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

Bipolar Depression Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03965871
• Other study ID #: 03KET2018
• Status: Completed
• Phase: Phase 2
• Start date: March 28, 2019
• Est. completion date: February 19, 2021

Study information

• Verified date: March 2021
• Source: Celon Pharma SA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: February 19, 2021
• Est. primary completion date: January 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Bipolar Depression
• Bipolar Disorder
• Depression
• Depressive Disorder

Intervention

Drug:
• Esketamine DPI - low dose
Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to low Esketamine dose.
• Esketamine DPI - medium dose
Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to medium Esketamine dose.
• Esketamine DPI - high dose
Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to high Esketamine dose.
• Placebo DPI
Placebo DPI is to be administered via dry powder inhaler.

Locations

Country	Name	City	State
Poland	Wojewodzki Szpital im. Jana Pawla II	Belchatow
Poland	Wojewodzki Szpital dla Nerwowo i Psychicznie Chorych	Boleslawiec
Poland	Samodzielny Publiczny Psychiatryczny Zaklad Opieki Zdrowotnej	Choroszcz
Poland	Szpital Miejski	Elblag
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Gornoslaskie Centrum Medyczne	Katowice
Poland	Specjalistyczny Psychiatryczny Zespol Opieki Zdrowotnej	Lodz
Poland	Pabianickie Centrum Medyczne	Pabianice
Poland	Mazowieckie Specjalistyczne Centrum Zdrowia	Pruszkow
Poland	Wojewodzki Szpital dla Nerwowo i Psychicznie Chorych	Swiecie
Poland	Mazowiecki Szpital i Centrum Diagnostyczne Allenort	Warsaw
Poland	Uniwersytecki Szpital Kliniczny	Wroclaw

Sponsors (2)

Lead Sponsor	Collaborator
Celon Pharma SA	National Center for Research and Development, Poland

Country where clinical trial is conducted

Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)		up to 8 weeks
Secondary	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
Secondary	Esketamine Cmax - maximum plasma concentration		up to 24 hours following the start of first and fourth administration
Secondary	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
Secondary	Esketamine Kel - terminal elimination rate constant		up to 24 hours following the start of first and fourth administration
Secondary	Esketamine t1/2 - plasma elimination half-life		up to 24 hours following the start of first and fourth administration
Secondary	Esketamine Tmax - time to reach maximum concentration in plasma		up to 24 hours following the start of first and fourth administration
Secondary	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
Secondary	Esnorketamine Cmax - maximum plasma concentration		up to 24 hours following the start of first and fourth administration
Secondary	Esnorketamine Tmax - time to reach maximum concentration in plasma		up to 24 hours following the start of first and fourth administration
Secondary	Changes between predose and postdose values for each administration in hematology and biochemistry		up to 6 weeks
Secondary	Changes between predose and postdose values for each administration in vital signs (heart rate, blood pressure, respiratory rate) and urinalysis		up to 8 weeks
Secondary	Changes between predose and postdose values for each administration in SpO2 (blood oxygen saturation)		up to 2 hours following the start of each administration