A multicentre, double-blind, randomised, placebo - controlled phase II study to assess efficacy, safety and pharmacokinetics of inhaled Esketamine in subjects with treatment-resistant bipolar depression.

INTERVENTION: Product Code: PG061 Pharmaceutical Form: Inhalation powder INN or Proposed INN: ESKETAMINE HYDROCHLORIDE CAS Number: 33643‐47‐9 Current Sponsor code: CZ06 Other descriptive name: ESKETAMINE HYDROCHLORIDE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 4‐ Pharmaceutical form of the placebo: Inhalation powder Route of administration of the placebo: Inhalation use CONDITION: Eketamine, ketamine’s enantiomer, is designed for use in tretment resistant depression, both unipolar and bipolar. Many publications have demonstrated the effect of ketamine/esketamine (mainly administered intravenously) in treatment resistant depression, with effect seen after an hour after administration. The therapeutic effect after single administration can last up to one week. In addition, it was shown that ketamine can reduce the intensity of suicidal thoughts. Therapeutic area: Psychiatry and Psychology [F] ‐ Mental Disorders [F03] PRIMARY OUTCOME: Main Objective: to determine the efficacy and dose response of Esketamine, administered by inhalation from Dry Powder Inhaler, compared with placebo, in subjects with treatment resistant bipolar depression, as assessed by change from baseline in the Montgomery‐Åsberg Depression Rating Scale (MADRS) total score at Day 14 of treatment phase. Primary end point(s): Change from baseline (day 1, predose) in MADRS total score at Day 14 (3 days post last dose) Secondary Objective: ‐To evaluate effect of inhaled Esketamine in TRBD subjects, compared to placebo; ‐To evaluate durability of Esketamine’s antidepressant response in TRBD subjects defined by ‘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. Time to relapse is to be computed from Day 14 to the first of two assessments exceeding 50% MADRS baseline total score value),; ‐To investigate safety and tolerability of inhaled Esketamine in TRBD subjects, ; ‐To evaluate the pharmacokinetic properties of inhaled Esketamine (and Esnorketamine) in TRBD subjects.; Exploratory objectives: ; ‐to investigate correlation of Val66Met BDNF polymorphism with Esketamine antidepressive efficacy in subjects with TRBD.; ‐to investigate levels of inflammatory cytokines as Esketamine’s efficacy predictive biomarkers.; ‐to measure Esketamine’s metabolites concentrations – hydroxynorketamines. Timepoint(s) of evaluation of this end point: at the end of treatment phase on Day 14 SECONDARY OUTCOME: Secondary end point(s): Change from baseline (Day 1, predose) in MADRS total score at each other than Day 14 timepoint,; • Clinical response, defined as greater than or equal to 50 % decrease in MADRS baseline score (day 1, predose) at Day 14 and every other timepoint. Subject is to be considered as a responder while having clinical response on Day 14,; • Onset of clinical response (= 50 % decrease in baseline MADRS score) that was sustained through the end of the 2‐week, double‐blind, treatment phase,; • Change from baseline (Day 1, predose), in depression severity, measured by Hamilton Depression Rating Scale (HDRS) at every timepoint,; • Clinical remission, defined as MADRS total score less than or equal to 10. Subject is to be considered as a remitter while having clinical remission on Day 14,; • 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. Time to relapse is to be computed from Day 14 to the first of two assessments exceeding 50% MADRS baseline total score value),; • Change from baseline (Day 1, predose) in Clinical Global Impression ‐ Severity (CGI‐S) score at Day 14 and every other timepoint,; • Change from baseline (Day 1, predose) in Columbia Suicide Severity Rating Scale (C‐SSRS) at Day 14 and every other timepoint,; • Change from baseline (Day 1, predose) in the Clinician Administered Dissociative States Scale (CADSS) at each day when IMP is administered (predose, 45 min, 2 h, 4 h and 24 h following the start of dosing),; • Change from baseline (Day 1, predose) in the Brief Psychiatric Rating Scale (BPRS) at each day when IMP is administered (predose, 45 min, 2 h, 4 h and 24 h following the start of dosing),; • Changes between predose and postdose values for each IMP administration in heart rate, blood pressure, respiratory rate, blood oxygen saturation (SpO2) at each timepoint, and clinically significant results in hematology, biochemistry and urinalysis parameters at each timepoint,; • Severity of manic behaviour as assessed by the Young Mania Rating Scale (YMRS),; • Potential withdrawal symptoms after Esketamine treatment, as measured by the 20‐item Physician Withdrawal Checklist (PWC‐20),; • Potential Esketamine effect on cognition as measured by Montreal Cognitive Assessment (MoCA),; • Number of subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs),; • Esketamine pharmacokinetic variables on Day 1 and Day 11:; AUC0‐24h, Cmax, Tmax, AUC0‐inf, , Kel, and t1/2,; • Esnorketamine pharmacokinetic variables on Day 1 and Day 11: AUC0‐24h, Cmax, Tmax.; Exploratory endpoints:; • Correlation of Val66Met BDNF polymorphism with Esketamine antidepressive efficacy in subjects with TRBD,; • Levels of inflammatory cytokines after Esketamine administration,; • Esketamine’s metabolites– hydroxynorketamines concentrations after Esketamine administration.; Timepoint(s) of evaluation of this end point: during the double‐blind treatment phase and during follow‐up phase INCLUSION CRITERIA: 1. Gender: female or male, 2. Age: 18 – 65 years old, inclusive, on the day of Screening, 3. Subject must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM‐5) diagnostic criteria for depressive episode in Bipolar Disorder type I or II, without psychotic features, based upon clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI), 4. Subject must have in Montgomery Åsberg Depression Rating Scale (MADRS) total score of greater than or equal to (=) 24 at Screening and predose on Day 1, 5. Subject 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. Sufficient duration and dose are understood as a treatment regimen dose in the therapeutic range (for lithium/valproate treatment a