Clinical trial NCT03965871: Efficacy, Safety and Pharmacokinetic Study of Inhaled Esketamine in Treatment-resistant Bipolar Depression
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bipolar Depression
Lead sponsor: Celon Pharma SA
Sponsor class: INDUSTRY
Collaborators: name: National Center for Research and Development, Poland
First posted: 2019-05-29
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Gender: female or male,
2. Age: 18 - 65 years old, inclusive, on the day of Screening,
3. 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),
4. Participant must have in Montgomery-Asberg Depression Rating Scale (MADRS) total score of \>= 24 at Screening and predose on Day 1,
5. 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,
6. Participant in the last mood stabilizing treatment regimen is to be administered at least one of the medication listed in the protocol,
7. Participant's last mood stabilizing treatment regimen is to be without antidepressant drugs from the class: SSRI, SNRI, TCA, MAOI or NaSSA,
8. 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,
9. 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,
10. 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,
11. Participant must be medically stable on the basis of clinical laboratory tests, physical examination, vital signs, 12-lead ECG,
12. Participant agrees to blood sample collection for DNA analysis,
13. Participant of childbearing potential willing to use acceptable forms of contraception.

Exclusion Criteria:

1. Participant has a current DSM-5 diagnosis, according to MINI, of any other than BD disorder,
2. Participant has a BD with a rapid-cycling course (≥ 4 episodes per year),
3. Participant has in Young Mania Rating Scale (YMRS) total score of greater than 12 at Screening and every other assessment,
4. 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,
5. 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,
6. Participant has uncontrolled hypertension,
7. Upper respiratory tract and/or chest infection and/or inflammation within 2 weeks preceding the first administration and during the treatment phase,
8. Participant took part in other clinical trial within 90 days preceding the Screening,
9. Known allergy or hypersensitivity, intolerance or contraindication to Esketamine/ketamine or its derivatives and/or to any study product excipients,
10. Blood drawn within 30 days prior to inclusion to the study,
11. History of drug, alcohol, chemical, sedatives or sleeping medications abuse or dependence (except nicotine or caffeine) within 2 years prior to Screening,
12. Lifetime abuse or dependence on ketamine or phencyclidine,
13. Positive results from pregnancy test for female participants,
14. Lactation in female participants,
15. Positive drug screen (except benzodiazepines evaluation during follow-up) or alcohol breath test.

Primary outcomes:
measure: Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Day 14
timeFrame: Day 1 and Day 14
Secondary outcomes:
measure: Change from baseline in MADRS total score at each other than Day 14 timepoint
timeFrame: Day 1, 2, 4, 5, 8, 9, 11, 12 and week 3, 4, 5, 6, 7 and 8
measure: Number of participants with clinical response (>= 50% decrease in MADRS baseline score)
timeFrame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and up to 6 weeks after the treatment phase
measure: Onset of clinical response that was sustained through the end of the 2-week, double-blind, treatment phase
timeFrame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14
measure: Change from baseline in depression severity, measured by Hamilton Depression Rating Scale (HDRS) at every timepoint
timeFrame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and week 3, 4, 5, 6, 7 and 8
measure: Number of participants with clinical remission (MADRS total score <= 10)
timeFrame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and up to 6 weeks after the treatment phase
measure: Time to relapse
timeFrame: Day 14 and week 3, 4, 5, 6, 7 and 8
measure: Change from baseline in Clinical Global Impression - Severity (CGI-S) score at Day 14 and every other timepoint
timeFrame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and week 3, 4, 5, 6, 7 and 8
measure: Change from baseline in Columbia Suicide Severity Rating Scale (C-SSRS) at Day 14 and every other timepoint
timeFrame: Day 1, 14 and week 5, 8
measure: Change from baseline in the Clinician Administered Dissociative States Scale (CADSS) at each day of administration
timeFrame: up to 24 hours following the start of each administration
measure: Change from baseline in the Brief Psychiatric Rating Scale (BPRS) at each day of administration
timeFrame: up to 24 hours following the start of each administration
measure: Severity of manic behaviour as assessed by the Young Mania Rating Scale (YMRS)
timeFrame: Day 0, 3, 7, 10, 14 and week 3, 4, 5, 6, 7, 8
measure: Potential withdrawal symptoms after Esketamine treatment, as measured by the 20-item Physician Withdrawal Checklist (PWC-20)
timeFrame: Day 0, week 3, 4 and 5
measure: Potential Esketamine effect on cognition as measured by Montreal Cognitive Assessment (MoCA)
timeFrame: Day 0, week 4 and 8
measure: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: up to 8 weeks
measure: Esketamine AUC0-24h - area under the plasma concentration - time curve from 0 to 24 h
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Esketamine Cmax - maximum plasma concentration
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Esketamine AUC0-inf - area under the plasma concentration - time curve from 0 to infinity
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Esketamine Kel - terminal elimination rate constant
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Esketamine t1/2 - plasma elimination half-life
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Esketamine Tmax - time to reach maximum concentration in plasma
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Esnorketamine AUC0-24h - area under the plasma concentration - time curve from 0 to 24 h
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Esnorketamine Cmax - maximum plasma concentration
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Esnorketamine Tmax - time to reach maximum concentration in plasma
timeFrame: up to 24 hours following the start of first and fourth administration
measure: Changes between predose and postdose values for each administration in hematology and biochemistry
timeFrame: up to 6 weeks
measure: Changes between predose and postdose values for each administration in vital signs (heart rate, blood pressure, respiratory rate) and urinalysis
timeFrame: up to 8 weeks
measure: Changes between predose and postdose values for each administration in SpO2 (blood oxygen saturation)
timeFrame: up to 2 hours following the start of each administration
Other outcomes:
Locations:
city: Belchatow
country: Poland
facility: Wojewodzki Szpital im. Jana Pawła II
city: Boleslawiec
country: Poland
facility: Wojewodzki Szpital dla Nerwowo i Psychicznie Chorych
city: Choroszcz
country: Poland
facility: Samodzielny Publiczny Psychiatryczny Zaklad Opieki Zdrowotnej
city: Elblag
country: Poland
facility: Szpital Miejski
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Katowice
country: Poland
facility: Gornoslaskie Centrum Medyczne
city: Lodz
country: Poland
facility: Specjalistyczny Psychiatryczny Zespol Opieki Zdrowotnej
city: Pabianice
country: Poland
facility: Pabianickie Centrum Medyczne
city: Pruszkow
country: Poland
facility: Mazowieckie Specjalistyczne Centrum Zdrowia
city: Swiecie
country: Poland
facility: Wojewodzki Szpital dla Nerwowo i Psychicznie Chorych
city: Warsaw
country: Poland
facility: Mazowiecki Szpital i Centrum Diagnostyczne Allenort
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny
Study officials:
References:
citation: Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021 Sep 12;9(9):CD011612. doi: 10.1002/14651858.CD011612.pub3.