Maintenance Ketamine Infusions for Treatment-Resistant Bipolar Depression (KET-BD-Sustain)
Primary Purpose
Bipolar Disorder, Bipolar Depression, Bipolar I Disorder
Status
Recruiting
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Ketamine Hydrochloride
Sponsored by
About this trial
This is an interventional treatment trial for Bipolar Disorder
Eligibility Criteria
Inclusion Criteria:
- Provide written, voluntary informed consent prior to study enrollment. Substitute decision makers will not be allowed to consent to study on a potential patient's behalf.
- Male or female between the age of 21 to 65, inclusive.
- Meets DSM-5 criteria for Bipolar I or II Disorder, currently experiencing a Major Depressive Episode without psychotic features. Diagnosis confirmed by study psychiatrist at the start of the parent KET-BD randomized clinical trial (RCT).
- Participant in the KET-BD RCT 4a. Participants in the ketamine arm of the KET-BD RCT must have experienced an antidepressant response (i.e. change in MADRS score ≥ 50% at day 14 compared to baseline or Clinical Global Impression-Improvement (CGI-I) = 2 'much improved' or 1 'very much improved') or experienced clinical remission of symptoms (i.e., MADRS score < 12 on day 14) 4b. Participants in the midazolam arm of the KET-BD RCT must present as moderately to severely depressed (MADRS >21) on days 14 and 28 of the parent RCT and must be responders or remitters following four flexibly dosed infusions over 2 weeks.
- Current depressive episode has inadequate response to two or more adequate first-line treatment trials for bipolar depression, as per the 2018 CANMAT Bipolar Disorder Guidelines. First line treatment trials include the use of lithium, valproate, carbamazepine, lamotrigine and/or any antipsychotic medication. Adequate medications confirmed at the start of the parent KET-BD RCT.
- Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month, including a therapeutic dose of a mood stabilizer.
Exclusion Criteria:
- Currently exhibiting symptoms of mania, hypomania, or mixed state bipolar, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
- Current symptoms of psychosis or a substance use disorder within the past 3 months. History of psychotic features during a mood episode will not be excluded.
- History of neurological disorders (including, but not limited to, uncontrolled seizure disorder, history of stroke within past 12 months, major head injuries, aneurysmal vascular disease [including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels], arteriovenous malformation, or intracerebral hemorrhage)
- Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder)
- Lifetime history of ketamine use disorder
- Presence of active suicidality, requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months.
- Presence of a contraindication to ketamine, including a drug allergy, uncontrolled hypertension (baseline systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg), low or labile blood pressure, myocardial infarction within past 12 months, cardiac arrhythmia, moderate to severe hepatic impairment (i.e., Child-Pugh score of B or C), moderate or severe renal impairment (glomerular filtration rate (GFR) < 45 milliliters/min), heart failure, or coronary artery disease
- Pregnant or breastfeeding women or women who intend to get pregnant. Patients who are sexually active must agree to use a highly effective contraceptive method (as outlined in section 5.9).
- Use of prohibited concomitant medications, including other forms of ketamine or esketamine, benzodiazepines, monoamine oxidase inhibitors, stimulants, medical or recreational cannabis of any form.
- Patients in the ketamine-arm of the parent RCT, that did not reasonably tolerate 4 infusions of flexibly-dosed ketamine, as determined by the investigator and/or patient
Sites / Locations
- Canadian Rapid Treatment Center of Excellence (CRTCE)
- Toronto Western HospitalRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Ketamine
Arm Description
Open-label ketamine infusions will be provided on a flexible schedule (every 2-4 weeks) with flexible dosing (0.5-1.0mg/kg over 40 minutes) titrated to optimize benefits, while minimizing the dosage and frequency over a 12-week extension period
Outcomes
Primary Outcome Measures
Change in depression severity using the Montgomery Asberg Depression Rating Scale (MADRS)
The MADRS is a clinician-rated scale measuring depression severity. It consists of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60. A higher score is indicative of greater depressive severity Response rates are defined as ≥ 50% decrease and Remission ≤ 10 actual score.
Secondary Outcome Measures
Recruitment and Retention Rates
The feasibility of ketamine as a treatment in bipolar disorder will be measured by recruitment and retention rates.
Treatment Emergent Adverse Events
Safety will be assessed using patient-reported treatment emergent adverse events.
Quality of Life (QOL)
Quality of life will be assessed using the Quality of Life-BD (QOL.BD) scale, which contains 56 questions over 12 domains. uses a 5-component scale that evaluates mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This scale is numbered from 56 to 280. 280 indicating a high quality of life, while 56 denotes a low quality of life.
Full Information
NCT ID
NCT05339074
First Posted
April 13, 2022
Last Updated
August 9, 2022
Sponsor
University Health Network, Toronto
1. Study Identification
Unique Protocol Identification Number
NCT05339074
Brief Title
Maintenance Ketamine Infusions for Treatment-Resistant Bipolar Depression
Acronym
KET-BD-Sustain
Official Title
Maintenance Ketamine Infusions for Treatment-Resistant Bipolar Depression: An Open-Label Extension Trial
Study Type
Interventional
2. Study Status
Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 10, 2022 (Anticipated)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
August 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Health Network, Toronto
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Growing evidence has supported rapid and robust antidepressant effects with subanesthetic doses of intravenous (IV) ketamine for treatment resistant depression (TRD). However, no completed or ongoing RCTs have evaluated the effects of repeated doses of IV ketamine for a homogenous sample of patients with treatment-resistant bipolar disorder depression (TRBD). The primary research goal is to determine the acute antidepressant efficacy, safety and tolerability of repeated sub-anesthetic maintenance doses of IV ketamine in, over a period of twelve weeks. Open-label ketamine infusions will be provided on a flexible schedule (every 2-4 weeks) with flexible dosing (0.5-1.0mg/kg over 40 minutes) titrated to optimize benefits, while minimizing the dosage and frequency over a 12-week extension period. All patients participating in this open-label study will have completed an acute course of infusions in a parent two-site, phase II, double-blinded midazolam-controlled RCT trial. In addition to this acute course of four infusions, a maximum of six infusions will be provided over the 12-week period. Secondary aims include evaluating effects of IV ketamine on suicidal ideations, quality of life, function and duration of effects. Herein, a two-site (University Health Network and Canadian Rapid Treatment Centre of Excellence), single-arm, open label, 12-week extension trial evaluating the effects of flexibly-dosed adjunctive ketamine infusions for TRBD to maintain antidepressant effects in participants who achieved an antidepressant response (MADRS decrease by >50%) or remission (MADRS < 12) following an acute course of four ketamine infusions is proposed. The primary outcome will be Montgomery-Åsberg Depression Rating Scale (MADRS) scores, determining by a linear mixed model from baseline to week 12. Secondary outcomes include evaluating response and remission rates, safety, tolerability (including treatment-emergent mania), and effects on suicidality, anxiety, quality of life, function and the duration of effects.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bipolar Disorder, Bipolar Depression, Bipolar I Disorder, Bipolar II Disorder
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Ketamine
Arm Type
Experimental
Arm Description
Open-label ketamine infusions will be provided on a flexible schedule (every 2-4 weeks) with flexible dosing (0.5-1.0mg/kg over 40 minutes) titrated to optimize benefits, while minimizing the dosage and frequency over a 12-week extension period
Intervention Type
Drug
Intervention Name(s)
Ketamine Hydrochloride
Intervention Description
60 patients will receive ketamine hydrochloride over 12 weeks, flexible dosed between 0.5 mg/kg to 1.0 mg/kg
Primary Outcome Measure Information:
Title
Change in depression severity using the Montgomery Asberg Depression Rating Scale (MADRS)
Description
The MADRS is a clinician-rated scale measuring depression severity. It consists of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60. A higher score is indicative of greater depressive severity Response rates are defined as ≥ 50% decrease and Remission ≤ 10 actual score.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Recruitment and Retention Rates
Description
The feasibility of ketamine as a treatment in bipolar disorder will be measured by recruitment and retention rates.
Time Frame
12 weeks
Title
Treatment Emergent Adverse Events
Description
Safety will be assessed using patient-reported treatment emergent adverse events.
Time Frame
12 weeks
Title
Quality of Life (QOL)
Description
Quality of life will be assessed using the Quality of Life-BD (QOL.BD) scale, which contains 56 questions over 12 domains. uses a 5-component scale that evaluates mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This scale is numbered from 56 to 280. 280 indicating a high quality of life, while 56 denotes a low quality of life.
Time Frame
12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Provide written, voluntary informed consent prior to study enrollment. Substitute decision makers will not be allowed to consent to study on a potential patient's behalf.
Male or female between the age of 21 to 65, inclusive.
Meets DSM-5 criteria for Bipolar I or II Disorder, currently experiencing a Major Depressive Episode without psychotic features. Diagnosis confirmed by study psychiatrist at the start of the parent KET-BD randomized clinical trial (RCT).
Participant in the KET-BD RCT 4a. Participants in the ketamine arm of the KET-BD RCT must have experienced an antidepressant response (i.e. change in MADRS score ≥ 50% at day 14 compared to baseline or Clinical Global Impression-Improvement (CGI-I) = 2 'much improved' or 1 'very much improved') or experienced clinical remission of symptoms (i.e., MADRS score < 12 on day 14) 4b. Participants in the midazolam arm of the KET-BD RCT must present as moderately to severely depressed (MADRS >21) on days 14 and 28 of the parent RCT and must be responders or remitters following four flexibly dosed infusions over 2 weeks.
Current depressive episode has inadequate response to two or more adequate first-line treatment trials for bipolar depression, as per the 2018 CANMAT Bipolar Disorder Guidelines. First line treatment trials include the use of lithium, valproate, carbamazepine, lamotrigine and/or any antipsychotic medication. Adequate medications confirmed at the start of the parent KET-BD RCT.
Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month, including a therapeutic dose of a mood stabilizer.
Exclusion Criteria:
Currently exhibiting symptoms of mania, hypomania, or mixed state bipolar, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
Current symptoms of psychosis or a substance use disorder within the past 3 months. History of psychotic features during a mood episode will not be excluded.
History of neurological disorders (including, but not limited to, uncontrolled seizure disorder, history of stroke within past 12 months, major head injuries, aneurysmal vascular disease [including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels], arteriovenous malformation, or intracerebral hemorrhage)
Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder)
Lifetime history of ketamine use disorder
Presence of active suicidality, requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months.
Presence of a contraindication to ketamine, including a drug allergy, uncontrolled hypertension (baseline systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg), low or labile blood pressure, myocardial infarction within past 12 months, cardiac arrhythmia, moderate to severe hepatic impairment (i.e., Child-Pugh score of B or C), moderate or severe renal impairment (glomerular filtration rate (GFR) < 45 milliliters/min), heart failure, or coronary artery disease
Pregnant or breastfeeding women or women who intend to get pregnant. Patients who are sexually active must agree to use a highly effective contraceptive method (as outlined in section 5.9).
Use of prohibited concomitant medications, including other forms of ketamine or esketamine, benzodiazepines, monoamine oxidase inhibitors, stimulants, medical or recreational cannabis of any form.
Patients in the ketamine-arm of the parent RCT, that did not reasonably tolerate 4 infusions of flexibly-dosed ketamine, as determined by the investigator and/or patient
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lee Phan, MSc
Phone
416-603-5800
Ext
3492
Email
lee.phan@uhnresearch.ca
Facility Information:
Facility Name
Canadian Rapid Treatment Center of Excellence (CRTCE)
City
Mississauga
State/Province
Ontario
ZIP/Postal Code
L5C 4E7
Country
Canada
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lee Phan, MSc
Email
lee.phan@uhnresearch.ca
Facility Name
Toronto Western Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5T 2S8
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lee Phan, MSc
Email
lee.phan@uhnresearch.ca
First Name & Middle Initial & Last Name & Degree
Joshua Rosenblat, MD, MSc
12. IPD Sharing Statement
Plan to Share IPD
No
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Maintenance Ketamine Infusions for Treatment-Resistant Bipolar Depression
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