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    EudraCT Number:2016-003990-17
    Sponsor's Protocol Code Number:54135419SUI3001
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-04-04
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2016-003990-17
    A.3Full title of the trial
    A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Subjects Assessed to be at Imminent Risk for Suicide
    Dvojito zaslepené, randomizované, placebom kontrolované skúšanie na vyhodnotenie účinnosti a bezpečnosti intranazálneho esketamínu doplneného ku komplexnej štandardnej starostlivosti na rýchle zmiernenie príznakov veľkej depresívnej poruchy, vrátane suicidálnych myšlienok, u dospelých subjektov posúdených ako bezprostredne ohrozených rizikom samovraždy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of the Efficacy and Safety of Intranasal Esketamine in the Rapid Reduction of Symptoms of Major Depressive Disorder, in Adults at Imminent Risk for Suicide
    A.4.1Sponsor's protocol code number54135419SUI3001
    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.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 International NV
    B.5.2Functional name of contact pointClinical Registry Group
    B.5.3 Address:
    B.5.3.1Street AddressJanssen Biologics BV - Clinical Registry Group - Archimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333CM
    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 (for (S)-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone)
    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 number140
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboNasal spray
    D.8.4Route of administration of the placeboNasal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Major Depressive Disorder with Imminent Risk of Suicide
    E.1.1.1Medical condition in easily understood language
    Depression with Risk of Suicide
    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 20.1
    E.1.2Level PT
    E.1.2Classification code 10042458
    E.1.2Term Suicidal ideation
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012397
    E.1.2Term Depression suicidal
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10065604
    E.1.2Term Suicidal behaviour
    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 is to evaluate the efficacy of intranasal esketamine 84 mg compared with intranasal placebo in addition to comprehensive standard of care in reducing the symptoms of MDD, including suicidal ideation, in subjects who are assessed to be at imminent risk for suicide, as measured by the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 24 hours post first dose.
    E.2.2Secondary objectives of the trial
    The key secondary objective is to assess the efficacy of intranasal esketamine compared with intranasal placebo in reducing severity of suicidality as measured by the clinical global impression of severity of suicidality revised version (CGI-SS-R) at 24 hours post first dose. Other secondary objectives are listed in Protocol Section 2.1.1.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject must be a man or woman, 18 to 64 years of age, inclusive.
    2. Subject must meet Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for MDD, without psychotic features, based upon clinical assessment and confirmed by the MINI.
    3. Subjects must have current suicidal ideation with intent, confirmed by a “Yes” response to Question B3 [Think (even momentarily) about harming or of hurting or of injuring yourself: with at least some intent or awareness that you might die as a result; or think about suicide (ie, about killing yourself)?] AND Question B10 [Intend to act on thoughts of killing yourself?] obtained from the MINI. Note: the response to B3 must refer to the present, whereas the response to B10 may reflect the past 24 hours. If the screening period is longer than 24 hours, assessment of B3 and B10 of MINI must be repeated prior to randomization to confirm eligibility.
    4. In the physician’s opinion, acute psychiatric hospitalization is clinically warranted due to subject’s imminent risk of suicide.
    5. Subject has a MADRS total score of >28 predose on Day 1.
    6. As part of standard of care treatment, subject agrees to be hospitalized voluntarily for a recommended period of 5 days after randomization (may be shorter or longer if clinically warranted in the investigator’s opinion) and take prescribed non-investigational antidepressant therapy(ies) for at least the duration of the double-blind treatment phase (Day 25).
    7. Subject is comfortable with self-administration of intranasal medication and able to follow instructions provided.
    8. Subject must be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening. If there are abnormalities, the subject may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the investigator.
    9. Subject must be medically stable on the basis of clinical laboratory tests performed by the local laboratory at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the investigator.
    10. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies.
    Before randomization, a woman must be either:
    a. Not of childbearing potential defined as:
    -postmenopausal (>45 years of age with amenorrhea for at least 12 months), permanently sterilized (eg, bilateral tubal occlusion/ligation procedures, hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy
    b. Of childbearing potential and
    -practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly)
    -agrees to use a highly effective method throughout the study and for at least 6 weeks after the last dose of study drug.
    11. A woman of childbearing potential must have a negative urine pregnancy test at screening.
    12. During the study (ie, from Day 1 of the double-blind phase) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study drug, a man who is sexually active with a woman of childbearing potential
    -must be practicing a highly effective method of contraception with his female partner
    -must use a condom if his partner is pregnant.
    -must agree not to donate sperm.
    Note: If the childbearing potential changes after start of the study, a female partner of a male study subject must begin a highly effective method of birth control.
    13. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
    14. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study.
    Note: Subjects with acute alcohol intoxication should not be screened (but can be screened once sober).
    15. Each subject must sign a separate informed consent form if he or she agrees to provide an optional DNA sample for research (where local regulations permit). Refusal to give consent for the optional DNA research sample does not exclude a subject from participation in the study.

    Additional information on inclusion criteria is found in Protocol Section 4.1
    E.4Principal exclusion criteria
    1. Subject has a current DSM-5 diagnosis of bipolar (or related disorders), antisocial personality disorder, or obsessive compulsive disorder.
    2. Subject currently meets DSM-5 criteria for borderline personality disorder.
    -Subjects not meeting full DSM-5 criteria for borderline personality disorder but exhibiting recurrent suicidal gestures, threats, or self-mutilating behaviors should also be excluded.
    3. Subject has a current clinical diagnosis of autism, dementia, or intellectual disability.
    4. Subject has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with psychotic features.
    5. Subject has a history of moderate or severe substance or alcohol use disorder, according to DSM-5 criteria, except nicotine or caffeine, within 6 months before screening.
    6. Subject has a history or current signs and symptoms of liver or renal insufficiency or of clinically significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic (including current or past history of seizures except uncomplicated childhood febrile seizures with no sequelae), hematologic, rheumatologic, or metabolic disease.
    7. Subject has uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg) despite diet, exercise or a stable dose of anti-hypertensive treatment for at least 2 weeks at screening; or any past history of hypertensive crisis.
    8. Subject has a positive urine test result(s) for phencyclidine (PCP), cocaine, or amphetamines at screening.
    -Subjects who have a positive test due to the appropriate use of prescribed opiates, benzodiazepines, or barbiturates may be eligible for study participation per clinician judgment. In addition, subjects who have a positive test for opiates, benzodiazepines, or barbiturates used without a prescription, may be considered eligible per clinician judgment and in consultation with the sponsor’s medical monitor.
    -Subjects who have a positive test due to opiates, benzodiazepines, or barbiturates taken in a suicide attempt (eg, overdose) may be eligible for study participation per clinician judgment and in consultation with the sponsor’s medical monitor.
    9. Subject has a history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered to have minimal risk of recurrence).
    10. Subject has any anatomical or medical condition that, per the investigator’s clinical judgment based on assessment, may impede delivery or absorption of intranasal study drug.
    11. Subject has known allergies, hypersensitivity, intolerance or contraindications to esketamine or ketamine or its excipients (refer to Investigator's Brochure for esketamine, Summary of Product Characteristics, US prescribing information).
    12. Subject has taken any disallowed therapy(ies) as noted in Section 8, Prestudy and Concomitant Therapy, and Attachment 1 of the protocol.
    13. Subject has received an investigational drug (including esketamine, ketamine, or investigational vaccines) or used an invasive investigational medical device within 60 days before the planned first dose of study drug or is currently enrolled in an investigational study.
    14. Subject is a woman who is pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug.
    15. Subject has any situation or condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
    16. Subject is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in depressive symptoms, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) total score
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1, predose to 24 hours post first dose
    E.5.2Secondary end point(s)
    1) Change from baseline in severity of suicidality, as measured by the clinical global impression of severity of suicidality revised version (CGI-SS-R)
    2) Remission rate (MADRS ≤12)
    3) Change from baseline of MADRS total score
    4) Change from baseline of CGI-SS-R
    5) Proportion of subjects achieving resolution of suicidality (CGI-SS-R score of 0 or 1)
    6) Change from baseline of clinical global impression of imminent suicide risk (CGI SR-I)
    7) Change from baseline of Beck Hopelessness Scale (BHS)
    8) Change from baseline of European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L)
    9) Change from baseline of Quality of Life in Depression Scale (QLDS)
    10) Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores
    11) Suicidal Ideation and Behaviors Assessment Tool (SIBAT): Change from baseline in Module 3 My Current Thinking and Module 5 My Risk, Question 3 (patient-reported frequency of suicidal thinking)
    12) Pharmacokinetics: Plasma esketamine and noresketamine concentrations will be summarized; plasma concentrations of esketamine (and noresketamine concentrations, if warranted) will be included in a population analysis
    13) Safety endpoints will be evaluated throughout the study - Monitoring of treatment emergent adverse events (TEAEs), Clinical laboratory tests, physical examination, nasal examination, 12-lead electrocardiogram (ECG), and vital signs, SIBAT, On dosing days only: MOAA/S, CADSS, and pulse oximetry
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) From day 1, predose to 24 hours post first dose
    2, 5, 6) 4 hours and 24 hours post first dose, and through the end of the double-blind treatment phase (Day 25)
    3,4) 4 hours post first dose and through the end of the double-blind treatment phase (Day 25)
    7, 8, 9, 10, 11) Through the end of the double-blind treatment phase (Day 25)
    12, 13) Throughout the study
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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. 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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
    Korea, Republic of
    South Africa
    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
    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 months4
    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 months4
    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.1.1.1In 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: 224
    F.1.3Elderly (>=65 years) No
    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 state17
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 87
    F.4.2.2In the whole clinical trial 224
    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)
    Not applicable
    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 Decision2017-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-27
    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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