A Study to Assess Feasibility of Using Clinician-directed and Digital Application Supported Cognitive Behavior Therapy (CBT) in Conjunction With Esketamine in Participants With Treatment-resistant Depression

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to explore feasibility of combining clinician-directed cognitive behavioral therapy (CBT) supplemented with the Mindset app with esketamine therapy in participants with Treatment-resistant Depression.

Official Title
-----------------
Assessment of Feasibility of Using Clinician-Directed Cognitive Behavior Therapy Supplemented by a Digital Application in Conjunction With Esketamine (SPRAVATO®) in Participants With Treatment-Resistant Depression

Conditions
-----------------
Depression

Intervention / Treatment
-----------------
* Drug: Esketamine
* Behavioral: Cognitive Behavioral Therapy (CBT)
* Drug: Antidepressant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Medically stable on the basis of physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at screening. Any abnormalities must be consistent with the underlying illness in the study population and this determination must be recorded in the participant's source documents and initialed by the investigator Participant must meet the Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) or recurrent MDD, without psychotic features, based upon clinical assessment confirmed by the Mini International Neuropsychiatric Interview (MINI) Participant must have had nonresponse to greater than or equal to (>=) 2 different oral antidepressant treatments of adequate dose and duration in the current episode of depression Participant must be currently taking an oral antidepressant. Participant must be comfortable with self-administration of nasal spray medication and be able to follow the nasal spray administration instructions provided Exclusion Criteria: Participant's depressive symptoms have previously demonstrated nonresponse to 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 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 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 the screening phase. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary Participant has any anatomical or medical condition that, per the investigator's clinical judgment based on assessment, may impede delivery or absorption of nasal spray study drug Participant has known allergies, hypersensitivity, intolerance, or contraindications to esketamine/ketamine and/or its excipients

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Esketamine<br>Participants will receive esketamine nasal spray (Dose 1 or Dose 2) twice weekly for 4 weeks (Induction Phase), followed by once a week dose (Dose 1 or Dose 2) for 8 weeks (Maintenance Phase), in conjunction with an oral antidepressant. Clinician-directed cognitive behavioral therapy (CBT) supplemented with the Mindset app will be administered by a clinician following esketamine dosing once the participants is considered ready to engage in therapy, based on the clinician judgement of CBT readiness. | Drug: Esketamine<br>* Esketamine will be self-administered as nasal spray.<br>* Other names: Non-Investigational Medicinal Product/Auxiliary Medicinal Product (NIMP/AxMP);Behavioral: Cognitive Behavioral Therapy (CBT)<br>* Clinician-directed CBT supplemented by the Mindset app will be administered.<br>Drug: Antidepressant<br>* Antidepressant will be administered orally.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| System Usability Scale (SUS) Scores (Participants) | The SUS provides a reliable tool for measuring the usability of a wide variety of products and services, including hardware, software, mobile devices, websites, and applications. It consists of a 10-item questionnaire with five response options for respondents; from strongly agree to strongly disagree. | Week 13 | 
| Net Promoter Scale Scores (Participants) | Net promoter score is a market research measure that asks respondents to rate the likelihood that they would recommend a company, product, or a service to a friend or colleague. Responses are on a rating on a scale of 0 (not at all likely) to 10 (extremely likely). | Week 13 | 
| Exit Survey | Exit survey is a survey including ratings regarding participant impression of features of the Mindset app. | Week 13 | 
| Time Spent on Mindset App | Time spent on Mindset app will be reported for participants. | From Week 2 up to Week 13 | 
| Number of Times Mindset App Used | Number of times the Mindset app is used will be reported. | From Week 2 up to Week 13 | 
| Pattern of Mindset App Used | Pattern of Mindset app usage will be reported. | From Week 2 up to Week 13 | 
| CBT Therapist Assessment of Completion of Action Plan | Assessment of completion of action plan will be done by CBT therapists through rating on a 5-point likert scale of the participant's progress. | From Week 2 up to Week 13 | 
| Participant Interviews | Optional qualitative feedback from study participants (participant's interviews) on the usefulness of the Mindset in conjunction with esketamine will be reported. | Week 20 | 
| SUS Scores (CBT Therapists) | The SUS provides a reliable tool for measuring the usability of a wide variety of products and services, including hardware, software, mobile devices, websites, and applications. It consists of a 10-item questionnaire with five response options for respondents; from strongly agree to strongly disagree. | Up to 14 months (at the end of study) | 
| Net Promoter Scale Scores (CBT Therapists) | Net promoter score is a market research measure that asks respondents to rate the likelihood that they would recommend a company, product, or a service to a friend or colleague. Responses are on a rating on a scale of 0 (not at all likely) to 10 (extremely likely). | Up to 14 months (at the end of study) | 
| Frequency of Use of Clinician Dashboard Used | Frequency of use of clinician dashboard will be reported. | From Week 2 up to Week 13 | 
| Clinician Feedback | Qualitative feedback on clinician dashboard and participant use of the mindset app in conjunction with esketamine (clinician feedback) will be reported. | Up to 14 months | 
| Percentage of Participants Able to Engage in CBT | Percentage of participants able to engage in CBT on the day of dosing for each week of the study and overall will be reported. | From Week 2 up to Week 13 | 
| Timing of CBT Readiness after Dosing | Timing of CBT readiness after dosing will be reported. Determination of readiness will be based on clinician judgement of CBT readiness to engage in CBT based on alertness and ability to concentrate after dosing. | From Week 2 up to Week 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Observer's Assessment of Alertness/Sedation (MOAA/S) Scale Score | The MOAA/S will be used to measure treatment-emergent sedation with correlation to levels of sedation defined by the American Society of Anesthesiologists (ASA) continuum. The MOAA/S scores range from 0=no response to painful stimulus (corresponds to ASA continuum for general anesthesia) to 5=readily responds to name spoken in normal tone (awake; corresponds to ASA continuum for minimal sedation). | Pre-dose, 40 minutes and 90 minutes post-dose up to Week 4 | 
| Clinician Administered Dissociative States Scale (CADSS) Score | The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. The CADSS consists of 23 subjective items, divided into 3 components: depersonalization (Items 3 to 7, 20, and 23), derealization (Items 1, 2, 8 to 13, 16 to 19, and 21) and amnesia (Items 14, 15, and 22). Participant's responses are coded on a 5-point scale (0=not at all through to 4=extremely). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition | Pre-dose, 40 minutes and 90 minutes post-dose up to Week 4 | 
| Number of Participants with Treatment-emergent Adverse Events (TEAEs) | Number of participants with TEAEs will be reported. An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs are defined as AEs with onset or worsening on or after date of first dose of study treatment | From Week 2 up to Week 13 | 
| Number of Participants with Abnormalities in Vital Signs | Number of participants with abnormalities in vital signs (pulse/heart rate, blood pressure, and body temperature) will be reported. | From Week 2 up to Week 13 | 
| Columbia Suicide Severity Rating (C-SSRS) Score | C-SSRS is semi structured clinician-administered questionnaire designed to solicit the occurrence, severity, and frequency of suicide-related ideation and behaviors. The maximum score assigned for each participant will also be summarized into one of three categories: no suicidal ideation or behavior (0), suicidal ideation (1-5), suicidal behavior (6-10). Total score ranges from 1 to 10. Higher scores indicate greater severity. | Up to Week 13 | 
| Clinical Global Assessment of Discharge Readiness (CGADR) Score | The CGADR will be used to measure the participant's current clinical status and is the clinician's assessment of the readiness to be discharged from the study site. The clinician will answer Yes or No to the question Is the participant considered ready to be discharged based on their overall clinical status (example, sedation, blood pressure, and other adverse events)? | From Week 2 up to Week 13 |