Clinical trial NCT03434041: A Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression
Official title: A Randomized, Double-blind, Multicenter Active-controlled Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Depressive Disorder, Treatment-Resistant
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2018-02-15
Enrollment: 252
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 evaluate the efficacy of switching adult participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (56 milligram \[mg\] or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms. Efficacy will be assessed by the change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score from Day 1 (before randomization) to the end of the 4-week double-blind treatment phase.


Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

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

  1. Esketamine or ketamine in the current major depressive episode per clinical judgment, or
  2. All of the oral antidepressant treatment options available in the respective country for the double-blind phase (that is, duloxetine, escitalopram, sertraline, and venlafaxine XR) in the current major depressive episode (based on MGH-ATRQ), or
  3. An adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT
* Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression
* Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the MINI), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 315.8, 317, 318.0, 318.1, 318.2 and 319), autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
* Participant has homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening/prospective observational phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or a history of suicidal behavior within the past year prior to the start of the screening/prospective observational phase. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the double-blind treatment phase should be excluded
* Participant has a history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the start of screening/prospective observational phase a. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary

Primary outcomes:
measure: Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score to the End of Double-blind Treatment Phase (Day 28)
timeFrame: Baseline up to end of the double-blind treatment phase (Day 28)
Secondary outcomes:
measure: Change From Baseline in Depressive Symptoms as Measured by the MADRS Total Score to 24 Hours Post First Dose (Day 2)
timeFrame: Baseline (Day 1: predose) to 24 hours post first dose (Day 2)
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score to the End of Double-blind Treatment Phase (Day 28)
timeFrame: Baseline up to end of the double-blind treatment phase (Day 28)
measure: Percentage of Participants With Onset of Clinical Response
timeFrame: Day 2 up to Day 28
measure: Percentage of Responders at the End of Double-blind Treatment Phase (Day 28)
timeFrame: Day 28
measure: Percentage of Participants in Remission at the End of Double-blind Treatment Phase (Day 28)
timeFrame: Day 28
measure: Percentage of Participants With Sustained Remission
timeFrame: Up to Day 28
measure: Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Score up to the Endpoint (Double-blind Treatment Phase [Day 28])
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
measure: Change From Baseline in Generalized Anxiety Disorder 7-item (GAD-7) Scale Score up to the Endpoint (Double-blind Treatment Phase [Day 28])
timeFrame: Baseline up to Endpoint (double-blind treatment phase [Day 28])
measure: Change From Baseline in Participant-Reported Health-Related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score up to the Endpoint (Double-blind Treatment Phase [Day 28]): Health Status Index
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
measure: Change From Baseline in Participant-Reported Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score up to the Endpoint (Double-blind Treatment Phase [Day 28]): Visual Analogue Scale (VAS)
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
measure: Change From Baseline in Participant-Reported Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to the Endpoint (Double-blind Treatment Phase [Day 28]): Sum Score
timeFrame: Baseline up to Double-blind Endpoint (Day 28)
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Shreveport
country: United States
facility: Biomedical Research Foundation of Northwest Louisiana
state: Louisiana
city: Gaithersburg
country: United States
facility: CBH Health
state: Maryland
city: Watertown
country: United States
facility: Adams Clinical
state: Massachusetts
city: New York
country: United States
facility: The Medical Research Network, LLC
state: New York
city: Oklahoma City
country: United States
facility: IPS Research Company
state: Oklahoma
city: Beijing
country: China
facility: Beijing Anding Hospital of Capital Medical University
city: Beijing
country: China
facility: Beijing HuiLong Guan Hospital
city: Beijing
country: China
facility: Peking University Sixth Hospital
city: Changsha
country: China
facility: The Second People's Hospital of Hunan Province / Brian Hospital of Hunan Province
city: Changsha
country: China
facility: The second Xiangya Hospital of Central South University
city: Chengdu
country: China
facility: West China Hospital Sichuan University
city: Chongqing
country: China
facility: Chongqing Mental Health Center
city: Guangzhou
country: China
facility: the 3rd Affiliated Hospital,Sun Yansen University
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital
city: Hangzhou
country: China
facility: Hangzhou Seventh People's Hospital
city: Hangzhou
country: China
facility: First Hospital, Zhejiang University Medical College
city: Hangzhou
country: China
facility: The Second Affiliated Hospital of Zhejiang University
city: Hu Zhou
country: China
facility: Huzhou third people's Hospital
city: Kunming City
country: China
facility: First Affiliated Hospital of Kunming Medical Unversity
city: Nanjing
country: China
facility: Nanjing Brain Hospital Affilicated to Nanjing Medical University
city: Shijiazhuang
country: China
facility: The First Hospital of Hebei Medical University
city: Tianjin
country: China
facility: Tianjin Anding Hospital
city: Urumqi
country: China
facility: Urumqi fourth Hospital
city: Urumqi
country: China
facility: The first affiliated hospital of Xinjiang medical university
city: Wuhan
country: China
facility: Renmin Hospital of Wuhan University
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xian Jiaotong University
city: Xi'an
country: China
facility: Xi'an Mental Health Center
city: Xia Men
country: China
facility: Xiamen Xianyue Hospital
city: Zheng Zhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References: