Clinical trial NCT02422186: A Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Participants With Treatment-resistant Depression
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Depressive Disorder, Treatment-Resistant
Keywords: Depressive Disorder, Treatment-Resistant
Esketamine
Oral Antidepressant
Elderly Participants
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-04-21
Enrollment: 139
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Baseline up to Endpoint (Double-blind Induction Phase[Day 28])
measure: 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
timeFrame: Baseline and Endpoint (Double-blind Induction Phase [Day 28])
Secondary outcomes:
measure: Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)
timeFrame: At Endpoint-Double-blind Induction Phase [Day 28]
measure: Percentage of Participants in Remission (MADRS<=12) at Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)
timeFrame: At Endpoint-Double-blind Induction Phase [Day 28]
measure: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis on Ranks
timeFrame: Baseline and Endpoint (Double-blind Induction Phase [Day 28])
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): Health Status Index
timeFrame: Baseline and Endpoint (Double-blind Induction Phase [Day 28])
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): EQ-VAS
timeFrame: Baseline and Endpoint (Double-blind Induction Phase [Day 28])
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) to Endpoint (Double-blind Induction Phase [Day 28]): Sum Score
timeFrame: Baseline and Endpoint (Double-blind Induction Phase [Day 28])
Other outcomes:
Locations:
city: San Diego
country: United States
state: California
city: New Haven
country: United States
state: Connecticut
city: Miami
country: United States
state: Florida
city: Marietta
country: United States
state: Georgia
city: Iowa City
country: United States
state: Iowa
city: Baltimore
country: United States
state: Maryland
city: Watertown
country: United States
state: Massachusetts
city: New York
country: United States
state: New York
city: Staten Island
country: United States
state: New York
city: Cincinnati
country: United States
state: Ohio
city: Allentown
country: United States
state: Pennsylvania
city: Dallas
country: United States
state: Texas
city: Wichita Falls
country: United States
state: Texas
city: Charlottesville
country: United States
state: Virginia
city: Richland
country: United States
state: Washington
city: Aalst
country: Belgium
city: Brugge
country: Belgium
city: Brussel
country: Belgium
city: Hasselt
country: Belgium
city: Heusden-Zolder
country: Belgium
city: Liège
country: Belgium
city: Belo Horizonte
country: Brazil
city: Fortaleza
country: Brazil
city: Rio de Janeiro
country: Brazil
city: Santo André
country: Brazil
city: Sao Jose do Rio Preto
country: Brazil
city: Sao Paulo
country: Brazil
city: São Paulo
country: Brazil
city: Bourgas
country: Bulgaria
city: Kardzhali
country: Bulgaria
city: Sofia
country: Bulgaria
city: Varna
country: Bulgaria
city: Helsinki
country: Finland
city: Kuopio
country: Finland
city: Issy-les-Moulineaux
country: France
city: La Tronche
country: France
city: Nice
country: France
city: Nimes Cedex 9
country: France
city: Paris
country: France
city: Poitiers
country: France
city: Toulon
country: France
city: Toulouse
country: France
city: TOURS cedex 9
country: France
city: Kaunas
country: Lithuania
city: Silute
country: Lithuania
city: Vilnius
country: Lithuania
city: Belchatow
country: Poland
city: Bydgoszcz
country: Poland
city: Gdansk
country: Poland
city: Torun
country: Poland
city: Tuszyn
country: Poland
city: Cape Town
country: South Africa
city: Garsfontein
country: South Africa
city: Pretoria
country: South Africa
city: Badajoz
country: Spain
city: Bilbao
country: Spain
city: Madrid
country: Spain
city: Ourense
country: Spain
city: Sant Boi de Llobregat
country: Spain
city: Torrevieja
country: Spain
city: Zamora
country: Spain
city: Goteborg
country: Sweden
city: Halmstad
country: Sweden
city: Lund
country: Sweden
city: Skövde
country: Sweden
city: Solna
country: Sweden
city: Stockholm
country: Sweden
city: Derbyshire
country: United Kingdom
city: Oxford
country: United Kingdom
city: Preston
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
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.