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

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

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.

Study Overview

• Status: Completed
• Conditions: Bipolar Depression
• Intervention / Treatment: Drug: Esketamine DPI - low dose; Drug: Esketamine DPI - medium dose; Drug: Esketamine DPI - high dose; Drug: Placebo DPI

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.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 2

Contacts and Locations

Study Locations

• Poland
  • Belchatow, Poland, 97-400
    • Wojewodzki Szpital im. Jana Pawła II
  • Boleslawiec, Poland, 59-700
    • Wojewódzki Szpital dla Nerwowo i Psychicznie Chorych
  • Choroszcz, Poland, 16-070
    • Samodzielny Publiczny Psychiatryczny Zaklad Opieki Zdrowotnej
  • Elblag, Poland, 82-300
    • Szpital Miejski
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Katowice, Poland, 40-635
    • Gornoslaskie Centrum Medyczne
  • Lodz, Poland, 91-229
    • Specjalistyczny Psychiatryczny Zespol Opieki Zdrowotnej
  • Pabianice, Poland, 95-200
    • Pabianickie Centrum Medyczne
  • Pruszkow, Poland, 05-802
    • Mazowieckie Specjalistyczne Centrum Zdrowia
  • Swiecie, Poland, 86-100
    • Wojewódzki Szpital dla Nerwowo i Psychicznie Chorych
  • Warsaw, Poland, 03-185
    • Mazowiecki Szpital i Centrum Diagnostyczne Allenort
  • Wroclaw, Poland, 50-556
    • Uniwersytecki Szpital Kliniczny

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Celon Pharma SA
• Collaborators: National Center for Research and Development, Poland

Publications and helpful links

General Publications

• 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:CD011612. doi: 10.1002/14651858.CD011612.pub3. Review.

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2019
• Primary Completion (Actual): January 3, 2021
• Study Completion (Actual): February 19, 2021

Study Registration Dates

• First Submitted: May 21, 2019
• First Submitted That Met QC Criteria: May 26, 2019
• First Posted (Actual): May 29, 2019

Study Record Updates

• Last Update Posted (Actual): March 19, 2021
• Last Update Submitted That Met QC Criteria: March 18, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Depression; Depressive Disorder; Bipolar Disorder; Psychotropic Drugs; Antidepressive Agents; Esketamine
• Other Study ID Numbers: 03KET2018

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No