Efficacy, Safety and Pharmacokinetic Study of Inhaled Esketamine in Treatment-resistant Bipolar Depression

Study Overview
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Brief Summary
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The purpose of the study is to determine the efficacy, safety and pharmacokinetics of inhaled Esketamine in participants with treatment-resistant bipolar depression (TRBD). The study is to determine the efficacy and dose response of three Esketamine doses, compared with placebo.

Detailed Description
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This is a randomized, multiple dose, placebo-controlled, double-blind, multicentre study of Esketamine DPI, inhalation powder delivered via dry powder inhaler (DPI) in participants with TRBD. There are 3 study phases: Screening phase, a two weeks double-blind treatment phase and a 6-week follow-up phase. Participants are to be randomized in 1:1:1:1 ratio to receive placebo or one of the three doses of Esketamine DPI. Participants from each group will receive different dosing sequences, consider as a single dose, corresponding to low, medium, high Esketamine dose or placebo. Participants will undergo one cycle of treatment consisting of four doses of Esketamine DPI or placebo over 14-day period. Participants safety will be monitored throughout the study.

Official Title
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A Multicentre, Double-blind, Randomised, Placebo - Controlled Phase II Study to Assess Efficacy, Safety and Pharmacokinetics of Inhaled Esketamine in Subject With Treatment-resistant Bipolar Depression

Conditions
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Bipolar Depression

Intervention / Treatment
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* Drug: Esketamine DPI - low dose
* Drug: Esketamine DPI - medium dose
* Drug: Esketamine DPI - high dose
* Drug: Placebo DPI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gender: female or male, Age: 18 - 65 years old, inclusive, on the day of Screening, Participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria for depressive episode in Bipolar Disorder (BD) type I or II, without psychotic features, confirmed by the Mini International Neuropsychiatric Interview (MINI), Participant must have in Montgomery-Asberg Depression Rating Scale (MADRS) total score of >= 24 at Screening and predose on Day 1, Participant is treatment resistant in the current episode of depression, defined as having an inadequate response to at least 2 adequate mood stabilizing treatment regimens administered for the sufficient duration and dose and administered in the current episode of depression, Participant in the last mood stabilizing treatment regimen is to be administered at least one of the medication listed in the protocol, Participant's last mood stabilizing treatment regimen is to be without antidepressant drugs from the class: SSRI, SNRI, TCA, MAOI or NaSSA, Participant must be on stable mood stabilizing treatment regimen (listed in the protocol), remain non-responsive to it and continue the treatment from Screening to at least the duration of the double-blind treatment phase, Participant's other drugs taken as a standard treatment for bipolar disorder, but not for depressive episode treatment, are to be allowed and may be continued through the study and it's administration is up to Investigator discretion, Participant agrees to be hospitalized voluntarily for a period of 12 h before first administration and until the end of treatment phase on Day 14, Participant must be medically stable on the basis of clinical laboratory tests, physical examination, vital signs, 12-lead ECG, Participant agrees to blood sample collection for DNA analysis, Participant of childbearing potential willing to use acceptable forms of contraception. Exclusion Criteria: Participant has a current DSM-5 diagnosis, according to MINI, of any other than BD disorder, Participant has a BD with a rapid-cycling course (≥ 4 episodes per year), Participant has in Young Mania Rating Scale (YMRS) total score of greater than 12 at Screening and every other assessment, Participant has suicidal ideation in MADRS 'suicidal thoughts' subscale score greater or equal to 2 and/or in C-SSRS score greater or equal to 4 at Screening and/or has a history of suicidal thoughts within 6 months prior to Screening and/or history of suicidal attempt within 1 year prior to Screening, Participant has a history or current signs and symptoms of chronic obstructive pulmonary disease (COPD), asthma, liver or renal insufficiency, significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, hematologic, neurologic, rheumatologic or metabolic disturbances that are uncontrolled with medication change during last three months before Screening and/or that could influence the present general health condition at the Investigator's discretion, Participant has uncontrolled hypertension, Upper respiratory tract and/or chest infection and/or inflammation within 2 weeks preceding the first administration and during the treatment phase, Participant took part in other clinical trial within 90 days preceding the Screening, Known allergy or hypersensitivity, intolerance or contraindication to Esketamine/ketamine or its derivatives and/or to any study product excipients, Blood drawn within 30 days prior to inclusion to the study, History of drug, alcohol, chemical, sedatives or sleeping medications abuse or dependence (except nicotine or caffeine) within 2 years prior to Screening, Lifetime abuse or dependence on ketamine or phencyclidine, Positive results from pregnancy test for female participants, Lactation in female participants, Positive drug screen (except benzodiazepines evaluation during follow-up) or alcohol breath test.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Esketamine low dose<br>Participants are to receive four doses of Esketamine DPI administered over 14-day period (on Day 1, 4, 8 and 11). | Drug: Esketamine DPI - low dose<br>* Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to low Esketamine dose.<br>|
| Experimental: Esketamine medium dose<br>Participants are to receive four doses of Esketamine DPI administered over 14-day period (on Day 1, 4, 8 and 11). | Drug: Esketamine DPI - medium dose<br>* Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to medium Esketamine dose.<br>|
| Experimental: Esketamine high dose<br>Participants are to receive four doses of Esketamine DPI administered over 14-day period (on Day 1, 4, 8 and 11). | Drug: Esketamine DPI - high dose<br>* Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to high Esketamine dose.<br>|
| Placebo Comparator: Placebo<br>Participants are to receive four doses of Placebo DPI administered over 14-day period (on Day 1, 4, 8 and 11). | Drug: Placebo DPI<br>* Placebo DPI is to be administered via dry powder inhaler.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Day 14 | The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The test consists of 10 items, each scored from 0 (symptoms not present or normal) to 6 (severe or continuous presence of the symptoms). Total score is 60. The higher MADRS total score, the more severe depression. | Day 1 and Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in MADRS total score at each other than Day 14 timepoint | The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The test consists of 10 items, each scored from 0 (symptoms not present or normal) to 6 (severe or continuous presence of the symptoms). Total score is 60. The higher MADRS total score, the more severe depression. | Day 1, 2, 4, 5, 8, 9, 11, 12 and week 3, 4, 5, 6, 7 and 8 | 
| Number of participants with clinical response (>= 50% decrease in MADRS baseline score) | Clinical response is to be defined as greater than or equal to 50 % decrease in MADRS baseline score at Day 14 and every other timepoint. | Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and up to 6 weeks after the treatment phase | 
| Onset of clinical response that was sustained through the end of the 2-week, double-blind, treatment phase |  | Day 1, 2, 4, 5, 8, 9, 11, 12, 14 | 
| Change from baseline in depression severity, measured by Hamilton Depression Rating Scale (HDRS) at every timepoint | HDRS is a questionnaire used to rate the severity of depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss and somatic symptoms.HDRS consists of 17 questions with maximum 4-points scale. The higher HDRS total score, the more severe depression. | Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and week 3, 4, 5, 6, 7 and 8 | 
| Number of participants with clinical remission (MADRS total score <= 10) | Clinical remission, defined as MADRS total score less than or equal to 10. | Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and up to 6 weeks after the treatment phase | 
| Time to relapse | Relapse assessed for responders and remitters and defined when MADRS total score in 2 consecutive assessments after Day 14 exceeds 50% MADRS baseline total score value. | Day 14 and week 3, 4, 5, 6, 7 and 8 | 
| Change from baseline in Clinical Global Impression - Severity (CGI-S) score at Day 14 and every other timepoint | CGI-S scale is a physician-rated scale that is designed to rate the severity of the patient's illness at the time of assessment. It is a 7-point assessment where 1 = normal (not at all ill) and 7 = among the most extremely ill patients. | Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and week 3, 4, 5, 6, 7 and 8 | 
| Change from baseline in Columbia Suicide Severity Rating Scale (C-SSRS) at Day 14 and every other timepoint | C-SSRS is a suicide ideation rating scale created by researchers at Columbia University. | Day 1, 14 and week 5, 8 | 
| Change from baseline in the Clinician Administered Dissociative States Scale (CADSS) at each day of administration | CADSS is a scale designed to assess dissociative symptoms. CADSS consists of 23 questions with 4-points scale, where 1=normal (not at all) and 4=Extremely. The higher CADSS total score, the more severe symptoms. | up to 24 hours following the start of each administration | 
| Change from baseline in the Brief Psychiatric Rating Scale (BPRS) at each day of administration | BPRS is a scale designed to rate psychotomimetic effects. BPRS consists of 18 questions with 7-points scale, from 1 (not present) to 7 (extremaly severe). The higher BPRS total score, the more severe effects. | up to 24 hours following the start of each administration | 
| Severity of manic behaviour as assessed by the Young Mania Rating Scale (YMRS) | Young Mania Rating Scale is a scale to rate manic-like mood elevation.YMRS consists of 11 items. The seven items have 4-points scale and four items have 8-points scale. The higher YMRS total score, the more severe manic symptoms. | Day 0, 3, 7, 10, 14 and week 3, 4, 5, 6, 7, 8 | 
| Potential withdrawal symptoms after Esketamine treatment, as measured by the 20-item Physician Withdrawal Checklist (PWC-20) | PWC-20 is a method to assess discontinuation symptoms. | Day 0, week 3, 4 and 5 | 
| Potential Esketamine effect on cognition as measured by Montreal Cognitive Assessment (MoCA) | MoCA is a screening assessment for detecting cognitive impairment. | Day 0, week 4 and 8 | 
| Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | up to 8 weeks | 
| Esketamine AUC0-24h - area under the plasma concentration - time curve from 0 to 24 h |  | up to 24 hours following the start of first and fourth administration | 
| Esketamine Cmax - maximum plasma concentration |  | up to 24 hours following the start of first and fourth administration | 
| Esketamine AUC0-inf - area under the plasma concentration - time curve from 0 to infinity |  | up to 24 hours following the start of first and fourth administration | 
| Esketamine Kel - terminal elimination rate constant |  | up to 24 hours following the start of first and fourth administration | 
| Esketamine t1/2 - plasma elimination half-life |  | up to 24 hours following the start of first and fourth administration | 
| Esketamine Tmax - time to reach maximum concentration in plasma |  | up to 24 hours following the start of first and fourth administration | 
| Esnorketamine AUC0-24h - area under the plasma concentration - time curve from 0 to 24 h |  | up to 24 hours following the start of first and fourth administration | 
| Esnorketamine Cmax - maximum plasma concentration |  | up to 24 hours following the start of first and fourth administration | 
| Esnorketamine Tmax - time to reach maximum concentration in plasma |  | up to 24 hours following the start of first and fourth administration | 
| Changes between predose and postdose values for each administration in hematology and biochemistry |  | up to 6 weeks | 
| Changes between predose and postdose values for each administration in vital signs (heart rate, blood pressure, respiratory rate) and urinalysis |  | up to 8 weeks | 
| Changes between predose and postdose values for each administration in SpO2 (blood oxygen saturation) |  | up to 2 hours following the start of each administration |