TRANSFORM-3: A Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Participants With Treatment-resistant Depression

Sponsor
Janssen Research & Development, LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT02422186
Collaborator
(none)
139
69
2
23.7
2
0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of switching elderly participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.

Condition or Disease Intervention/Treatment Phase
  • Drug: Esketamine
  • Drug: Placebo
  • Drug: Duloxetine (Oral Antidepressant)
  • Drug: Escitalopram (Oral Antidepressant)
  • Drug: Sertraline (Oral Antidepressant)
  • Drug: Venlafaxine Extended Release (XR) (New Antidepressant)
Phase 3

Detailed Description

This is a randomized, double-blind (neither the researchers nor the participants know what treatment the participant is receiving), active-controlled, multicenter study (more than 1 study site) in elderly participants with TRD to assess the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. The study will consist of 3 phases: Screening/Prospective Observational Phase (4 to 7 weeks), Double-blind induction Phase (4 weeks), Follow up Phase (2 weeks). Participants who rollover into a long-term open-label safety study will not participate in the Follow-up Phase. At the start of the Screening/Prospective observational Phase, participant must have had documented nonresponse to at least one antidepressant treatment (based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire [MGH-ATRQ] criteria) in the current episode of depression, and 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. This antidepressant treatment will be discontinued prior to the double-blind induction Phase. Participants taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (example, zolpidem, zaleplon) during the screening/prospective observational phase can continue these medications. All participants will start with first dose (Day 1 as 28 milligram [mg]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability. In addition, each participant will be assigned to receive 1 of 4 oral antidepressant medications from 2 different classes of antidepressant treatments, a Selective Serotonin Reuptake Inhibitor (SSRI) (escitalopram or sertraline) or a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) [duloxetine or venlafaxine extended release (XR)], initiated on Day 1 and continued through the double-blind induction Phase. Participants will be primarily evaluated for improvement in depressive symptoms as assessed by change in Montgomery Asberg Depression Rating Scale (MADRS) total score at Week 4. Participants' safety will be monitored throughout the study.

Study Design

Study Type:
Interventional
Actual Enrollment :
139 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Subjects With Treatment-resistant Depression
Actual Study Start Date :
Aug 20, 2015
Actual Primary Completion Date :
Aug 10, 2017
Actual Study Completion Date :
Aug 10, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Intranasal Esketamine plus Oral Antidepressant

Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Induction Phase. All participants will start with first dose (Day 1 as 28 milligram [mg]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability. In addition participants will simultaneously initiate a new, open-label oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine extended release [XR]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.

Drug: Esketamine
All participants will start with first dose (Day 1 as 28 milligram [mg]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability.

Drug: Duloxetine (Oral Antidepressant)
Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital -Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).

Drug: Escitalopram (Oral Antidepressant)
Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be given at a dose of 10 mg/day throughout the Double-Blind Induction Phase. This dose (10 mg/day) is the also the minimum therapeutic dose.

Drug: Sertraline (Oral Antidepressant)
Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.

Drug: Venlafaxine Extended Release (XR) (New Antidepressant)
Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.

Active Comparator: Placebo plus Oral Antidepressant

Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a flexible dose regimen in Double-Blind Induction Phase using the same titration as Esketamine. In addition participants will simultaneously initiate a new, open-label oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.

Drug: Placebo
Participants will self-administer matching placebo, intranasally, twice per week for 4-weeks as a flexible dose regimen in the Double-Blind Induction Phase.

Drug: Duloxetine (Oral Antidepressant)
Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital -Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).

Drug: Escitalopram (Oral Antidepressant)
Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be given at a dose of 10 mg/day throughout the Double-Blind Induction Phase. This dose (10 mg/day) is the also the minimum therapeutic dose.

Drug: Sertraline (Oral Antidepressant)
Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.

Drug: Venlafaxine Extended Release (XR) (New Antidepressant)
Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.

Outcome Measures

Primary Outcome Measures

  1. Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis [Baseline up to Endpoint (Double-blind Induction Phase[Day 28])]

    The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items (to evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel [interest level], pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0-60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

  2. Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis [Baseline and Endpoint (Double-blind Induction Phase [Day 28])]

    The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items (to evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel [interest level], pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0-60. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using Last Observation Carried Forward (LOCF) method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.

Secondary Outcome Measures

  1. Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data) [At Endpoint-Double-blind Induction Phase [Day 28]]

    Percentage of participants with greater than or equal to (>=50) percent (%) reduction from baseline are reported. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.

  2. Percentage of Participants in Remission (MADRS<=12) at Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data) [At Endpoint-Double-blind Induction Phase [Day 28]]

    Remission was defined as participants who had a MADRS total score of less than or equal to (=<) 12. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.

  3. Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis on Ranks [Baseline and Endpoint (Double-blind Induction Phase [Day 28])]

    CGI-S provides an overall clinician-determined summary measure of the severity of the participants illness including participants history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participants ability to function. 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 patients. Missing data was imputed using LOCF method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.

  4. Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): Health Status Index [Baseline and Endpoint (Double-blind Induction Phase [Day 28])]

    EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a health status index (HSI). HSI ranges from -0.148 (health state value equal to dead) and 0.949 (full health), is anchored at 0 (dead) and 1 (full health).

  5. Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): EQ-VAS [Baseline and Endpoint (Double-blind Induction Phase [Day 28])]

    EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. 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 (the worst health you can imagine) to 100 (the best health you can imagine).

  6. Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): Sum Score [Baseline and Endpoint (Double-blind Induction Phase [Day 28])]

    EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). HSI ranges from -0.148 (health state value equal to dead) and 0.949 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) *5. Higher score indicates worst health state.

Eligibility Criteria

Criteria

Ages Eligible for Study:
65 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • At the time of signing the informed consent form (ICF), participant must be a man or woman 65 years of age or older

  • At the start of the Screening/prospective observational Phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) [if single-episode 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 the start of the Screening/Prospective observational Phase, participant must have an Inventory of Depressive Symptomatology-Clinician rated (IDS-C30) total score of greater than or equal to (>=) 31

  • At the start of the Screening/Prospective observational Phase, participants must have had nonresponse (less than or equal to 25% improvement) to >=1 but less than or equal to (<=) 8 oral antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented records by medical and pharmacy/prescription records, or a letter from the treating physician, for the current episode of depression

  • Participant must be taking one of the oral antidepressant treatment with nonresponse that is documented on the MGH-ATRQ at the start of the screening/prospective observational phase

  • The participant's current major depressive episode, depression symptom severity (Week 1 MADRS total score greater than or equal to 24 required) and treatment response to antidepressant treatments used in the current depressive episode (retrospectively assessed) must be confirmed for participation in a clinical study based on a Site-Independent Qualification Assessment

  • Participant must be medically stable on the basis of clinical laboratory tests performed in the screening/prospective observational phase

Exclusion Criteria:
  • The participant's depressive symptoms have previously demonstrated nonresponse to: Esketamine or ketamine in the current major depressive episode per clinical judgment, or all of the 4 oral antidepressant treatment options available for the double-blind induction Phase (Duloxetine, Escitalopram, Sertraline, and Venlafaxine extended release [XR]) in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral ECT

  • Participants who has received vagal nerve stimulation (VNS) or who 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 psychosis, bipolar or related disorders (confirmed by the MINI), obsessive compulsive disorder (current episode only), intellectual disability ( intellectual disability [DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319]), 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) and also includes history of suicidal behavior within the past year prior to start of the screening/prospective observational phase

  • Participant has a history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder\

  • Participant has a Mini Mental State Examination (MMSE) < 25 or <22 for those participants with less than an equivalent of high school education

  • Participant has neurodegenerative disorder (eg, Alzheimer's Disease, Vascular dementia, Parkinson's disease with clinical evidence of cognitive impairment) or evidence of mild cognitive impairment (MCI)

  • Participant has a history of uncontrolled hypertension; current or past history of significant pulmonary insufficiency/condition;clinically significant ECG abnormalities; current or past history of seizures; clinically significant cardiovascular disorders including cerebral and cardiac vascular disease

Contacts and Locations

Locations

Site City State Country Postal Code
1 San Diego California United States
2 New Haven Connecticut United States
3 Miami Florida United States
4 Marietta Georgia United States
5 Iowa City Iowa United States
6 Baltimore Maryland United States
7 Watertown Massachusetts United States
8 New York New York United States
9 Staten Island New York United States
10 Cincinnati Ohio United States
11 Allentown Pennsylvania United States
12 Dallas Texas United States
13 Wichita Falls Texas United States
14 Charlottesville Virginia United States
15 Richland Washington United States
16 Aalst Belgium
17 Brugge Belgium
18 Brussel Belgium
19 Hasselt Belgium
20 Heusden-Zolder Belgium
21 Liège Belgium
22 Belo Horizonte Brazil
23 Fortaleza Brazil
24 Rio de Janeiro Brazil
25 Santo André Brazil
26 São José do Rio Preto Brazil
27 São Paulo Brazil
28 Bourgas Bulgaria
29 Kardzhali Bulgaria
30 Sofia Bulgaria
31 Varna Bulgaria
32 Helsinki Finland
33 Kuopio Finland
34 Issy-les-Moulineaux France
35 La Tronche France
36 Nice France
37 Nimes Cedex 9 France
38 Paris France
39 Poitiers France
40 Toulon France
41 Toulouse France
42 TOURS cedex 9 France
43 Kaunas Lithuania
44 Silute Lithuania
45 Vilnius Lithuania
46 Belchatow Poland
47 Bydgoszcz Poland
48 Gdansk Poland
49 Torun Poland
50 Tuszyn Poland
51 Cape Town South Africa
52 Garsfontein South Africa
53 Pretoria South Africa
54 Badajoz Spain
55 Bilbao Spain
56 Madrid Spain
57 Ourense Spain
58 Sant Boi de Llobregat Spain
59 Torrevieja Spain
60 Zamora Spain
61 Goteborg Sweden
62 Halmstad Sweden
63 Lund Sweden
64 Skövde Sweden
65 Solna Sweden
66 Stockholm Sweden
67 Derbyshire United Kingdom
68 Oxford United Kingdom
69 Preston United Kingdom

Sponsors and Collaborators

  • Janssen Research & Development, LLC

Investigators

  • Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT02422186
Other Study ID Numbers:
  • CR107129
  • ESKETINTRD3005
  • 2014-004588-19
First Posted:
Apr 21, 2015
Last Update Posted:
Sep 29, 2021
Last Verified:
Aug 1, 2021

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail Total 139 participants were enrolled, out of which 138 were randomized and 1 participant was excluded due to Good Clinical Practice (GCP) non-compliance.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg plus oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day-Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day-Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day-Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day-Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo plus oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Period Title: Double-blind Induction Phase (4 Weeks)
STARTED 72 66
Full Analysis Set (FAS) 72 65
Safety Analysis Set 72 65
COMPLETED 62 60
NOT COMPLETED 10 6
Period Title: Double-blind Induction Phase (4 Weeks)
STARTED 12 3
COMPLETED 8 3
NOT COMPLETED 4 0

Baseline Characteristics

Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo Total
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Total of all reporting groups
Overall Participants 72 65 137
Age (Count of Participants)
<=18 years
0
0%
0
0%
0
0%
Between 18 and 65 years
0
0%
0
0%
0
0%
>=65 years
72
100%
65
100%
137
100%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
70.6
(4.79)
69.4
(4.15)
70
(4.52)
Sex: Female, Male (Count of Participants)
Female
45
62.5%
40
61.5%
85
62%
Male
27
37.5%
25
38.5%
52
38%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
10
13.9%
5
7.7%
15
10.9%
Not Hispanic or Latino
59
81.9%
59
90.8%
118
86.1%
Unknown or Not Reported
3
4.2%
1
1.5%
4
2.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
0
0%
0
0%
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
0
0%
0
0%
0
0%
White
66
91.7%
64
98.5%
130
94.9%
More than one race
4
5.6%
0
0%
4
2.9%
Unknown or Not Reported
2
2.8%
1
1.5%
3
2.2%
Region of Enrollment (Count of Participants)
Belgium
2
2.8%
4
6.2%
6
4.4%
Brazil
1
1.4%
0
0%
1
0.7%
Bulgaria
3
4.2%
0
0%
3
2.2%
Finland
1
1.4%
1
1.5%
2
1.5%
France
4
5.6%
3
4.6%
7
5.1%
Italy
6
8.3%
3
4.6%
9
6.6%
Lithuania
2
2.8%
0
0%
2
1.5%
Poland
4
5.6%
3
4.6%
7
5.1%
South Africa
2
2.8%
5
7.7%
7
5.1%
Spain
4
5.6%
4
6.2%
8
5.8%
Sweden
8
11.1%
6
9.2%
14
10.2%
United Kingdom
1
1.4%
0
0%
1
0.7%
United States
34
47.2%
36
55.4%
70
51.1%

Outcome Measures

1. Primary Outcome
Title Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis
Description The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items (to evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel [interest level], pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0-60. Higher scores represent a more severe condition. Negative change in score indicates improvement.
Time Frame Baseline up to Endpoint (Double-blind Induction Phase[Day 28])

Outcome Measure Data

Analysis Population Description
The full analysis set (FAS) was defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Overall number of participants analyzed) signifies number of participants who were evaluable for this endpoint.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Measure Participants 63 60
Mean (Standard Deviation) [Units on a scale]
-10.0
(12.74)
-6.3
(8.86)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Intranasal Esketamine Plus Oral Antidepressant (AD), Oral AD Plus Intranasal Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value =0.059
Comments
Method Mixed Model for Repeated Measures
Comments
Method of Estimation Estimation Parameter Difference of Least Square (LS) Means
Estimated Value -3.6
Confidence Interval (2-Sided) 95%
-7.20 to 0.07
Parameter Dispersion Type:
Value:
Estimation Comments
2. Primary Outcome
Title Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis
Description The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items (to evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel [interest level], pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0-60. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using Last Observation Carried Forward (LOCF) method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.
Time Frame Baseline and Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description
The full analysis set was defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Overall number of participants analyzed) signifies number of participants who were evaluable for this endpoint.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Measure Participants 71 64
Mean (Standard Deviation) [Units on a scale]
-9.3
(12.28)
-5.6
(9.11)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Intranasal Esketamine Plus Oral Antidepressant (AD), Oral AD Plus Intranasal Placebo
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value =0.052
Comments
Method ANCOVA
Comments
Method of Estimation Estimation Parameter Least Square (LS) Mean Difference
Estimated Value -3.6
Confidence Interval (2-Sided) 95%
-7.16 to -0.03
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)
Description Percentage of participants with greater than or equal to (>=50) percent (%) reduction from baseline are reported. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.
Time Frame At Endpoint-Double-blind Induction Phase [Day 28]

Outcome Measure Data

Analysis Population Description
The full analysis set was defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Overall number of participants analyzed) signifies number of participants who were evaluable for this endpoint.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Measure Participants 71 64
Number [Percentage of Participants]
23.9
33.2%
12.5
19.2%
4. Secondary Outcome
Title Percentage of Participants in Remission (MADRS<=12) at Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)
Description Remission was defined as participants who had a MADRS total score of less than or equal to (=<) 12. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.
Time Frame At Endpoint-Double-blind Induction Phase [Day 28]

Outcome Measure Data

Analysis Population Description
The full analysis set was defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Overall number of participants analyzed) signifies number of participants who were evaluable for this endpoint.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Measure Participants 71 64
Number [Percentage of Participants]
15.5
21.5%
6.3
9.7%
5. Secondary Outcome
Title Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis on Ranks
Description CGI-S provides an overall clinician-determined summary measure of the severity of the participants illness including participants history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participants ability to function. 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 patients. Missing data was imputed using LOCF method and last post baseline observation during the double-blind induction phase was carried forward as the "End Point" for that phase.
Time Frame Baseline and Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description
The full analysis set was defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Overall number of participants analyzed) signifies number of participants who were evaluable for this endpoint.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Measure Participants 71 65
Median (Full Range) [Units on a scale]
-1.0
0.0
6. Secondary Outcome
Title Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): Health Status Index
Description EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a health status index (HSI). HSI ranges from -0.148 (health state value equal to dead) and 0.949 (full health), is anchored at 0 (dead) and 1 (full health).
Time Frame Baseline and Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description
The full analysis set was defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Overall number of participants analyzed) signifies number of participants who were evaluable for this endpoint.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Measure Participants 70 64
Mean (Standard Deviation) [Units on a scale]
0.081
(0.2624)
0.026
(0.2235)
7. Secondary Outcome
Title Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): EQ-VAS
Description EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. 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 (the worst health you can imagine) to 100 (the best health you can imagine).
Time Frame Baseline and Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description
The full analysis set was defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Overall number of participants analyzed) signifies number of participants who were evaluable for this endpoint.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Measure Participants 70 64
Mean (Standard Deviation) [Units on a scale]
6.2
(22.78)
4.4
(20.60)
8. Secondary Outcome
Title Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): Sum Score
Description EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). HSI ranges from -0.148 (health state value equal to dead) and 0.949 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) *5. Higher score indicates worst health state.
Time Frame Baseline and Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description
The full analysis set was defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Overall number of participants analyzed) signifies number of participants who were evaluable for this endpoint.
Arm/Group Title Intranasal Esketamine Plus Oral Antidepressant (AD) Oral AD Plus Intranasal Placebo
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
Measure Participants 70 64
Mean (Standard Deviation) [Units on a scale]
-6.6
(20.53)
-1.6
(16.21)

Adverse Events

Time Frame Up to 13 weeks
Adverse Event Reporting Description The population analyzed included safety analysis set- all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase and follow-up analysis set- all participants who entered the follow-up phase.
Arm/Group Title DB Phase: Intranasal Esketamine + Oral AD (4 Weeks) DB Phase: Oral AD + Intranasal Placebo (4 Weeks) Follow-up Phase: Intranasal Esketamine + Oral AD (2 Weeks) Follow-up Phase: Oral AD + Intranasal Placebo (2 Weeks)
Arm/Group Description Participants self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in DB induction phase. Also, participants initiated titration schedule for open-label oral AD with one of following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with MDT at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine extended release (XR) (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (Day 1, 4, 8, 11, 15, 18, 22, 25) in double-blind (DB) induction phase. Also, participants initiated titration schedule for open-label oral antidepressant (AD) with one of the following: [Duloxetine (30 mg/day- Week 1, 60 mg/day- Weeks 2, 3 and 4 with minimum dose for tolerability (MDT) at 30 mg/day); Escitalopram (10 mg/day- Weeks 1-4 with MDT at 5 mg/day); Sertraline (25 mg/day- Week 1, 50 mg/day- Week 2, 100 mg/day- Week 3, 150 mg/day- Week 4 with MDT of 25 mg/Day) or Venlafaxine XR (37.5 mg/day- Week 1, 75 mg/day- Week 2, 150 mg/day- Weeks 3, 4 with MDT of 75 mg/day)] in DB induction phase. Participants who withdrew early, before end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal esketamine 28 mg or 56 mg or 84 mg+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks. Participants who withdrew early, before the end of DB induction phase, or chose not to participate in ESKETINTRD3004 (NCT02497287) long-term safety and efficacy study, and had received at least 1 dose of intranasal placebo+ oral AD in DB induction phase were continued to follow-up phase for 2 weeks.
All Cause Mortality
DB Phase: Intranasal Esketamine + Oral AD (4 Weeks) DB Phase: Oral AD + Intranasal Placebo (4 Weeks) Follow-up Phase: Intranasal Esketamine + Oral AD (2 Weeks) Follow-up Phase: Oral AD + Intranasal Placebo (2 Weeks)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/72 (0%) 0/65 (0%) 0/12 (0%) 0/3 (0%)
Serious Adverse Events
DB Phase: Intranasal Esketamine + Oral AD (4 Weeks) DB Phase: Oral AD + Intranasal Placebo (4 Weeks) Follow-up Phase: Intranasal Esketamine + Oral AD (2 Weeks) Follow-up Phase: Oral AD + Intranasal Placebo (2 Weeks)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 3/72 (4.2%) 2/65 (3.1%) 0/12 (0%) 0/3 (0%)
General disorders
Gait Disturbance 0/72 (0%) 1/65 (1.5%) 0/12 (0%) 0/3 (0%)
Injury, poisoning and procedural complications
Hip Fracture 1/72 (1.4%) 0/65 (0%) 0/12 (0%) 0/3 (0%)
Investigations
Blood Pressure Increased 1/72 (1.4%) 0/65 (0%) 0/12 (0%) 0/3 (0%)
Nervous system disorders
Dizziness 0/72 (0%) 1/65 (1.5%) 0/12 (0%) 0/3 (0%)
Psychiatric disorders
Anxiety Disorder 1/72 (1.4%) 0/65 (0%) 0/12 (0%) 0/3 (0%)
Feeling of Despair 0/72 (0%) 1/65 (1.5%) 0/12 (0%) 0/3 (0%)
Other (Not Including Serious) Adverse Events
DB Phase: Intranasal Esketamine + Oral AD (4 Weeks) DB Phase: Oral AD + Intranasal Placebo (4 Weeks) Follow-up Phase: Intranasal Esketamine + Oral AD (2 Weeks) Follow-up Phase: Oral AD + Intranasal Placebo (2 Weeks)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 44/72 (61.1%) 22/65 (33.8%) 1/12 (8.3%) 1/3 (33.3%)
Ear and labyrinth disorders
Vertigo 8/72 (11.1%) 2/65 (3.1%) 0/12 (0%) 0/3 (0%)
Eye disorders
Eye Pruritus 0/72 (0%) 1/65 (1.5%) 0/12 (0%) 1/3 (33.3%)
Gastrointestinal disorders
Constipation 0/72 (0%) 0/65 (0%) 1/12 (8.3%) 0/3 (0%)
Hypoaesthesia Oral 5/72 (6.9%) 0/65 (0%) 0/12 (0%) 0/3 (0%)
Nausea 13/72 (18.1%) 3/65 (4.6%) 0/12 (0%) 0/3 (0%)
Vomiting 5/72 (6.9%) 1/65 (1.5%) 0/12 (0%) 1/3 (33.3%)
General disorders
Fatigue 9/72 (12.5%) 5/65 (7.7%) 0/12 (0%) 0/3 (0%)
Infections and infestations
Urinary Tract Infection 6/72 (8.3%) 1/65 (1.5%) 0/12 (0%) 0/3 (0%)
Investigations
Blood Pressure Increased 9/72 (12.5%) 3/65 (4.6%) 0/12 (0%) 0/3 (0%)
Nervous system disorders
Dizziness 15/72 (20.8%) 4/65 (6.2%) 0/12 (0%) 0/3 (0%)
Dysgeusia 4/72 (5.6%) 3/65 (4.6%) 0/12 (0%) 0/3 (0%)
Headache 9/72 (12.5%) 2/65 (3.1%) 0/12 (0%) 0/3 (0%)
Hypoaesthesia 4/72 (5.6%) 1/65 (1.5%) 0/12 (0%) 0/3 (0%)
Paraesthesia 4/72 (5.6%) 2/65 (3.1%) 0/12 (0%) 0/3 (0%)
Psychiatric disorders
Anxiety 2/72 (2.8%) 5/65 (7.7%) 0/12 (0%) 0/3 (0%)
Dissociation 9/72 (12.5%) 1/65 (1.5%) 0/12 (0%) 0/3 (0%)
Dysphoria 4/72 (5.6%) 0/65 (0%) 0/12 (0%) 0/3 (0%)
Insomnia 4/72 (5.6%) 3/65 (4.6%) 0/12 (0%) 0/3 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will be withheld such publication for up to an additional 60 days.

Results Point of Contact

Name/Title Senior Director
Organization Janssen Research & Development, LLC
Phone 844-434-4210
Email ClinicalTrialDisclosure@its.jnj.com
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT02422186
Other Study ID Numbers:
  • CR107129
  • ESKETINTRD3005
  • 2014-004588-19
First Posted:
Apr 21, 2015
Last Update Posted:
Sep 29, 2021
Last Verified:
Aug 1, 2021