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A 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 Participants Assessed to be at Imminent Risk for Suicide (Aspire II)

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ClinicalTrials.gov Identifier: NCT03097133
Recruitment Status : Recruiting
First Posted : March 31, 2017
Last Update Posted : September 24, 2018
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Brief Summary:
The purpose of this study is to evaluate the efficacy of intranasal esketamine 84 milligram (mg) compared with intranasal placebo in addition to comprehensive standard of care in reducing the symptoms of Major Depressive Disorder (MDD), including suicidal ideation, in participants 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.

Condition or disease Intervention/treatment Phase
Depressive Disorder, Major Drug: Esketamine Drug: Placebo Other: Standard of Care Phase 3

Detailed Description:
If you or a loved one are having thoughts of suicide, please seek immediate medical help. Go to the emergency room or call the National Suicide Prevention Lifeline at 1-800-273-8255.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 224 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 15, 2017
Estimated Primary Completion Date : July 29, 2019
Estimated Study Completion Date : July 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Suicide

Arm Intervention/treatment
Experimental: Esketamine + Standard of care
Participants will receive intranasal esketamine 84 milligram (mg) on Day 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment.
Drug: Esketamine
Participants will receive intranasal esketamine 84 milligram (mg) two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25).

Other: Standard of Care
The standard of care antidepressant treatment (antidepressant monotherapy or antidepressant plus augmentation therapy) will be determined by the treating physician(s) based on clinical judgement and practice guidelines prior to randomization, and the treatment will be initiated on Day 1.

Placebo Comparator: Placebo + Standard of care
Participants will receive intranasal placebo on Day 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment.
Drug: Placebo
Participants will receive intranasal placebo two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25).

Other: Standard of Care
The standard of care antidepressant treatment (antidepressant monotherapy or antidepressant plus augmentation therapy) will be determined by the treating physician(s) based on clinical judgement and practice guidelines prior to randomization, and the treatment will be initiated on Day 1.




Primary Outcome Measures :
  1. Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at 24 Hours Post First Dose [ Time Frame: Baseline and 24 Hours post first dose (Day 2) ]
    MADRS is a clinician-rated scale designed to be used in participants with Major Depressive Disorder (MDD) to measure depression severity and detect changes due to antidepressant treatment. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.


Secondary Outcome Measures :
  1. Change From Baseline in Clinical Global Impression-Severity of Suicidality- Revised (CGI-SS-R) Scale at 24 Hours Post First Dose [ Time Frame: Baseline and 24 Hours post first dose (Day 2) ]
    CGI-SS-R is derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a participants illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants).

  2. Percentage of Participants With Remission (MADRS Less Than or Equal to [<=] 12) [ Time Frame: At 4, 24 hours post first dose and through the end of the double-blind treatment phase (Day 25) ]
    MADRS is a clinician-rated scale designed to be used in participants with Major Depressive Disorder (MDD) to measure depression severity and detect changes due to antidepressant treatment. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

  3. Change From Baseline in MADRS Total Score at 4 Hours Post First Dose on Day 1 and Through the end of the Double-Blind Treatment Phase (Day 25) [ Time Frame: Baseline and 4 hours post first dose (Day 1) and through the end of the double-blind treatment phase (Day 25) ]
    MADRS is a clinician-rated scale designed to be used in participants with Major Depressive Disorder (MDD) to measure depression severity and detect changes due to antidepressant treatment. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

  4. Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose on Day 1 and Through the end of the Double-Blind Treatment Phase (Day 25) [ Time Frame: Baseline and 4 hours post first dose (Day 1) and through the end of the double-blind treatment phase (Day 25) ]
    CGI-SS-R is derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a participants illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants).

  5. Percentage of Participants Achieving Resolution of Suicidality (CGI-SS-R Score of 0 or 1) [ Time Frame: At 4, 24 hours post first dose and through the end of the double-blind treatment phase (Day 25) ]
    CGI-SS-R is derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a participants illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants).

  6. Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at 4 Hours Post First Dose and Through the end of the Double-Blind Treatment Phase [ Time Frame: Baseline and 4, 24 hours post first dose and through the end of the double-blind treatment phase (Day 25) ]
    CGI-SR-I describes aspects of participant's suicidal thinking, behavior and related contributory/protective factors, what is best clinical judgment of participant's imminent risk for suicide within the next 7 days. Scale indicates: 0 (No imminent suicide risk), 1 (Minimal imminent), 2 (Mild imminent), 3 (Moderate imminent), 4 (Marked imminent), 5 (Severely imminent), 6 (Extreme imminent).

  7. Change From Baseline in Beck Hopelessness Scale (BHS) Score Through the end of the Double-Blind Treatment Phase (Day 25) [ Time Frame: Baseline through the end of the double-blind treatment phase (Day 25) ]
    BHS is a self-reported measure to assess one's level of negative expectations or pessimism regarding the future. It consists of 20 true-false items that examine the respondent's attitude over the past week by either endorsing a pessimistic statement or denying an optimistic statement; 9 are keyed false and 11 are keyed true. For every statement, each response is assigned a score of 0 or 1. The total BHS score is a sum of item responses and can range from 0 to 20, with a higher score representing a higher level of hopelessness. Total scores that range from 0 to 3 are considered within the normal range, scores 4 to 8 identify mild hopelessness, scores 9 to 14 identify moderate hopelessness, and scores greater than 14 identify severe hopelessness.

  8. Change From Baseline in European Quality of Life Group, 5-Dimension, 5-Level (EQ-5D-5L) Through the end of the Double-Blind Treatment Phase (Day 25) [ Time Frame: Baseline through the end of the double-blind treatment phase (Day 25) ]
    The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. It consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The participant selects an answer for each of the 5 dimensions considering the response that best matches his or her health "today." The descriptive system can be represented as a health state. The EQ-VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (worst imaginable health) to 100 (best imaginable health). EQ-5D scores include EQ-5D valuation index score (a weighted scoring of the 5 dimension scores with a possible range from 0 to 1) and EQ-5D descriptive system scores (five scores reflecting each of the 5 EQ-5D health dimensions ranging from 1 [no limitation] to 5 [incapacity]).

  9. Change From Baseline in Quality of Life in Depression Scale (QLDS) Score Through the end of the Double-Blind Treatment Phase [ Time Frame: Baseline through the end of the double-blind treatment phase (Day 25) ]
    The QLDS is a disease specific patient-reported outcome designed to assess health related quality of life in participants with Major Depressive Disorder. The instrument has a recall period of "at the moment", contains 34-items with "yes"/"no" or "true/not true" response options and takes approximately 5-10 minutes to complete. The score range is from 0 (good quality of life) to 34 (very poor quality of life).

  10. Treatment Satisfaction Questionnaire for Medication (TSQM-9) Score [ Time Frame: Baseline through the end of the double-blind treatment phase (Day 25) ]
    TSQM-9 is a 9-item generic patient reported outcome instrument to assess participant's satisfaction with medication and covers domains of effectiveness, convenience and global satisfaction. The instrument is scored by domain with scores ranging from 0-100 where a lower score indicates lower satisfaction.

  11. Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Participant-Reported Frequency of Suicidal Thinking) [ Time Frame: Baseline through the end of the double-blind treatment phase (Day 25) ]
    The SIBAT is a suicide assessment tool that captures suicidal ideation and behavior(s) as reported by patients and reviewed by clinicians permitting efficient collection and documentation of clinical impression of severity of suicidality and imminent and long-term suicide risk and treatment plans. The 8 modules of the SIBAT are divided into patient-reported (Modules 1-5) and clinician-rated (Modules 6-8) sections. Patient-reported suicidality will be assessed based on SIBAT tool including Module 5 My Risk, Question 3 (patient-reported frequency of suicidal thinking). Participant-reported frequency of suicidal thinking is scored from 0 (have no suicidal thoughts) to 4 (have suicidal thoughts all of the time).

  12. Plasma Concentrations of Esketamine and Noresketamine [ Time Frame: Day 1 and 4: 30-50 min, 1.5 hour to 2.5 hours, and 4 hours to 12 hours postdose ]
    Plasma concentrations of Esketamine and noresketamine will be evaluated.

  13. Number of Participants with Treatment Emergent Adverse Events (AEs) as a Measure of Safety and Tolerability [ Time Frame: Up to Day 90 (final visit) ]
    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between administration of study drug and up to Day 90 that were absent before treatment or that worsened relative to pre-treatment state.

  14. Number of Participants With Abnormal Clinical Laboratory Findings as a Measure of Safety and Tolerability [ Time Frame: Up to end of the double-blind treatment phase (Day 25) ]
    Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will be collected. The investigator must review the laboratory results, document this review, and record any clinically relevant changes occurring during the study in the adverse event section of the eCRF.

  15. Number of Participants With Nasal Examination Findings as a Measure of Safety and Tolerability [ Time Frame: Up to end of the double-blind treatment phase (Day 25) ]
    Nasal examination will consist of a visual inspection of the nostrils, nasal mucosa, and throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis and will be graded as follows: none, mild, moderate, or severe

  16. Number of Participants With Electrocardiogram (ECG) Abnormalities Findings as a Measure of Safety and Tolerability [ Time Frame: Day 1, 8 and end of the double-blind treatment phase (Day 25) ]
    Number of participants with ECG abnormalities will be calculated as a measure of safety and tolerability.

  17. Number of Participants With Vital Sign Abnormalities as a Measure of Safety and Tolerability [ Time Frame: Day 1, 4, 8, 11, 15, 18, 22, 25 (end of the double-blind treatment phase) and 90 (final visit) ]
    Vital signs includes Temperature, Pulse/Heart Rate, Respiratory Rate and Blood Pressure.

  18. Suicide Ideation and Behavior Assessment Tool (SIBAT) [ Time Frame: Up to Day 90 (final visit) ]
    The SIBAT is a suicide assessment tool that captures suicidal ideation and behavior(s) as reported by patients and reviewed by clinicians permitting efficient collection and documentation of clinical impression of severity of suicidality and imminent and long-term suicide risk and treatment plans. The SIBAT is used to capture treatment emergent suicidal ideation and behavior(s).

  19. Modified Observer's Assessment of Alertness/Sedation (MOAA/S) Scale Score [ Time Frame: Up to end of the double-blind treatment phase (Day 25) ]
    The MOAA/S will be used to measure treatment-emergent sedation, with correlation to levels of sedation defined by the American Society of Anesthesiologists (ASA) continuum. The MOAA/S scores range from 0=no response to painful stimulus (corresponds to ASA continuum for general anesthesia) to 5=readily responds to name spoken in normal tone (awake; corresponds to ASA continuum for minimal sedation).

  20. Clinician Administered Dissociative States Scale (CADSS) [ Time Frame: Baseline up to end of the double-blind treatment phase (Day 25) ]
    CADSS is an instrument for the measurement of present-state dissociative symptoms and will be administered to assess treatment-emergent dissociative symptoms. CADSS consists of 23 subjective items, divided into 3 components: depersonalization (items 3 to 7, 20, and 23), derealization (items 1, 2, 8 to 13, 16 to 19, and 21) and amnesia (items 14, 15, and 22). The participants responses are coded on a 5-point scale (from 0=not at all to 4=extremely). The total score is sum of the 23 items and range from 0 to 92 - best is 0 and worst is 92.

  21. Arterial Oxygen Saturation (SpO2) [ Time Frame: Up to end of the double-blind treatment phase (Day 25) ]
    Pulse oximetry will be used to measure arterial oxygen saturation (SpO2).On each dosing day, the device will be attached to the finger, toe, or ear, and SpO2 will be monitored and documented from predose to 1.5 hours postdose.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant must meet Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for major depressive disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the Mini International Psychiatric Interview (MINI)
  • Participants 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
  • In the physician's opinion, acute psychiatric hospitalization is clinically warranted due to participant's imminent risk of suicide
  • Participant has a Montgomery Asberg Depression Rating Scale (MADRS) total score of greater than (>) 28 predose on Day 1
  • As part of standard of care treatment, participant agrees to be hospitalized voluntarily for a recommended period of 14 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)

Exclusion Criteria:

  • Participant has a current DSM-5 diagnosis of bipolar (or related disorders), antisocial personality disorder, or obsessive compulsive disorder
  • Participant currently meets DSM-5 criteria for borderline personality disorder. Note: Participant not meeting full DSM-5 criteria for borderline personality disorder but exhibiting recurrent suicidal gestures, threats, or self-mutilating behaviors should also be excluded
  • Participant has a current clinical diagnosis of autism, dementia, or intellectual disability
  • Participant has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with psychotic features
  • Participant meets the DSM-5 severity criteria for moderate or severe substance or alcohol use disorder, (except for nicotine or caffeine), within the 12 months before Screening. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary
  • Participant has a history or current signs and symptoms of liver or renal insufficiency, clinically significant cardiac (including unstable coronary artery disease and congestive heart failure, tachyarrhythmias and recent myocardial infarction) or vascular, pulmonary, gastrointestinal, endocrine (including uncontrolled hyperthyroidism), neurologic (including current or past history of seizures except uncomplicated childhood febrile seizures with no sequelae), hematologic, rheumatologic, or metabolic (including severe dehydration/ hypovolemia) disease
  • Participant has known allergies, hypersensitivity, intolerance or contraindications to esketamine or ketamine or its excipients

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03097133


Contacts
Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com

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Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Additional Information:
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03097133     History of Changes
Other Study ID Numbers: CR108285
2016-003992-23 ( EudraCT Number )
54135419SUI3002 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: March 31, 2017    Key Record Dates
Last Update Posted: September 24, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Disease
Depressive Disorder
Depression
Depressive Disorder, Major
Suicide
Suicidal Ideation
Pathologic Processes
Mood Disorders
Mental Disorders
Behavioral Symptoms
Self-Injurious Behavior
Antidepressive Agents
Psychotropic Drugs