A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression
TRANSFORM-1
A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression
3 other identifiers
interventional
346
9 countries
90
Brief Summary
The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) participants 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Aug 2015
Typical duration for phase_3
90 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 10, 2015
CompletedFirst Posted
Study publicly available on registry
April 15, 2015
CompletedStudy Start
First participant enrolled
August 10, 2015
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 20, 2018
CompletedStudy Completion
Last participant's last visit for all outcomes
February 20, 2018
CompletedResults Posted
Study results publicly available
April 18, 2019
CompletedApril 29, 2025
April 1, 2025
2.5 years
April 10, 2015
March 28, 2019
April 25, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis
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.
Baseline up to Day 28 of Double-blind Induction Phase
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
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 Last Observation Carried Forward (LOCF) method and last post baseline observation during double-blind induction phase was carried forward as "End Point" for that phase.
Baseline up to Double-blind Endpoint (Day 28)
Secondary Outcomes (14)
Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8
Day 2 up to Day 28 and Day 8 up to Day 28
Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
Baseline up to Day 28 of Double-blind Induction phase
Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
Baseline up to Double-blind Endpoint (Day 28)
Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
Baseline up to Day 28 of Double-blind Induction phase
Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
Baseline up to Double-blind Endpoint (Day 28)
- +9 more secondary outcomes
Study Arms (3)
Intranasal Esketamine 84mg plus Oral Antidepressant
EXPERIMENTALAs part of an initial titration, participants will self-administer 56 milligrams (mg) of esketamine intranasally on Day 1, and then 84 mg from Day 4 onwards, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Esketamine 56 mg plus Oral Antidepressant
EXPERIMENTALStarting from Day 1, participants will self-administer 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Placebo plus Oral Antidepressant
ACTIVE COMPARATORParticipants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (i.e, duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Interventions
Participants will self-administer either 84 mg or 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase.
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase.
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).
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 titrated up to a dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.
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 will be titrated up to a dose of 200 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.
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 will be titrated up to a dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.
Eligibility Criteria
You may qualify if:
- 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, participants must have had non-response (less 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 taken at adequate dosage and for adequate duration, as 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.
- 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
You may not qualify if:
- 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 (i.e, 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 psychotic features bipolar or related disorders (confirmed by the MINI), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, 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)
- Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (90)
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Birmingham, Alabama, United States
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Little Rock, Arkansas, United States
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Garden Grove, California, United States
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Orange, California, United States
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San Diego, California, United States
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San Marcos, California, United States
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San Rafael, California, United States
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Bradenton, Florida, United States
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Miami, Florida, United States
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Orlando, Florida, United States
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Chicago, Illinois, United States
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Hoffman Estates, Illinois, United States
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Maywood, Illinois, United States
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Schaumburg, Illinois, United States
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Wichita, Kansas, United States
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Gaithersburg, Maryland, United States
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Boston, Massachusetts, United States
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Quincy, Massachusetts, United States
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Watertown, Massachusetts, United States
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Worcester, Massachusetts, United States
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Minneapolis, Minnesota, United States
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O'Fallon, Missouri, United States
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Saint Charles, Missouri, United States
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Omaha, Nebraska, United States
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New York, New York, United States
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Durham, North Carolina, United States
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Dayton, Ohio, United States
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Oklahoma City, Oklahoma, United States
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Media, Pennsylvania, United States
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Philadelphia, Pennsylvania, United States
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Lincoln, Rhode Island, United States
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Austin, Texas, United States
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Dallas, Texas, United States
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Houston, Texas, United States
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Woodstock, Vermont, United States
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Bothell, Washington, United States
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Middleton, Wisconsin, United States
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Aalst, Belgium
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Bruges, Belgium
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Brussels, Belgium
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Ghent, Belgium
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Hasselt, Belgium
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Heusden-Zolder, Belgium
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Liège, Belgium
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Spa, Belgium
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Yvoir, Belgium
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Belo Horizonte, Brazil
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Curitiba, Brazil
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Fortaleza, Brazil
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Passo Fundo, Brazil
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Porto Alegre, Brazil
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Rio de Janeiro, Brazil
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Santo André, Brazil
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Calgary, Alberta, Canada
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Vancouver, British Columbia, Canada
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Kingston, Ontario, Canada
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Ottawa, Ontario, Canada
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Toronto, Ontario, Canada
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Montreal, Quebec, Canada
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Pärnu, Estonia
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Tallinn, Estonia
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Tartu, Estonia
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Besançon, France
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Clermont-Ferrand, France
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Douai, France
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Issy-les-Moulineaux, France
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La Tronche, France
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Lille, France
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Limoges, France
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Montpellier, France
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Nantes, France
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Neuilly-sur-Marne, France
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Nîmes, France
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Paris, France
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Poitiers, France
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Toulon, France
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Tours, France
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Budapest, Hungary
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Vác, Hungary
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Guadalajara, Mexico
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León, Mexico
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Mazatlán, Mexico
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Mexico City, Mexico
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Monterrey, Mexico
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San Luis Potosí City, Mexico
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Bratislava, Slovakia
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Liptovský Mikuláš, Slovakia
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Rimavská Sobota, Slovakia
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Rožňava, Slovakia
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Svidník, Slovakia
Related Publications (12)
Kern Sliwa J, Naranjo RR Jr, Turkoz I, Petrillo MP, Cabrera P, Trivedi M. Effects of esketamine nasal spray on depressive symptom severity in adults with treatment-resistant depression and associations between the Montgomery-Asberg Depression Rating Scale and the 9-item Patient Health Questionnaire. CNS Spectr. 2024 Jun;29(3):176-186. doi: 10.1017/S1092852924000105. Epub 2024 Apr 1.
PMID: 38557430DERIVEDTurkoz I, Nelson JC, Wilkinson ST, Borentain S, Macaluso M, Trivedi MH, Williamson D, Sheehan JJ, Salvadore G, Singh J, Daly E. Predictors of response and remission in patients with treatment-resistant depression: A post hoc pooled analysis of two acute trials of esketamine nasal spray. Psychiatry Res. 2023 May;323:115165. doi: 10.1016/j.psychres.2023.115165. Epub 2023 Mar 16.
PMID: 37019044DERIVEDJha 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.
PMID: 36273682DERIVEDChen 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.
PMID: 35022754DERIVEDJones 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.
PMID: 34973081DERIVEDDean 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.
PMID: 34510411DERIVEDTurkoz 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.
PMID: 34288609DERIVEDDoty 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.
PMID: 34235612DERIVEDPerez-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.
PMID: 33128208DERIVEDKatz 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.
PMID: 32860422DERIVEDSaad 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.
PMID: 32367114DERIVEDFedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, Vitagliano D, Blier P, Fava M, Liebowitz M, Ravindran A, Gaillard R, Ameele HVD, Preskorn S, Manji H, Hough D, Drevets WC, Singh JB. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019 Oct 1;22(10):616-630. doi: 10.1093/ijnp/pyz039.
PMID: 31290965DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Limitations and Caveats
Transient, dissociative effects of esketamine are difficult to blind, site staff who observed treatment sessions could have been biased. To ensure unbiased efficacy evaluations, independent, remote, blinded MADRS raters assessed treatment response.
Results Point of Contact
- Title
- Senior Director
- Organization
- Janssen Research & Development, LLC
Study Officials
- STUDY DIRECTOR
Janssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 10, 2015
First Posted
April 15, 2015
Study Start
August 10, 2015
Primary Completion
February 20, 2018
Study Completion
February 20, 2018
Last Updated
April 29, 2025
Results First Posted
April 18, 2019
Record last verified: 2025-04