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

March 18, 2021 updated by: Celon Pharma SA

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
88

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

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
        • Górnośląskie 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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Day 14
Time Frame: Day 1 and 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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change from baseline in MADRS total score at each other than Day 14 timepoint
Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12 and week 3, 4, 5, 6, 7 and 8
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)
Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and up to 6 weeks after the treatment phase
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
Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14
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
Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and week 3, 4, 5, 6, 7 and 8
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)
Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and up to 6 weeks after the treatment phase
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
Time Frame: Day 14 and week 3, 4, 5, 6, 7 and 8
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
Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and week 3, 4, 5, 6, 7 and 8
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
Time Frame: Day 1, 14 and week 5, 8
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
Time Frame: up to 24 hours following the start of each 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
Time Frame: up to 24 hours following the start of each 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)
Time Frame: Day 0, 3, 7, 10, 14 and week 3, 4, 5, 6, 7, 8
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)
Time Frame: Day 0, week 3, 4 and 5
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)
Time Frame: Day 0, week 4 and 8
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)
Time Frame: up to 8 weeks
up to 8 weeks
Esketamine AUC0-24h - area under the plasma concentration - time curve from 0 to 24 h
Time Frame: up to 24 hours following the start of first and fourth administration
up to 24 hours following the start of first and fourth administration
Esketamine Cmax - maximum plasma concentration
Time Frame: up to 24 hours following the start of first and fourth administration
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
Time Frame: up to 24 hours following the start of first and fourth administration
up to 24 hours following the start of first and fourth administration
Esketamine Kel - terminal elimination rate constant
Time Frame: up to 24 hours following the start of first and fourth administration
up to 24 hours following the start of first and fourth administration
Esketamine t1/2 - plasma elimination half-life
Time Frame: up to 24 hours following the start of first and fourth administration
up to 24 hours following the start of first and fourth administration
Esketamine Tmax - time to reach maximum concentration in plasma
Time Frame: up to 24 hours following the start of first and fourth administration
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
Time Frame: up to 24 hours following the start of first and fourth administration
up to 24 hours following the start of first and fourth administration
Esnorketamine Cmax - maximum plasma concentration
Time Frame: up to 24 hours following the start of first and fourth administration
up to 24 hours following the start of first and fourth administration
Esnorketamine Tmax - time to reach maximum concentration in plasma
Time Frame: up to 24 hours following the start of first and fourth administration
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
Time Frame: up to 6 weeks
up to 6 weeks
Changes between predose and postdose values for each administration in vital signs (heart rate, blood pressure, respiratory rate) and urinalysis
Time Frame: up to 8 weeks
up to 8 weeks
Changes between predose and postdose values for each administration in SpO2 (blood oxygen saturation)
Time Frame: up to 2 hours following the start of each administration
up to 2 hours following the start of each administration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Celon Pharma SA

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Center for Research and Development, Poland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 28, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 3, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 19, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 21, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 26, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 29, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 19, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 18, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

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