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    Summary
    EudraCT Number:2014-004587-38
    Sponsor's Protocol Code Number:ESKETINTRD3004
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-02-22
    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 ConcernedItaly - Italian Medicines Agency
    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
    Uno studio in aperto, a lungo termine, sulla sicurezza ed efficacia di Esketamine intra nasale nella depressione resistente al trattamento
    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 exketamine in treatment- resistant depression
    Studio a lungo termine, sulla sicurezza ed efficacia di Esketamine intra nasale nella depressione resistente al trattamento
    A.3.2Name or abbreviated title of the trial where available
    SUSTAIN-2
    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.1.3.4CountryItaly
    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 CILAG SPA
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportJANSSEN CILAG INTERNATIONAL NV
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International NV
    B.5.2Functional name of contact pointClinical Registry Group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 71 524 21 66
    B.5.5Fax number+31 71 524 21 10
    B.5.6E-mailClinicalTrialsEU@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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNesketamine cloridrato
    D.3.9.2Current sponsor codeESKETAMINE cloridrato
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 AuthorisationBelgium
    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 IMP
    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.3.9.2Current sponsor coden/a
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNescitalopram
    D.3.9.2Current sponsor code.
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNsertralina cloridrato
    D.3.9.2Current sponsor code.
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNvenlafaxina cloridrato
    D.3.9.2Current sponsor code.
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNvenlafaxina cloridrato
    D.3.9.2Current sponsor code.
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Prolonged-release capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNsertralina cloridrato
    D.3.9.2Current sponsor code.
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    DEPRESSIONE MAGGIORE RESISTENTE AL TRATTAMENTO
    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 DEPRESSIONE E' UN DISORDINE MENTALE
    CARATTERIZZATO DA UMORE NEGATIVO E / O PERDITA DI INTERESSE O DI PIACERE IN QUASI TUTTE LE ATTIVITA'
    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 20.0
    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
    L'obiettivo primario di questo studio è determinare la sicurezza e la tollerabilità a lungo termine di Esketamine intra nasale abbinata ad un nuovo antidepressivo orale nei soggetti affetti da TRD, prestando particolare attenzione a:
    • Effetti potenziali sulla funzione cognitiva
    • Potenziali sintomi di cistite e/o sintomi del tratto urinario inferiore emersi col trattamento
    • Potenziali sintomi da sospensione e/o ripresa in seguito all’interruzione del trattamento con Esketamine intra nasale
    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:
    - 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
    Valutare gli effetti di Esketamine intra nasale abbinata ad un nuovo antidepressivo orale nei soggetti affetti da TRD su:
    • Sicurezza e tollerabilità prestando particolare attenzione a:
     Eventi avversi insorti con il trattamento (TEAEs), compresi TEAEs di speciale interesse
     Tollerabilità nasale locale
     Effetti su frequenza cardiaca, pressione sanguigna, frequenza respiratoria e saturazione dell'ossigeno nel sangue
     Effetti su stato di coscienza e sedazione
     Potenziali effetti simil-psicotici
     Sintomi dissociativi
     Potenziali effetti su intenti/comportamenti suicidi.
    • Efficacia a lungo termine, compresi gli effetti su:
     Sintomi depressivi - vedere protocollo per dettagli
     Tasso di risposta nel tempo
     Tasso di remissione nel tempo
    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 in this study, if they meet the study specific eligibility criteria
    Soggetti ad ammissione diretta
    I seguenti criteri si applicano soltanto ai soggetti che entrano direttamente a far parte dello studio
    Per poter essere arruolato nello studio, ciascun potenziale soggetto deve soddisfare tutti i seguenti criteri.
    1. Il soggetto deve essere un uomo o una donna di età 18 anni.
    2. All'inizio della fase di screening tutti i soggetti devono soddisfare i criteri di diagnosi DSM-5 per MDD con episodio singolo (in caso di MDD con episodio singolo la durata dell'episodio deve essere 2 anni) o MDD ricorrente, senza caratteristiche psicotiche, sulla base di una valutazione clinica e con conferma tramite intervista MINI.
    3. All'inizio della fase di screening tutti i soggetti devono aver presentato l'assenza di risposta a 2 regimi di trattamento con antidepressivo orale nel corso dell'episodio attuale di depressione, sulla base di una valutazione effettuata tramite questionario MGH-ATRQ e confermata da anamnesi/cartelle cliniche documentate.
    4. In fase di screening il soggetto deve riportare un punteggio totale della MADRS 22.
    5. Il soggetto deve presentare una condizione medica stabile definita sulla base dei risultati di esame obiettivo, anamnesi, segni vitali (compresa pressione sanguigna), pulsossimetria ed ECG a 12 derivazioni, ottenuti nella fase di screening. Se vengono riscontrate anomalie non specificate nei criteri di inclusione ed esclusione, la relativa significatività clinica deve essere determinata dallo sperimentatore, registrata nei documenti fonte del paziente e sottoscritta dallo sperimentatore.
    6. Criterio modificato per emendamento 1
    6.1 Il soggetto deve presentare una condizione medica stabile definita sulla base dei test clinici di laboratorio effettuati nella fase di screening. Se i risultati delle analisi sierologiche, delle analisi ematologiche o delle analisi delle urine non rientrano nei normali intervalli di riferimento, il soggetto può essere incluso soltanto se lo sperimentatore ritiene che le anomalie o deviazioni dalla norma non siano clinicamente significative o le considera appropriate e ragionevoli per la popolazione oggetto di studio. Lo sperimentatore deve registrare tale decisione nei documenti fonte del soggetto e sottoscriverli.
    - Per quesi soggetti senza una storia preesistente di ipotiroidismo, è richiesto un valore di TSH nei range di normalità allo screening.¶
    - Se il valore di TSH è al di sotto del range di normalità, dovranno essere misurati i livelli di fT4 e se questi saranno all’interno dei range di normalità il soggetto potrà essere arruolato.
    - I soggetti con storia pregressa di malattia/disturbo alla tiroide e attualmente trattati con ormoni tiroidei devono assumere un dosaggio stabile da almeno 3 mesi prima dell'inizio della fase di screening e, in fase di screening, devono presentare livelli di ormone tireotropo [TSH] nella norma.
    7. Il soggetto deve avere dimestichezza con l'auto-somministrazione del farmaco intra nasale, nonché deve essere in grado di seguire le istruzioni fornite al riguardo.
    8. Prima dell'inizio della fase di screening, le donne devono rientrare in uno dei seguenti casi:
    a. Non essere in età fertile: Stato post-menopausale (>45 anni di età con amenorrea negli ultimi 12 mesi o qualsiasi età con amenorrea negli ultimi 6 mesi e livello dell'ormone follicolo-stimolante (FSH) >40 IU/L o mIU/mL); sterilizzata permanentemente (ad es. legatura delle tube, isterectomia, salpingectomia bilaterale); o sterile per altri motivi,
    b. Essere fertile e utilizzare metodi contraccettivi altamente efficaci coerenti con la normativa locale concernente l'uso di metodi contraccettivi per soggetti che partecipano a studi clinici: ad es. uso costante di contraccettivi ormonali orali, iniettati o impiantati; posizionamento di un dispositivo (IUD) o sistema (IUS) intrauterino; metodi contraccettivi a barriera: (ad es. profilattico con schiuma/gel/film/crema/supposta spermicida o cappuccio occlusivo [diaframma o cappuccio cervicale] con schiuma/gel/film/crema/supposta spermicida; sterilizzazione del partner maschile (il partner vasectomizzato deve essere l'unico partner del soggetto); o reale astinenza (se in linea con lo stile di vita preferito e consueto del soggetto)
    Nota: Se la situazione di fertilità dovesse cambiare dopo l'inizio dello studio (ad es. una donna non eterosessualmente attiva diventa attiva), la donna deve cominciare a utilizzare un metodo contraccettivo altamente efficace, come precedentemente descritto.
    c. Le donne devono impegnarsi a continuare a utilizzare i suddetti metodi contraccettivi per l'intera durata dello studio e per almeno 6 settimane dopo l'assunzione dell'ultima dose del farmaco di studio.
    9. Una donna in età fertile deve presentare un test di gravidanza su siero negativo (-gonadotropina corionica umana [-hCG]) all'inizio della fase di screening e un test di gravidanza sulle urine negativo al Giorno 1 della fase di induzione in aperto antecedente alla prima sessione di trattamento intra nasale.
    E.4Principal 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
    Criteri di esclusione
    I potenziali soggetti che soddisfino uno qualsiasi dei criteri seguenti saranno esclusi dalla partecipazione allo studio.
    Soggetti trasferiti
    1. Il soggetto ha assunto terapie non ammesse che non consentirebbero il dosaggio nel Giorno 1, come indicato nella sezione 8 (Prestudio e Terapia Concomitante) e nell'allegato 1.
    2. Il soggetto presenta qualsiasi condizione o situazione/circostanza per cui, secondo il giudizio dello sperimentatore, la partecipazione non sarebbe nel suo migliore interesse (ad es. ne comprometterebbe il benessere) o potrebbe impedire, limitare o confondere le valutazioni specificate dal protocollo.
    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)sicurezza e tollerabilità a lungo termine
    2) variazione dalla baseline per il Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS) score >18 nel tempo
    3) variazione dalla baseline nel test cognitivo Cogstate® e HVLT-R 4) incidenza o manifestazione di sintomi di sospensione valutati dalla Physician Withdrawal Checklist (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) giorno 1 dopo la dose fino alla fine della fase di follow up (settimana 56) 2) dal baseline fino alla fine della fase di follow up (settimana 56) 3) dal baseline fino alla fine della fase di follow up (settimana 56) 4) settimana 54 (la settimana 2 della fase di follow up) e la settimana 56 (la settimana 4 della fase di follow up)
    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) incidenza di tutti gli eventi avversi e di tutti gli eventi avversi seri 2) variazione dalla baseline (predose) nel battito caridaco, nella pressione sanguigna sistolica e diastolica, nella frequenza respiratoria, nella saturazione ematica dell'ossigeno, nel punteggio MOAA/S, nel punteggio totale BPRS, nel punteggio CADSS, CSSRS, tollerabilità nasale. 3) variazione dal baseline nel punteggio MADRS, alla fine della fase di mantenimento/ottimizzazione 4) variazione dal baseline nel punteggio CGI-S alla fine della fase di mantenimento/ottimizzazione 5) variazioni dal baseline nel punteggio PHQ-9 alla fine della fase di mantenimento/ottimizzazione; 6) variazioni dal baseline nel punteggio GAD-7 alla fine della fase di mantenimento/ottimizzazione 7) variazione dal baseline nel punteggio del questionario EQ-5D-5L alla fine della fase di mantenimento/ottimizzazione 8) variazione dalla baseline del punteggio del test SDS alla fine della fase di mantenimento/ottimizzazione 9) percentuale di pazienti responsivi al trattamento 10) percentuali di pazienti con remissione della malattia
    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) dal Giorno 1 alla fine della end-up phase 2) dal baseline di ogni sessione di somministrazione (prima della dose e post dose) fino all'ultima misurazione post dose 1,5 ore o più nel periodo di induzione fino alla fine della fase di mantenimento/ottimizzazione (settimana 52)
    3) dalla baseline fino alla fine del periodo di ottimizzazione/mantenimento (settimana 52) 4) dalla baseline fino alla fine del periodo di ottimizzazione/mantenimento (settimana 52) 5) dalla baseline fino alla fine del periodo di ottimizzazione/mantenimento (settimana 52) 6) dalla baseline fino alla fine del periodo di ottimizzazione/mantenimento (settimana 52) 7) dalla baseline fino alla fine del periodo di ottimizzazione/mantenimento (settimana 52) 8) dalla baseline fino alla fine del periodo di ottimizzazione/mant
    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 Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    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 concerned4
    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 Information not present in EudraCT
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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: 127
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 370
    F.4.2.2In the whole clinical trial 877
    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.
    i soggetti torneranno allo standard of care
    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 Decision2015-10-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-05
    P. End of Trial
    P.End of Trial StatusCompleted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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