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

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ClinicalTrials.gov Identifier: NCT03434041
Recruitment Status : Recruiting
First Posted : February 15, 2018
Last Update Posted : April 8, 2019
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Tracking Information
First Submitted Date  ICMJE February 9, 2018
First Posted Date  ICMJE February 15, 2018
Last Update Posted Date April 8, 2019
Actual Study Start Date  ICMJE May 25, 2018
Estimated Primary Completion Date April 28, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 9, 2018)
Change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at End of Double-blind Treatment Phase (Week 4) [ Time Frame: Baseline and End of Double-Blind Treatment Phase (Week 4) ]
The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale 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. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03434041 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 9, 2018)
  • Percentage of Participants with Onset of Clinical Response [ Time Frame: Day 2 through End of Double-Blind Treatment Phase (Week 4) ]
    Onset of Clinical Response is defined as greater than or equal to (>=) 50 percent (%) improvement in MADRS total score by the day after taking the first dose [that is, Day 2] of double blind intranasal medication, that is sustained through the end of the 4-week double-blind treatment phase. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale 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. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
  • Change from Baseline in Sheehan Disability Scale (SDS) Total Score at End of Double-blind Treatment Phase (Week 4) [ Time Frame: Baseline and End of Double-blind Treatment Phase (Week 4) ]
    The SDS is a participant-reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30 where a higher score indicates greater impairment.
  • Percentage of Responders [ Time Frame: At End of Double-blind Treatment Phase (Week 4) ]
    Percentage of responders (defined as >=50% reduction from baseline in MADRS total score) will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale 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. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
  • Percentage of Participants in Remission [ Time Frame: At End of Double-blind Treatment Phase (Week 4) ]
    Percentage of participants in remission (defined as MADRS total score less than or equal to [<=]12) will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale 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. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
  • Percentage of Participants with Sustained Remission [ Time Frame: Up to 8 weeks ]
    Percentage of participants with sustained remission (defined as MADRS total score <=12) will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale 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. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
  • Change from Baseline in Clinical Global Impression Severity (CGI-S) scale at End of Double-blind Treatment Phase (Week 4) [ Time Frame: Baseline and End of Double-Blind Treatment Phase (Week 4) ]
    The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill participants. Higher score indicates worsening. The CGI-S permits a global evaluation of the participant's condition at a given time.
  • Change from Baseline in Generalized Anxiety Disorder 7-item (GAD-7) Scale at End of Double-blind Treatment Phase (Week 4) [ Time Frame: Baseline and End of Double-blind Treatment Phase (Week 4) ]
    The GAD-7 is a participant-reported brief and validated measure of overall anxiety. Each item is rated on a 4-point scale (0=not at all; 1=several days; 2=more than half the days; 3=nearly every day). Item responses are summed to yield a total score (range of 0 to 21), with higher scores indicating more anxiety.
  • Change from Baseline in Participant-Reported Health-Related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Valuation Index Score at End of Double-blind Treatment Phase (Week 4) [ Time Frame: Baseline and End of Double-blind Treatment Phase (Week 4) ]
    The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. The EQ-5D-5L descriptive system comprises following 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1: no problem, Level 2: slight problems, Level 3: moderate problems, Level 4: severe problems, and Level 5: extreme problems). The participant selects an answer for each of 5 dimensions considering response that best matches his or her health "today". The descriptive system can be represented as a health state.
  • Change from Baseline in Participant-Reported Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Visual Analog Scale (VAS) at End of Double-blind Treatment Phase (Week 4) [ Time Frame: Baseline and End of Double-blind Treatment Phase (Week 4) ]
    The EQ-VAS self-rating scale records respondent's own assessment of his or her overall health status at time of completion, on a scale of 0 (worst imaginable health) to 100 (best imaginable health).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression
Official Title  ICMJE A Randomized, Double-blind, Multicenter Active-controlled Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression
Brief Summary The purpose of this study is to evaluate the efficacy of switching adult participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (56 milligram [mg] or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms. Efficacy will be assessed by the change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score from Day 1 (before randomization) to the end of the 4-week double-blind treatment phase.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Depressive Disorder, Treatment-Resistant
Intervention  ICMJE
  • Drug: Esketamine 56 mg
    Participants will self-administer 56 mg of esketamine as intranasal spray.
  • Drug: Esketamine 84 mg
    Participants will self-administer 84 mg of esketamine as intranasal spray.
  • Drug: Placebo
    Participants will self-administer matching placebo as intranasal spray.
  • Drug: Duloxetine (Oral Antidepressant)
    Duloxetine can be selected as the oral antidepressant medication based on investigator's discretion. The minimum therapeutic dose is 60 milligram per day (mg/day).
  • Drug: Escitalopram (Oral Antidepressant)
    Escitalopram can be selected as the oral antidepressant medication based on investigator's discretion. Escitalopram will be started at a dose of 10 mg/day and up-titrated to a maximum dose of 20 mg/day.
  • Drug: Sertraline (Oral Antidepressant)
    Sertraline can be selected as the oral antidepressant medication based on investigator's discretion. Sertraline will be started at a dose of 50 mg/day and up-titrated to a maximum dose of 200 mg/day.
  • Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)
    Venlafaxine XR can be selected as the oral antidepressant medication based on investigator's discretion. Venlafaxine XR will be started at a dose of 75 mg/day and up-titrated to a maximum dose of 225 mg/day.
Study Arms  ICMJE
  • Experimental: Intranasal Esketamine plus Oral Antidepressant
    Eligible participants will self-administer esketamine (56 mg or 84 mg) intranasally twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Treatment Phase. All participants will start at a dose of 56 milligram (mg) on Day 1. The dose may be increased to 84 mg or maintained at 56 mg per investigator's discretion. In addition, participants will simultaneously initiate a new, open-label 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 that will be continued for the duration of the 4-week Double-Blind Treatment Phase.
    Interventions:
    • Drug: Esketamine 56 mg
    • Drug: Esketamine 84 mg
    • Drug: Duloxetine (Oral Antidepressant)
    • Drug: Escitalopram (Oral Antidepressant)
    • Drug: Sertraline (Oral Antidepressant)
    • Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)
  • Active Comparator: Oral Antidepressant plus Intranasal Placebo
    Eligible Participants will self-administer matching placebo intranasally twice per week for 4 weeks in Double-Blind Treatment Phase. In addition, participants will simultaneously initiate a new, open-label oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Treatment Phase.
    Interventions:
    • Drug: Placebo
    • Drug: Duloxetine (Oral Antidepressant)
    • Drug: Escitalopram (Oral Antidepressant)
    • Drug: Sertraline (Oral Antidepressant)
    • Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 9, 2018)
234
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 30, 2021
Estimated Primary Completion Date April 28, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) diagnostic criteria for recurrent major depressive disorder (MDD) or single-episode MDD (if single-episode MDD, the duration must be greater than or equal to [>=] 2 years), without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (mental status questionnaire) (MINI)
  • At the start of the screening/prospective observational phase, participant must have had non-response (less than or equal to [<=] 25 percent [%] improvement) to >=1 but <=5 (if current episode is greater than (>) 2 years or not definable, upper limit is applicable to only the last 2 years) oral antidepressant treatments in the current episode of depression, assessed using the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and confirmed by documented records (for example, medical/ pharmacy/prescription records or letter from a treating physician). In addition, the participant is taking a different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose
  • The participant's current major depressive episode, depression symptom severity (Week 1 Montgomery-Asberg Depression Rating Scale [MADRS] total score >=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment
  • Participant must be medically stable on the basis of physical examination, medical history, vital signs (including blood pressure), pulse oximetry, and 12-lead electrocardiogram (ECG) performed in the screening/prospective observational phase. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, they must be consistent with the underlying illness in the study population. This determination must be recorded in the participant's source documents and initialed or signed by the investigator
  • Participant must be medically stable on the basis of clinical laboratory tests performed in the screening/prospective observational phase. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed or signed by the investigator

Exclusion Criteria:

  • The participant's depressive symptoms have previously demonstrated non-response to:

    1. Esketamine or ketamine in the current major depressive episode per clinical judgment, or
    2. All of the oral antidepressant treatment options available in the respective country for the double-blind phase (that is, duloxetine, escitalopram, sertraline, and venlafaxine XR) in the current major depressive episode (based on MGH-ATRQ), or
    3. An adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT
  • Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression
  • Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the MINI), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 315.8, 317, 318.0, 318.1, 318.2 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/prospective observational phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or a history of suicidal behavior within the past year prior to the start of the screening/prospective observational phase. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the double-blind treatment phase should be excluded
  • Participant 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 the start of screening/prospective observational phase a. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com
Listed Location Countries  ICMJE China,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03434041
Other Study ID Numbers  ICMJE CR108418
ESKETINTRD3006 ( Other Identifier: Janssen Research & Development, LLC )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Janssen Research & Development, LLC
Study Sponsor  ICMJE Janssen Research & Development, LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
PRS Account Janssen Research & Development, LLC
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP