Clinical Trials Register

Summary
EudraCT Number:	2014-004585-22
Sponsor's Protocol Code Number:	ESKETINTRD3002
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-10-05
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

2014-004585-22

A.3

Full title of the trial

A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects with Treatment-resistant Depression

Estudio multicéntrico, aleatorizado, doble ciego controlado con producto activo para evaluar la eficacia, seguridad y tolerabilidad de dosis flexibles de esketamina intranasal más un antidepresivo oral en sujetos adultos con depresión resistente al tratamiento

A.3.1

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

A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression

Estudio para evaluar la eficacia, seguridad y tolerabilidad de dosis flexibles de esketamina intranasal más un antidepresivo oral en sujetos adultos con depresión resistente al tratamiento

A.3.2

Name or abbreviated title of the trial where available

TRANSFORM-2

A.4.1

Sponsor's protocol code number

ESKETINTRD3002

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	Janssen-Cilag International NV
B.1.3.4	Country	Belgium
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	Janssen Research & Development
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	Janssen-Cilag, S.A.
B.5.2	Functional name of contact point	Global Clinical Operations Spain
B.5.3	Address:
B.5.3.1	Street Address	Paseo de las Doce Estrellas, 5-7
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28042
B.5.3.4	Country	Spain
B.5.4	Telephone number	3491722 8100
B.5.5	Fax number	3491722 8628
B.5.6	E-mail	agonza45@its.jnj.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	No
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	Esketamine - Nasal Solution - eq 140mg/mL esketamine base (eq 161.4 mg/mL esketamine HCl)
D.3.4	Pharmaceutical form	Nasal spray, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Nasal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ESKETAMINE Esketamine (for (S)-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone)
D.3.9.3	Other descriptive name	ESKETAMINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB25811
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	161.4
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	Comparator
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	Cymbalta 30 mg hard gastro-resistant capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Gastro-resistant capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DULOXETINE HYDROCHLORIDE
D.3.9.1	CAS number	136434-34-9
D.3.9.3	Other descriptive name	DULOXETINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB20026
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	30
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	Comparator
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	CIPRALEX® 10 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	H. Lundbeck A/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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.3.4	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	ESCITALOPRAM
D.3.9.3	Other descriptive name	ESCITALOPRAM
D.3.9.4	EV Substance Code	SUB16425MIG
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	10
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: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	ZOLOFT
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
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.3.4	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	SERTRALINE HYDROCHLORIDE
D.3.9.3	Other descriptive name	SERTRALINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB04375MIG
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	50
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: 5
D.1.2 and D.1.3	IMP Role	Comparator
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	Trevilor® retard 75 mg hard, prolonged-release capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER PHARMA GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Prolonged-release capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VENLAFAXINE HYDROCHLORIDE
D.3.9.3	Other descriptive name	VENLAFAXINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB05087MIG
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	75
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Nasal spray
D.8.4	Route of administration of the placebo	Nasal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment-resistant Major Depression

Depresión resistente al tratamiento

E.1.1.1

Medical condition in easily understood language

Depression is a mental disorder characterized by low mood and/or loss of interest or pleasure in nearly all activities.

La depresión es un trastorno mental que se caracteriza por un bajo estado de ánimo y / o pérdida de interés o placer en casi todas las actividades.

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10057840
E.1.2	Term	Major depression
E.1.2	System Organ Class	10037175 - Psychiatric disorders

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 efficacy of switching adult subjects with TRD from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms, as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (pre-randomization) to the end of the 4-week double-blind induction phase.

El objetivo principal de este estudio es evaluar la eficacia de la sustitución, en adultos con DRT, de un tratamiento antidepresivo previo (al cual no hayan respondido) por esketamina intranasal en dosis flexible (56 mg u 84 mg) más un antidepresivo oral recién iniciado en comparación con la sustitución por un antidepresivo oral recién iniciado (fármaco comparador activo) más placebo intranasal, en cuanto a la mejoría de los síntomas depresivos, valorada mediante la variación de la puntuación total de la Escala de evaluación de la depresión de Montgomery-Asberg (MADRS) con respecto al momento basal entre el día 1 (antes de la aleatorización) y el final de la fase de inducción doble ciego de 4 semanas.

E.2.2

Secondary objectives of the trial

The key secondary objectives are to assess the effect of intranasal esketamine plus a newly initiated oral antidepressant (AD) compared with a newly initiated oral AD plus intranasal placebo on the following parameters in adult subjects with TRD:
- Depressive symptoms (subject-reported)
- Onset of clinical response by Day 2
- Functioning and associated disability

Other Secondary Objectives
To assess the effect of intranasal esketamine plus a newly initiated oral AD compared with a newly initiated oral AD plus intranasal placebo on additional parameters in adult subjects with TRD (see protocol for details)

To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral AD compared with a newly initiated oral AD plus intranasal placebo in adult subjects with TRD (see protocol for details)

To assess the pharmacokinetics (PK) of intranasal esketamine in adult subjects with TRD receiving intranasal esketamine plus a newly-initiated oral AD

Los objetivos secundarios esenciales son evaluar el efecto de esketamina intranasal más un antidepresivo oral recién iniciado en comparación con placebo intranasal más un antidepresivo oral recién iniciado (fármaco comparador activo) en adultos con DRT en los parámetros siguientes:
- Síntomas depresivos (comunicados por el paciente)
- Inicio de la respuesta clínica el día 2
- Funcionamiento y discapacidad asociada
Otros objetivos secundarios (Ver protocolo para más detalles)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than [>]18) to 64 years of age, inclusive
- At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single-episode MDD, the duration must be greater than or equal to [>=] 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (MINI)
- At the start of the screening/prospective observational phase, participant must have an Inventory of Depressive Symptomatology-Clinician rated ( IDS-C30) total score of greater than or equal to (>=) 34
- At the start of the screening/prospective observational phase, participants must have had nonresponse to >=2 but less than or equal to (<=) 5 oral antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using the Massachusetts General Hospital
- Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by medical history and pharmacy/prescription records, for
the current episode of depression: Subject must be taking an oral antidepressant treatment with nonresponse at the start of the screening/prospective observational phase
- The participant?s current major depressive episode and treatment response to antidepressant treatments used in the current depressive episode (retrospectively assessed) must be deemed valid for participation in a clinical study based on a Site-Independent Qualification Assessment

En el momento de la firma del Documento de Consentimiento Informado (DCI), el paciente debe ser un hombre o una mujer de 18 (o mayor si la edad legal mínima de consentimiento en el país en el que se realice el estudio es >18) a 64 años de edad, inclusive.
Al principio de la fase de selección/observacional prospectiva, el paciente debe cumplir los criterios diagnósticos del DSM-5 para TDM de episodio único (en caso de TDM de episodio único, la duración del episodio debe ser >=2 años) o TDM recurrente, sin síntomas psicóticos, basándose en la evaluación clínica y confirmándose mediante la MINI.
Al principio de la fase de selección/observacional prospectiva, el paciente debe tener una puntuación total de >=34 en IDS-C30.
Al comienzo de la fase de selección/observacional prospectiva, el paciente no debe haber respondido a >=2 pero <=5 antidepresivos orales en el episodio de depresión actual, evaluado mediante MGH-ATRQ y confirmado mediante la historia clínica y los registros de farmacia y prescripción documentados. El paciente debe estar tomando un antidepresivo oral con falta de respuesta al principio de la fase de selección/observacional prospectiva.
El episodio de depresión mayor actual del paciente, y la respuesta al tratamiento antidepresivo en dicho episodio, se deben confirmar mediante la evaluación de la calificación independiente del centro.

E.4

Principal exclusion criteria

- Participants who have previously demonstrated nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine extended release [XR]) in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with
electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral ECT
- Participant currently has an implant for vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depressIon
- Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis, bipolar or related disorders (confirmed by the
MINI), comorbid obsessive compulsive disorder, intellectual disability (only DSM-5 diagnostic code 319), borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
- Participant has homicidal ideation/intent, per the investigator?s clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening/prospective observational phase, per the investigator?s clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS)
- Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria

Se ha demostrado anteriormente que los síntomas depresivos del paciente no han respondido a:
Esketamina o ketamina en el episodio depresivo mayor actual o todas las opciones de tratamiento antidepresivo oral disponibles durante la fase de inducción doble ciego (es decir, duloxetina, escitalopram, sertralina y venlafaxina XR) en el episodio actual de depresión mayor (basado en MGH-ATRQ) o un ciclo adecuado de tratamiento con terapia electroconvulsiva (TEC) en el episodio actual de depresión mayor, definido como el menos 7 tratamientos con TEC unilateral.
El paciente presenta actualmente un implante para estimulación nerviosa vagal (ENV) o ha recibido estimulación cerebral profunda (ECP) en el episodio de depresión actual.
El paciente tiene un diagnóstico actual o previo según el DSM-5 de trastorno psicótico o TDM con psicosis, trastorno bipolar o trastornos relacionados (confirmados mediante la MINI), trastorno obsesivo-compulsivo concomitante, discapacidad intelectual (solo el código diagnóstico 319 del DSM-5), trastorno límite de la personalidad, trastorno antisocial de la personalidad, trastorno histriónico de la personalidad o trastorno narcisista de la personalidad.
El paciente tiene ideación/intención homicida, según el criterio clínico del investigador, o tiene ideación suicida con alguna intención de actuar en los 6 meses previos al comienzo de la fase de selección/observacional prospectiva, según el criterio clínico del investigador o la C-SSRS.
El paciente tiene antecedentes de trastorno moderado o grave de abuso de sustancias psicoactivas o alcohol según los criterios del DSM-5.

E.5 End points

E.5.1

Primary end point(s)

Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at End of Double-blind Induction Phase

Cambio respecto al momento basal en la puntuación total de la Escala de evaluación de la depresión de Montgomery-Asberg (MADRS) al final de la fase de inducción doble ciego

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline and End of Doubleblind Induction Phase (Week 4)

Momento basal y final de la fase de inducción doble ciego (Semana 4)

E.5.2

Secondary end point(s)

1) Change from Baseline in Subject-reported Depressive Symptoms Using the Patient Health Questionnaire-9 (PHQ-9) Total Score at End of Double-blind
Induction Phase
2) Change From Baseline in Subject-reported Functioning and Associated Disability as assessed by the Sheehan Disability Scale (SDS) Total Score at End of
Double-blind Induction Phase
3) Change From Baseline in Clinical Global Impression ? Severity (CGI-S) Score at End of Double-blind Induction Phase
4) Change From Baseline in Subject-reported Generalized Anxiety Disorder (GAD-7) Total Score at End of Double-blind Induction Phase
5) Change From Baseline in Subject-reported Health-related Quality of Life and Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) at
End of Double-blind Induction Phase
6) Number of Participants with Adverse Events (AEs) and Serious AEs
7) Onset of Clinical Response That Continued Through the End of the 4-Week Double-blind Induction Phase

1) Cambio desde el momento basal en los síntomas depresivos referidos por el paciente utilizando la puntuación total del Cuestionario de salud del paciente -9 (PHQ-9) al final de la fase de inducción doble ciego
2) Cambio respecto al momento basal en la funcionalidad y discapacidad referidas por el paciente valorado por la puntuación total de la escala de discapacidad Sheehan Disability Scale (SDS) al final de la fase de inducción doble ciego
3) Cambio respecto al momento basal en la puntuación Impresión Clínica Global - Gravedad (CGI-S) al final de la fase de inducción doble ciego
4) Cambio respecto al momento basal en la puntuación total del Trastorno de Ansiedad Generalizada (GAD-7) referido por el paciente al final de la fase de inducción doble ciego.
5) Cambio respecto al momento basal en la calidad de vida relacionada con la salud y estado de salud, según EuroQol de 5 dimensiones y 5 niveles (EQ-5D-5L) al final de la fase de inducción doble ciego.
6) Número de participantes con eventos adversos (EA) y AEs graves
7) Inicio de la respuesta clínica continuada hasta el final de la fase de inducción doble ciego de 4 semanas.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Baseline and End of Double-blind Induction Phase (Week 4)
2) Baseline and End of Double-blind Induction Phase (Week 4)
3) Baseline and End of Double-blind Induction Phase (Week 4)
4) Baseline and End of Double-blind Induction Phase (Week 4)
5) Baseline and End of Double-blind Induction Phase (Week 4)
6) Screening up to End of Follow-up Phase (approximately up to 32 - 35 weeks)
7) Day 2 through the End of Double-Blind Induction Phase (Week 4)

1) Momento basal y final de la fase de inducción doble ciego (Semana 4)
2) Momento basal y final de la fase de inducción doble ciego (Semana 4)
3) Momento basal y final de la fase de inducción doble ciego (Semana 4)
4) Momento basal y final de la fase de inducción doble ciego (Semana 4)
5) Momento basal y final de la fase de inducción doble ciego (Semana 4)
6) Selección hasta final de fase de seguimiento (aproximadamente hasta 32 - 35 semanas)
7) Día 2 hasta el final de la fase de inducción doble ciego (Semana 4)

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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)

Yes

E.8.2.2

Placebo

Yes

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

Brazil

Czech Republic

Germany

Poland

Spain

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

LVLS

Última Visita Último Paciente

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

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

196

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

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

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

128

F.4.2.2

In the whole clinical trial

196

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)

At the end of the induction phase, subjects who are responders may be eligible to participate in the subsequent maintenance study ESKETINTRD3003, if they meet all other study entry criteria. For non-responders and those who do not enter ESKETINTRD3003, further clinical/standard of care for the treatment of depression will be arranged by the study investigator and/or the subject's treating physician.

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

2015-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-11-06

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