Clinical trial NCT02418585: A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression
Official title: A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Treatment-resistant Depression
Keywords: Treatment-resistant Depression
Esketamine
Placebo
Oral Antidepressant
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-04-16
Enrollment: 236
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) subjects 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.

Detailed description: This is a randomized, double-blind (neither the researchers nor the subjects know what treatment the subject is receiving), active-controlled, multicenter study (more than 1 study site) in subjects 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 (4-7 weeks), Double-blind Induction Phase (4-weeks), Follow-up Phase (24-weeks). Subjects who rollover into a long-term maintenance study will not participate in the Follow-up Phase. The antidepressant treatment, as well as any other ongoing medications being taken for depression at screening (including adjunctive/ augmentation therapies), will continue unchanged, at the same dosage, from the start of Week 1 through the end of Week 4 of the screening/prospective observational phase. Subjects' safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than \[\>\]18) to 64 years of age, inclusive
* 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 (\>=) 34
* At the start of the screening/prospective observational phase, participant must have had non-response (greater than or equal to \[\<=25\] percent \[%\] improvement) to ≥1 but less than or equal to (\<=) 5 (if current episode is \>2 years, 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 documented by medical history and pharmacy/prescription records, for the current episode of depression. 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 MADRS total score \>=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment

Exclusion Criteria:

* Participants who have previously demonstrated nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (ie, 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/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 psychosis, bipolar or related disorders (confirmed by the MINI), comorbid obsessive compulsive disorder, intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), 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)
* Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria

Primary outcomes:
measure: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 in the Double-blind Induction Phase- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis
timeFrame: Baseline up to Day 28 of Double-blind Induction Phase
measure: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis
timeFrame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
Secondary outcomes:
measure: Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8
timeFrame: Day 2 up to Day 28 and Day 8 up to Day 28
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
timeFrame: Baseline up to Day 28 of Double-blind Induction phase
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
timeFrame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
measure: Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
timeFrame: Baseline up to Day 28 of Double-blind Induction phase
measure: Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
timeFrame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
measure: Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28])
timeFrame: At Endpoint (Double-blind Induction Phase [Day 28])
measure: Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])
timeFrame: At Endpoint (Double-blind Induction Phase [Day 28])
measure: Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28)
timeFrame: At Day 28 [end of Double-blind Induction Phase]
measure: Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28)
timeFrame: At Day 28 (End of Double-blind Induction Phase)
measure: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
timeFrame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
measure: Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
timeFrame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
measure: Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28)
timeFrame: Baseline up to End of Double-blind Induction Phase (Day 28)
measure: Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28)
timeFrame: Baseline up to End of Double-blind Induction Phase (Day 28)
measure: Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28)
timeFrame: Baseline up to End of Double-blind Induction Phase (Day 28)
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Orange
country: United States
state: California
city: San Rafael
country: United States
state: California
city: Maitland
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Gaithersburg
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Philadelphia
country: United States
state: Pennsylvania
city: Dallas
country: United States
state: Texas
city: Klecany
country: Czechia
city: Litomerice
country: Czechia
city: Plzen
country: Czechia
city: Prague
country: Czechia
city: Praha 10
country: Czechia
city: Praha 6
country: Czechia
city: Prerov
country: Czechia
city: Berlin
country: Germany
city: Cham
country: Germany
city: Dresden
country: Germany
city: Gelsenkirchen
country: Germany
city: Halle (Saale)
country: Germany
city: Leipzig
country: Germany
city: Mainz
country: Germany
city: Mannheim
country: Germany
city: Mittweida
country: Germany
city: Pfaffenhofen
country: Germany
city: Prien
country: Germany
city: Tübingen
country: Germany
city: Bialystok
country: Poland
city: Bydgoszcz
country: Poland
city: Gdansk
country: Poland
city: Krakow
country: Poland
city: Myslowice
country: Poland
city: Pruszkow
country: Poland
city: Torun
country: Poland
city: Tuszyn
country: Poland
city: Warszawa
country: Poland
city: Alcorcón
country: Spain
city: Barcelona
country: Spain
city: Córdoba
country: Spain
city: Malaga
country: Spain
city: Mostoles
country: Spain
city: Murcia
country: Spain
city: Palma
country: Spain
city: Pamplona
country: Spain
city: Sabadell
country: Spain
city: Salamanca
country: Spain
city: Santa Coloma De Gramanet
country: Spain
city: Vitoria Gasteiz
country: Spain
city: Vitoria-Gasteiz
country: Spain
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Jha MK, Williamson DJ, Magharehabed G, Turkoz I, Daly EJ, Trivedi MH. Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability. J Affect Disord. 2023 Jan 15;321:153-160. doi: 10.1016/j.jad.2022.10.020. Epub 2022 Oct 20.
citation: Floden L, Hudgens S, Jamieson C, Popova V, Drevets WC, Cooper K, Singh J. Evaluation of Individual Items of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) in Adults with Treatment-Resistant Depression Treated with Esketamine Nasal Spray Combined with a New Oral Antidepressant. CNS Drugs. 2022 Jun;36(6):649-658. doi: 10.1007/s40263-022-00916-2. Epub 2022 Apr 20.
citation: Chen G, Chen L, Zhang Y, Li X, Lane R, Lim P, Daly EJ, Furey ML, Fedgchin M, Popova V, Singh JB, Drevets WC. Relationship Between Dissociation and Antidepressant Effects of Esketamine Nasal Spray in Patients With Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2022 Apr 19;25(4):269-279. doi: 10.1093/ijnp/pyab084.
citation: Jones RR, Freeman MP, Kornstein SG, Cooper K, Daly EJ, Canuso CM, Nicholson S. Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials. Arch Womens Ment Health. 2022 Apr;25(2):313-326. doi: 10.1007/s00737-021-01185-6. Epub 2022 Jan 1.
citation: Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021 Sep 12;9(9):CD011612. doi: 10.1002/14651858.CD011612.pub3.
citation: Daly EJ, Turkoz I, Salvadore G, Fedgchin M, Ionescu DF, Starr HL, Borentain S, Trivedi MH, Thase ME, Singh JB. The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder. Depress Anxiety. 2021 Nov;38(11):1120-1130. doi: 10.1002/da.23193. Epub 2021 Jul 22.
citation: Turkoz I, Daly E, Singh J, Lin X, Tymofyeyev Y, Williamson D, Salvadore G, Nash AI, Macaluso M, Wilkinson ST, Nelson JC. Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies. J Clin Psychiatry. 2021 Jul 20;82(4):20m13800. doi: 10.4088/JCP.20m13800.
citation: Doty RL, Popova V, Wylie C, Fedgchin M, Daly E, Janik A, Ochs-Ross R, Lane R, Lim P, Cooper K, Melkote R, Jamieson C, Singh J, Drevets WC. Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies. CNS Drugs. 2021 Jul;35(7):781-794. doi: 10.1007/s40263-021-00826-9. Epub 2021 Jul 7.
citation: Perez-Ruixo C, Rossenu S, Zannikos P, Nandy P, Singh J, Drevets WC, Perez-Ruixo JJ. Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Clin Pharmacokinet. 2021 Apr;60(4):501-516. doi: 10.1007/s40262-020-00953-4. Epub 2020 Oct 31.
citation: Katz EG, Hough D, Doherty T, Lane R, Singh J, Levitan B. Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression. Clin Pharmacol Ther. 2021 Feb;109(2):536-546. doi: 10.1002/cpt.2024. Epub 2020 Oct 13.
citation: Saad Z, Hibar D, Fedgchin M, Popova V, Furey ML, Singh JB, Kolb H, Drevets WC, Chen G. Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials. Int J Neuropsychopharmacol. 2020 Dec 3;23(9):549-558. doi: 10.1093/ijnp/pyaa030.
citation: Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, Mazzucco C, Hough D, Thase ME, Shelton RC, Molero P, Vieta E, Bajbouj M, Manji H, Drevets WC, Singh JB. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019 Jun 1;176(6):428-438. doi: 10.1176/appi.ajp.2019.19020172. Epub 2019 May 21.