eg, every 3 to 4 months), in reasonably stable dosages and locations (subject to investigator’s judgement) to treat lower limb spasticity or dystonia.
10. Patient has received any of the following concomitant medications for dystonia or chorea within the specified exclusionary windows of day 1 of this study: (a) within 3 months: depot neuroleptics; (b) within 30 days: tetrabenazine or valbenazine; (c) within 21 days: reserpine; (d) within 14 days: neuroleptics (oral), typical and atypical antipsychotics, metoclopramide, levodopa, dopamine agonists, and monoamine oxidase inhibitors.
11. Patient has received treatment with stem cells, deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation for treatment of abnormal movements or CP, or the patient is not in a stable clinical condition.
12. Patient has recent surgical procedure or is anticipated to have a surgical procedure during the study that, in the opinion of the investigator, makes the patient unsuitable for the study.
13. Patient has a severe mental disability or an unstable or serious medical illness (eg, epilepsy) that, in the opinion of the investigator, could jeopardize or would compromise the patient’s ability to participate in this study.
14. Patient has a QT interval (QTc) corrected for heart rate using Fridericia’s formula (QTcF) value >450 msec on 12-lead ECG at day 1 of this study.
15. Patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure.
16. Patient has evidence of hepatic impairment, as indicated by the following: (a) aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5× the upper limit of the normal range (ULN) at day 1 of this study; (b) alkaline phosphatase (ALP) or total bilirubin (Tbil) >2×ULN at day 1 of this study. 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.
17. Patient has evidence of clinically significant renal impairment, indicated by a serum creatinine >1.5×ULN at day 1 of this study.
18. Patient has a known allergy to any of the components of TEV-50717.
19. Patient has participated in an investigational drug or device study other than Study TV50717-CNS-30080 and received IMP/intervention within 30 days or 5 drug half-lives of day 1 of this study, whichever is longer.
20. Patient is pregnant or breastfeeding.
21. Patient has a history of or acknowledges alcohol or substance abuse, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V™).
22. Patient has a positive urine drug screen test result or is unable to refrain from substance abuse throughout the study.

Los pacientes quedaran excluidos del estudio si cumplen alguno de los siguientes criterios:
1.El paciente padece un trastorno del movimiento predominante distinto de la discinesia.
2.Los síntomas motores predominantes del paciente son distónicos.
3.Los síntomas motores predominantes del paciente son espásticos.
4.El paciente padece otro trastorno del movimiento que podría dificultar la evaluación motriz de la parte II de la MD-CRS.
5.El paciente padece una depresión clínicamente significativa el día 1 del estudio.Nota: los pacientes que tomen antidepresivos podrán participar si la dosis es estable.
6.El paciente tiene antecedentes de intento de suicidio o conductas relacionadas: (a)intento previo de actuar según ideaciones suicidas con un plan específico, independientemente del grado de ambivalencia, en el momento del pensamiento suicida; (b)conducta o actos preparatorios suicidas previos
7.El paciente tiene antecedentes de un intento de suicidio anterior real, interrumpido o cancelado.
8.El paciente tuvo un familiar de primer grado que se suicidó.
9.El paciente está recibiendo o ha recibido neurotoxina botulínica (NTB) en un ensayo clínico de investigación.
Nota: los pacientes podrán participar en el estudio si reciben al menos 2 tratamientos de NTB aprobada por la Administración de Alimentos y Medicamentos con un intervalo regular (p. ej. cada 3 o 4 meses), en dosis y ubicaciones razonablemente estables (en opinión del investigador) para tratar la espasticidad o la distonía de los miembros inferiores.
10.El paciente ha recibido alguno de los siguientes medicamentos concomitantes para la distonía o la corea en los intervalos de exclusión especificados con respecto al día 1 de este estudio:(a)3 meses antes: neurolépticos de liberación prolongada; (b)30 días antes: tetrabenazina o valbenazina; (c)21 días antes: reserpina; (d)14 días antes: neurolépticos (orales), antipsicóticos típicos y atípicos, metoclopramida, levodopa, agonistas de la dopamina e inhibidores de la monoaminooxidasa
11.El paciente ha recibido tratamiento con células madre, estimulación cerebral profunda, estimulación transmagnética o estimulación mediante corriente directa transcraneal para el tratamiento de los movimientos anómalos o la parálisis cerebral o no está en un estado clínico estable.
12.El paciente se ha sometido recientemente, o lo hará durante el estudio, a un procedimiento quirúrgico que, en opinión del investigador, hace que no sea apto para el estudio.
13.El paciente padece una discapacidad mental grave o una enfermedad grave o inestable (como epilepsia) que, en opinión del investigador, podría poner en peligro o comprometer la capacidad del paciente para participar en este estudio.
14.El paciente tiene un intervalo QT corregido de frecuencia cardíaca (QTc) según la fórmula de Fridericia (QTcF) >450 ms en el ECG de 12 derivaciones el día 1 de este estudio.
15.Los pacientes con antecedentes de taquicardia ventricular en entorchado, síndrome de QT largo congénito, bradiarritmias, otras arritmias cardíacas o insuficiencia cardíaca descompensada.
16.El paciente presenta muestras de insuficiencia hepática, indicada por lo siguiente:(a)aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT) >2,5 veces el límite superior de la normalidad (LSN) el día 1 de este estudio; (b)fosfatasa alcalina (FA) o bilirrubina total (BiT) >2 veces el LSN el día 1 de este estudio.
Nota: los pacientes con síndrome de Gilbert podrán participar si lo aprueba el supervisor médico.
Nota: los pacientes con anomalías en 2 o más de los siguientes parámetros analíticos clínicos deberán tener la aprobación del supervisor médico para su inclusión: AST, ALT, FA y BiT.
17.El paciente presenta muestras de insuficiencia renal clínicamente significativa, indicada por un índice de creatinina en suero >1,5 veces el LSN el día 1 de este estudio.
18.El paciente tiene alergia conocida a alguno de los componentes del TEV-50717.
19.El paciente ha participado en un estudio de un fármaco en fase de investigación o producto sanitario diferente al estudio TV50717-CNS-30080 y recibió PEI/intervención en los 30 días o 5 semividas del fármaco anteriores al día 1 de este estudio, el plazo que sea mayor.
20.La paciente está embarazada o dando el pecho.
21.El paciente tiene antecedentes de alcoholismo o toxicomanía o reconoce sufrirlos, según se definen en el Manual diagnóstico y estadístico de los trastornos mentales, quinta edición (DSM-V™).
22.El paciente da positivo en un análisis de drogas en orina o es incapaz de evitar el consumo de drogas durante el estudio.

E.5 End points

E.5.1

Primary end point(s)

Safety measures/endpoints:
- Incidence of adverse events
- Observed values and changes in vital signs from day 1 to each visit in which vital signs are assessed
- Observed values and changes in children’s C-SSRS (Columbia-Suicide Severity Rating Scale) from day 1 to each visit in which the scale is administered
- Observed values in electrocardiogram (ECG) parameters and shifts for clinically significant abnormal findings from day 1 to each visit in which the ECG test is performed
- Observed values and changes in clinical laboratory parameters (hematology, serum chemistry and urinalysis) from day 1 to each visit in which the laboratory parameters are assessed
- Observed values and changes in ESSRS (Extrapyramidal Symptom Rating Scale - subscales I and II) from day 1 to each visit in which the scale is administered
- Observed values and changes in CBCL (Child Behavior Checklist) from day 1 to each visit in which the scale is administered
- Observed values and changes in ESS (Epworth Sleepiness Scale) from day 1 to each visit in which the scale is administered.

Las variables/criterios de valoración de la seguridad son los siguientes:
-índice de acontecimientos adversos
-Los valores y cambios observados en los resultados de las constantes vitales desde el día 1 a cada visita donde se valoren las constantes vitales.
-Valores y cambios observados en la escala C-SSRS ( escala Columbia para evaluar el riesgo de suicidio) des del dia 1 ;hasta cada visita donde se administra la escala
-Valores y cambios observados en los parámetros del Electrocardiograma (ECG) para hallazgos anormales clínicamente significativos desde el día 1 hasta cada visita en la que se realiza la prueba de ECG
- Valores observados y cambios en los parámetros de laboratorio clínico (hematología, química del suero y análisis de orina) desde el día 1 hasta cada visita en la que se evalúan los parámetros de laboratorio.
-Valores y cambios observados en ESRS (Escala de calificación de síntomas extrapiramidales - subescalas I y II) desde el día 1 hasta cada visita en la que se administra la escala
-Valores observados y cambios en CBCL (Lista de verificación de la conducta infantil) desde el día 1 hasta cada visita en la que se administra la escala
-Valores observados y cambios en ESS (Escala de somnolencia de Epworth) desde el día 1 hasta cada visita en la que se administra la escala.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 1 to each visit the assessments are performed/scale is administered until W55 (End of Study).

El día 1 de cada visita se realizan las evaluaciones / se administra la escala hasta la semana 55 (Fin del estudio).

E.5.2

Secondary end point(s)

Efficacy measures/endpoints:
- Change in the total score of MD-CRS (Movement Disorder-Childhood Rating Scale) part I from day 1 to each visit in which the scale is administered
- Change in the total score of MD-CRS (Movement Disorder-Childhood Rating Scale) part II from day 1 to each visit in which the scale is administered
- Change in the MD-CRS Global Index (calculated from MD-CRS part I and II total scores) from day 1 to each visit in which MD-CRS part I and II are administered
- Change in the Ca-GI-I (Caregiver Global Impression of Improvement) score from week 14 to each visit in which the scale is administered
- Change in the CGI-I (Clinical Global Impression of Improvement) score from week 1 to each visit in which the scale is administered
- Change in the CGI-S (Clinical Global Impression of Severity) score from day 1 to each visit in which the scale is administered
- Change in the PEDI-CAT (Pediatric Evaluation Disability Inventory-Computer Adapted Test) score from day 1 to each visit in which the scale is administered
- Change in the UHDRS-TMS (Unified Huntington’s Disease Rating Scale-Total Motor Score) score from day 1 to each visit in which the scale is administered
- Change in the COPM (Canadian Occupational Performance Measure) score from day 1 to each visit in which the scale is administered

Las variables/criterios de valoración de la eficacia son los siguientes:
-Cambio en la puntuación total de MD-CRS (Escala de calificación escala de calificación de trastornos del movimiento en niños) parte I desde el día 1 hasta cada visita en la que se administra la escala
-Cambio en la puntuación total de MD-CRS (Escala de calificación escala de calificación de trastornos del movimiento en niños) parte II desde el día 1 hasta cada visita en la que se administra la escala
- Cambio en el índice global MD-CRS (calculado a partir de las puntuaciones totales de MD-CRS parte I y II) desde el día 1 hasta cada visita en la que se administran las partes I y II de MD-CRS
-Cambio en la puntuación CaGI-I (impresión global del cuidador sobre la mejoría) des de la semana 14 a cada visita en la que se administra la escala
-Cambio en la puntuación CGI-I (: impresión global clínica sobre la mejoría;) des de la semana 1 a cada visita en la que se administra la escala
-Cambio en la puntuación CGI-S (impresión global clínica sobre la gravedad;) des de la semana 1 a cada visita en la que se administra la escala
- Cambio en la puntuación PEDI-CAT (inventario de evaluación pediátrica de la discapacidad adaptada para ordenador) desde el día 1 a cada visita en la que se administra la escala
-Cambio en la puntuación UHDRS-TMS (escala de calificación de la enfermedad de Huntington unificada, puntuación motriz total) del día 1 a cada visita en la que se administra la escala

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 1/week 1/week 14 to each visit the scale is administered until W53-54-55 (depending on the scale).

El día 1 /semana 1/semana 14 de cada visita se administra la escala hasta la semana 53-54-55 (segun la escala).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tolerabilidad

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Canada

Denmark

Israel

Italy

Poland

Russian Federation

Slovakia

Spain

Ukraine

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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 55 follow-up telephone contact of the last participant.
Justification: Week 55 is a telephone contact for safety assessments that occurs about 2 weeks after stopping deutetrabenazine. As the patient will have already been assessed by a face-to-face visit on Week 54 after 1 week washout, there is no need for an additional face-to face visit at Week 55.

El final del estudio se define como la fecha del contacto telefónico de seguimiento de la semana 55 del último participante.
Justificación: La semana 55 es un contacto telefónico para evaluaciones de seguridad que ocurre aproximadamente 2 semanas después de suspender la deutetrabenazina. Como el paciente ya habrá sido evaluado en una visita cara a cara en la semana 54 después de una semana de lavado, no hay necesidad de una visita cara a cara adicional en la semana 55.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

185

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients below the age of 14 require informed consent or co-consent for patients 14 years of age and older, where applicable.

Los pacientes menores de 14 años requieren consentimiento informado o co-consentimiento para pacientes de 14 años de edad y mayores, cuando corresponda

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

185

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)

None

Ninguno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-11-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-16

P. End of Trial
P.	End of Trial Status	Ongoing

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