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    Summary
    EudraCT Number:2014-004587-38
    Sponsor's Protocol Code Number:ESKETINTRD3004
    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:2015-08-25
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-004587-38
    A.3Full title of the trial
    An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression
    Estudio a largo plazo, abierto, de seguridad y eficacia de esketamina intranasal en depresión resistente a tratamiento
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression
    Estudio a largo plazo, de seguridad y eficacia de esketamina intranasal en depresión resistente a tratamiento
    A.3.2Name or abbreviated title of the trial where available
    SUSTAIN-2
    A.4.1Sponsor's protocol code numberESKETINTRD3004
    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 SponsorJanssen-Cilag International NV
    B.1.3.4CountryBelgium
    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 supportJanssen Research & Development
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag, S.A.
    B.5.2Functional name of contact pointGlobal Clinical Operations Spain
    B.5.3 Address:
    B.5.3.1Street AddressPaseo de las Doce Estrellas, 5-7
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28042
    B.5.3.4CountrySpain
    B.5.4Telephone number34917228100
    B.5.5Fax number34917228628
    B.5.6E-mailagonza45@its.jnj.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.3.1Product nameEsketamine - Nasal Solution - eq 140mg/mL esketamine base (eq 161.4 mg/mL esketamine HCl)
    D.3.4Pharmaceutical form Nasal spray, solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPNasal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEsketamine hydrochloride (for (S)-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride)
    D.3.9.3Other descriptive nameESKETAMINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB25811
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number161.4
    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 RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cymbalta 30 mg hard gastro-resistant capsules
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Gastro-resistant capsule, hard
    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 INNDULOXETINE HYDROCHLORIDE
    D.3.9.1CAS number 136434-34-9
    D.3.9.3Other descriptive nameDULOXETINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB20026
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name CIPRALEX® 10 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderH. Lundbeck A/S
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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.3.4Pharmaceutical form Film-coated 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 INNESCITALOPRAM
    D.3.9.3Other descriptive nameESCITALOPRAM
    D.3.9.4EV Substance CodeSUB16425MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name ZOLOFT
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical form Film-coated 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 INNSERTRALINE HYDROCHLORIDE
    D.3.9.3Other descriptive nameSERTRALINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB04375MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Trevilor® retard 75 mg hard, prolonged-release capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER PHARMA GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Prolonged-release capsule, hard
    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 INNVENLAFAXINE HYDROCHLORIDE
    D.3.9.3Other descriptive nameVENLAFAXINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB05087MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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: 6
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Trevilor® retard 37.5 mg hard, prolonged-release capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER PHARMA GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Prolonged-release capsule, hard
    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 INNVENLAFAXINE HYDROCHLORIDE
    D.3.9.3Other descriptive nameVENLAFAXINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB05087MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number37.5
    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: 7
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name ZOLOFT
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical form Film-coated 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 INNSERTRALINE HYDROCHLORIDE
    D.3.9.3Other descriptive nameSERTRALINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB04375MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment-resistant Major Depression
    Depresión mayor resistente al tratamiento
    E.1.1.1Medical 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.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10057840
    E.1.2Term Major depression
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to assess the long-term safety and tolerability of intranasal esketamine plus a newly initiated oral antidepressant in subjects with TRD, with special attention to the following:

    - Potential effects on cognitive function
    - Potential treatment-emergent symptoms of cystitis and/or lower urinary tract symptoms
    - Potential withdrawal and/or rebound symptoms following cessation of intranasal esketamine treatment
    El objetivo principal del estudio es evaluar la seguridad y la tolerabilidad a largo plazo de esketamina intranasal más un antidepresivo oral recién iniciado en pacientes con DRT, prestando una atención especial a lo siguiente: -Posibles efectos en la función cognitiva -Posibles síntomas surgidos durante el tratamiento de cistitis y/o síntomas de las vías urinarias inferiores- Posibles síntomas de abstinencia y/o de rebote tras la interrupción del tratamiento con esketamina intranasal
    E.2.2Secondary objectives of the trial
    To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant in subjects with TRD on:

    - Safety and tolerability with special attention to the following (see protocol for details)
    - Treatment-emergent adverse events (TEAEs), including TEAEs of special interest
    - Local nasal tolerability
    - Effects on heart rate, blood pressure, respiratory rate and blood oxygen saturation
    - Effects on alertness and sedation
    - Potential psychosis-like effects
    - Dissociative symptoms
    - Potential effects on suicidal ideation/behavior

    - Long-term efficacy, including effects on:

    - Depressive symptoms
    - Response rate over time
    - Remission rate over time

    (See protocol for details)
    Evaluar el efecto de esketamina intranasal más un antidepresivo oral recién iniciado en pacientes con DRT en cuanto a: -Seguridad y tolerabilidad, prestando una atención especial a lo siguiente (véase protocolo para más detalle) - Acontecimientos adversos surgidos durante el tratamiento (AAST), incluidos los AAST de interés especial - Tolerabilidad nasal local- Efectos en la frecuencia cardiaca, la presión arterial, la frecuencia respiratoria y la saturación sanguínea de oxígeno - Efectos en la alerta y sedación - Posibles efectos pseudopsicóticos - Síntomas disociativos - Posibles efectos en la ideación/comportamiento suicida.- Eficacia a largo plazo, que incluye los efectos en: -Síntomas depresivos - Tasa de respuesta a lo largo del tiempo - Tasa de remisión a lo largo del tiempo(véase protocolo para más detalle)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A). For Direct-Entry Participants
    - 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)
    - At the start of the screening phase, participant must meet the
    Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic
    criteria for single-episode major depressive disorder (MDD) (if singleepisode
    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 screening, participant must have a MADRS total score of >=22
    - At the start of the screening phase, participants must have had
    nonresponse to >=2 oral antidepressant treatments taken at adequate
    dosage and for adequate duration, as assessed using the Massachusetts General Hospital

    B). For Transferred-entry Participants
    -All participants who completed the double-blind induction phase of
    ESKETINTRD3005 study, regardless of their response status, will be
    eligible to participate
    A) Participantes de inclusión directa
    - A la hora de la firma del consentimiento informado, el participante tiene que ser un varón o mujer de edad >= 18 años (o mayor si la edad mínima legal para consentir en el país en el cual tenga lugar el estudio es superior a 18). - Al principio de la fase de selección, el participante debe cumplir los criterios diagnósticos del Manual Diagnóstico y Estadístico de Trastornos Mentales (DSM-5) para el trastorno depresivo mayor de episodio único (TDM) (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 confirmado mediante la Minientrevista Neuropsiquiátrica Internacional (MINI). - La puntuación total de la MADRS en el momento de la selección debe ser >= 22. - Al comienzo de la fase de selección, los participantes deben no haber respondido a dos o más antidepresivos orales tomados a una dosis adecuada y durante el tiempo adecuado, evaluado mediante la escala del Hospital General de Massachusetts (MGH-ATRQ).

    B) Participantes transferidos.
    -Todos los participantes que hayan completado la fase de inducción doble ciego del estudio ESKETINTRD3005, sea cual sea su estado en cuanto a la respuesta, serán elegibles para participar en este estudio, siempre que cumplan los criterios de elegibilidad específicos.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    A). For Direct-Entry Participants
    - Participant's depressive symptoms have previously not responded to:
    1).Esketamine or ketamine in the current major depressive episode per
    clinical judgment,
    2). All of the 4 oral antidepressant treatment options available in the
    respective country for the open-label induction phase (that is,
    duloxetine, escitalopram, sertraline, and venlafaxine XR) in the current
    major depressive episode (based on Massachusetts General Hospital -
    Antidepressant Treatment Response Questionnaire [ MGH-ATRQ]) -
    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 (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and
    319), autism spectrum disorder, 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 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
    - Participants aged greater than or equal to 65 years: Has a Mini Mental
    State Examination (MMSE) <25; Has neurodegenerative disorder
    (example, Alzheimer's disease, vascular dementia, Parkinson's disease),
    or evidence of mild cognitive impairment (MCI)
    B). Transferred-Entry Participants
    - Participant has taken any prohibited therapies that would not permit
    dosing on Day 1
    A). Participantes de inclusión directa
    -Los síntomas depresivos del participante no han respondido a:
    1) Esketamina o ketamina en el episodio depresivo mayor actual, según el criterio clínico
    2) Las cuatro opciones de tratamiento antidepresivo oral disponibles en el país respectivo para la fase de inducción abierta (es decir, duloxetina, escitalopram, sertralina y venlafaxina XR) en el episodio actual de depresión mayor (según el Cuestionario de Respuesta al Tratamiento Antidepresivo del Hospital General de Massachusetts (MGH-ATRQ)). - El participante 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 (códigos diagnósticos 317, 318.0, 318.2, 315.8 y 319 del DSM-5), trastorno del espectro autista, trastorno límite de la personalidad, trastorno antisocial de la personalidad, trastorno histriónico de la personalidad o trastorno narcisista de la personalidad. - El participante 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, según el criterio clínico del investigador o basándose en la Escala de valoración de la gravedad del comportamiento suicida (C-SSRS). - El participante tiene antecedentes de trastorno moderado o grave de abuso de sustancias psicoactivas o alcohol según los criterios del DSM-5. - Participantes de edad >= 65 años: con una puntuación en el Mini Examen del Estado Mental (MMSE) < 25; Presencia de trastorno neurodegenerativo (p. ej., enfermedad de Alzheimer, demencia vascular, enfermedad de Parkinson) o signos de deterioro cognitivo leve (DCL).

    B). Participantes Trasferidos
    El participante ha recibido algún tratamiento prohibido que impide la administración de la dosis en el Día 1
    E.5 End points
    E.5.1Primary end point(s)
    1) Long-term safety and tolerability
    2) Change from baseline in Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS) score >18 over time
    3) Change from baseline in Cogstate® computerized cognitive battery domains and HVLT-R
    4) Incidence of withdrawal symptoms assessed by Physician Withdrawal Checklist (PWC-20)
    1) Seguridad y la tolerabilidad a largo plazo 2) Cambio desde el momento basal en la puntuación de la escala de Síntomas de Dolor Vesical/Cistitis Intersticial (BPIC-SS) > 18 a lo largo del tiempo 3) Cambio desde el momento basal en la Batería cognitiva computarizada y HVLT-R 4) Incidencia de los síntomas de abstinencia evaluados mediante la Lista de comprobación de la Abstinencia por el Médico (PWC-20)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) Day 1 post dose through end of Follow Up Phase (Week 56)
    2) Baseline and up to end of Follow Up phase (Week 56)
    3) Baseline and up to end of Follow Up Phase (Week 56)
    4)Week 54 (week 2 of Follow Up phase) and Week 56 (week 4 of Follow Up phase)
    1) Día 1 después de la dosis hasta el final de la Fase de Seguimiento (Semana
    56) 2) Momento basal y hasta el final de la Fase de Seguimiento (Semana 56) 3) Momento basal y hasta el final del seguimiento de fase (Semana 56) 4) Semana 54 (Semana 2 de la fase de seguimiento) y la semana 56 (semana 4 de la fase de seguimiento)
    E.5.2Secondary end point(s)
    1) Incidence of all Adverse Events and Serious Advers Events
    2) Change from baseline (predose) in heart rate, systolic and diastolic blood pressure, respiratory rate, blood oxygen saturation, MOAA/S score, BPRS total score, CADSS total score, CSSRS, nasal tolerability
    3) Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at end of Optimization/Maintenance Phase
    4) Change from baseline in CGI-S score at the end of Optimization/Maintenance phase
    5) Change From Baseline in Subject-reported Depressive Symptoms Using the Patient Health Questionnaire - 9 (PHQ-9) Total Score at end of
    Optimization/Maintenance Phase
    6) Change From Baseline in Subject-reported Generalized Anxiety Disorder (GAD-7) Score at end of Optimization/Maintenance Phase
    7) 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 Optimization/Maintenance Phase
    8) Change From Baseline in Subject-reported Functioning and Associated Disability as Assessed by the Sheehan Disability Scale (SDS) Total Score at end of
    Optimization/Maintenance Phase
    9) Percentage of participants with Response
    10) Percentage of participants with Remission
    1) Incidencia de todos los acontecimientos adversos y acontecimientos adversos serios 2) Variación respecto al momento basal (antes de la dosis) en la frecuencia cardíaca, presión arterial sistólica y diastólica, frecuencia respiratoria, saturación de oxígeno en sangre, la puntuación MOAA/S, la puntuación total BPRS, puntuación total CADSS, C-SSRS, tolerabilidad nasal 3) Variación en la puntuación total de la Escala de Evaluación de la Depresión de Montgomery-Asberg (MADRS) al final de la fase de optimización y mantenimiento, respecto al momento basal 4) Variación en la puntuación total del CGI-S al final de la fase de optimización y mantenimiento, respecto al momento basal 5) Variación en la puntuación total en los síntomas depresivos comunicados por el paciente, empleando el Cuestionario de Salud del Paciente de 9 ítems (PHQ-9) al final de la fase de optimización y mantenimiento, respecto al momento basal 6) Variación en la puntuación total en la Escala del Trastorno de Ansiedad Generalizada de 7 ítems (GAD-7) al final de la fase de optimización y mantenimiento, respecto al momento basal 7) Variación en la puntuación total en la escala cumplimentada por el paciente de 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 optimización y mantenimiento, respecto al momento basal 8) Variación en la puntuación total en el deterioro funcional y la discapacidad relacionada reportado por el paciente evaluado mediante Escala de la Discapacidad de Sheehan (SDS) al final de la fase de optimización y mantenimiento, respecto al momento basal 9) Porcentaje de participantes con respuesta 10) Porcentaje de participantes con remisión
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Day 1 post dose to End of Follow-up Phase
    2) Baseline of each dosing session (predose) to last post-dose measurement (1.5 hour or longer) in the period from Start of Induction Phase to End of Optimization/Maintenance Phase (week 52)
    3) Baseline to End of Optimization/Maintenance Phase (Week 52)
    4) Baseline to End of Optimization/Maintenance Phase (Week 52)
    5) Baseline to End of Optimization/Maintenance Phase (Week 52)
    6) Baseline to End of Optimization/Maintenance Phase (Week 52)
    7) Baseline to End of Optimization/Maintenance Phase (Week 52)
    8) Baseline to End of Optimization/Maintenance Phase (Week 52)
    9) End of Optimization/Maintenance Phase (Week 52)
    10) End of Optimization/Maintenance Phase (Week 52)
    1) Día 1 después de la dosis al final de la fase de seguimiento 2) Momento basal antes de la dosis hasta la última medida post-dosis (1,5 hora o más), en cada dosis de administración, en el período comprendido entre el inicio de la fase de inducción hasta el final de la fase de optimización y mantenimiento (Semana 52) 3)- 8) Momento basal al final de la fase de optimización y mantenimiento (Semana 52) 9) Final de la fase de optimización y mantenimiento (Semana 52) 10) Final de la fase de optimización y mantenimiento (Semana 52)
    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 Yes
    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 No
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA73
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Bulgaria
    France
    Germany
    Italy
    Korea, Republic of
    Malaysia
    Mexico
    Poland
    Romania
    South Africa
    Spain
    Sweden
    Taiwan
    Turkey
    United Kingdom
    United States
    E.8.7Trial 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 del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 750
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 370
    F.4.2.2In the whole clinical trial 850
    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)
    Subjects will return to standard of care treatment following participation in the study.
    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 Decision2015-10-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-30
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