Ketamine as an Adjunctive Therapy for Major Depression (2) (KARMA-Dep2)
Primary Purpose
Major Depressive Episode, Unipolar Depression, Bipolar Depression
Status
Recruiting
Phase
Phase 3
Locations
Ireland
Study Type
Interventional
Intervention
Ketamine
Midazolam
Sponsored by
About this trial
This is an interventional treatment trial for Major Depressive Episode focused on measuring ketamine, glutamate
Eligibility Criteria
Inclusion Criteria:
- ≥18 years old.
- Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 20 at screening and start of the first infusion.
- Voluntary admission for treatment of an acute depressive episode
- Meet DSM-5 criteria for a major depressive disorder or bipolar affective disorder (current episode depression). Diagnosis of a major depressive disorder or bipolar affective disorder (DSM-5) will be confirmed by the structured diagnostic Mini International Neuropsychiatric Interview (MINI; updated Version 7 for DSM-5).
Exclusion Criteria:
- Current involuntary admission.
- Medical condition rendering unfit for ketamine/midazolam.
- Currently taking any of the contraindicated medications that may alter the pharmacokinetics of ketamine.
- Active suicidal intention.
- Dementia.
- Active (i.e., in the past six months) Axis 1 comorbidity (with the exception of anxiety if secondary to depression) or lifetime history of schizophrenia or schizoaffective disorder
- Electroconvulsive Therapy (ECT) administered within the last two months.
- Alcohol/substance dependence in previous six-months.
- Pregnancy, breastfeeding or considering becoming pregnancy whilst on the trial for up to 12 weeks after last dose or inability to confirm use of adequate contraception during the trial.
- Breastfeeding women.
Sites / Locations
- St Patrick's Univeristy HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Ketamine
Midazolam
Arm Description
Participants will receive up to a four-week course of twice-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist.
Participants will receive up to a four-week course of twice-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist.
Outcomes
Primary Outcome Measures
Montgomery Asberg Depression Rating Scale-10 item version (MADRS)
The MADRS is a validated, 10-item, observer-rated scale that measures the symptoms and severity of depression. The primary outcome measure will be the change from baseline in the MADRS score to 24 hours after the eighth/final infusion.
MADRS will be completed at screening (prior to randomisation), before and after all infusion sessions (at the following timepoints: -40 (±20) mins before the infusion begins; +60 (±10) mins and +120 (±10) mins after the infusion begins; +24 (±1) hours after the infusion ends) and at the 6, 12 and 24 weeks follow-up time points. Sleep and appetite scores will be carried over from -40 minutes to +60 minutes, +120 minutes, and 24 hours after each infusion.
Response to treatment is defined as a ≥50% improvement from baseline MADRS score. Remission is defined as achieving a MADRS score ≤10. For those deemed to be treatment "responders", relapse at follow-up time points is defined as maintaining <50% improvement in MADRS score from baseline MADRS score.
Secondary Outcome Measures
The Clinician-Administered Dissociative States Scale (CADSS)
The CADSS will measure dissociative symptoms, as a possible subjective side effect of either ketamine or midazolam. The CADSS consists of 23 items and scores for each item range from 0 to 4. The CADSS measures dissociative symptoms in the following domains: identity, proprioception, time perception, colour and depth perception, and other modalities. The maximum score is 92, with higher scores indicating more dissociative symptoms.
The CADSS will be completed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).
The Brief Psychiatric Rating Scale (BPRS)
The positive symptoms subscale of the BPRS will be used to measure psychotomimetic effects of either ketamine or midazolam. This 4-item positive symptoms subscale measures suspiciousness, hallucinations, unusual thought content, and conceptual disorganisation. Each item is scored between 0 and 7. The maximum score is 28, with higher scores indicating more severe psychotic symptom.
Participants will complete the BPRS three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).
Young Mania Rating Scale (YMRS; mood item)
The YMRS is an observer-rated assessment tool for severity of mania and hypomania. The single mood item of the YMRS, rated from 0 to 4 (representing a range from normal mood to frank euphoria), will be used to assess for possible mood elevation during the infusion sessions. Higher scores reflect more elevated mood.
Participants will have the YMRS performed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).
Observer's Assessment of Alertness/Sedation; responsiveness subscale (OAA/S-R)
The OAA/S-R is an observer-rated assessment that will be used to measure levels of sedation experienced by participants during either ketamine or midazolam infusion. The OAA/S-R ranges in score from 1 to 5, where 1 denotes deep sleep (i.e. no response to mild prodding or shaking) and 5 denotes fully alert.
The OAA/S-R will be completed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).
20-item Physician Withdrawal Checklist (PWC-20)
The PWC-20 will be used to assess for potential withdrawal symptoms during and after completion of the allocated course of ketamine/midazolam infusions. The PWC-20 is a brief checklist and each item is rated from 0 (not present) to 3 (severe). PWC-20 scores range from 0 to 60, with higher scores indicating more withdrawal symptoms with greater severity.
The PWC-20 will be completed at screening (prior to randomisation), 24 (±1) hours after the end of the fourth and final/eighth infusions, and the 6- and 12-week follow-up timepoints.
The Quick Inventory of Depressive Symptoms, self-report version (QIDS-SR)
The QIDS-SR is a validated, self-report measure of depressive symptoms. The QIDS-SR consists of 16 items, with each item rated on a scale from 0 to 3. Total scores range from 0 to 48, with higher scores reflecting greater burden of depressive symptoms.
The QIDS-SR will be completed at screening (prior to randomisation), before and after all infusion sessions (at the following timepoints: -40 (±20) mins before the infusion begins; +60 (±10) mins and +120 (±10) mins after the infusion begins; +24 (±1) hours after the infusion ends) and at the 6, 12 and 24 weeks follow-up time points. Sleep and appetite items 1,2,3,4,6,7,8 & 9 on the QIDS-SR will be carried over from -40 minutes before each infusion to +60 minutes, +120 minutes & 24 hours after each infusion in line with the methodology of previous literature. Item 17 for medication adherence will also be carried over from -40 minutes before each infusion to +60 minutes, +120 minutes and 24 hours after each infusion.
Patient-Rated Inventory of Side Effects (PRISE)
The PRISE is a 9-item, self-report measure that will document general adverse events experienced by patients during each infusion, by identifying and evaluating the tolerability of each adverse event. The PRISE assesses adverse events in the following symptom domains; Gastrointestinal, Heart, Skin, Nervous System, Eyes/Ears, Genital/Urinary, Sleep, Sexual Functioning, and Other. Each domain has multiple symptoms which can be endorsed. For each domain the patient rate whether or not the symptoms are tolerable or distressing.
The PRISE will be completed at screening (prior to randomisation), after all infusion sessions (+120 (±10) mins after the infusion begins), and at the 6, 12 and 24 weeks follow-up time points.
The Montreal Cognitive Assessment (MoCA)
The MoCA is a rapid screening instrument for mild cognitive dysfunction. It assesses the following cognitive domains: attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. The maximum score is 30, with higher scores indicating better cognition.
The MoCA will be completed at screening (prior to randomisation), at +120 (±10) mins after the infusion begins during the first and eighth/final infusion sessions, and at the 12 and 24 weeks follow-up time points.
EuroQol-5 dimensions-5 level scale for health status (EQ-5D-5L)
Health-related quality-of-life will be measured using the EQ-5D-5L. The EQ-5D-5L consists of the EQ-5D descriptive system, and the EQ visual analogue scale (EQ VAS).
The EQ-5D descriptive system includes the following five dimensions that assess an individual's self-rated health status: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is rated on a 5-point Likert scale. The digits related to each response to the five dimensions are combined into a 5-digit number, which describes the patient's health state.
The EQ VAS includes a vertical visual analogue as a quantitative measure of subjectively rated health, with endpoints labelled as 'Best imaginable health status' and 'Worst imaginable health status'.
The EQ-5D-5L will be administered at screening (prior to randomisation) and at the 6-, 12- and 24-week follow up time periods.
Client Service Receipt Inventory (CSRI)
The CSRI will calculate healthcare costs using the following data: sociodemographic information, usual living situation, employment status and income levels and the care services and supports used by participants. Currently prescribed medicines will also be recorded.
Healthcare costs will be estimated using the CSRI at baseline and at the 6-, 12- and 24-week follow-up timepoints.
Adverse events (AE) and serious adverse events (SAE) review
AEs and SAEs will be reviewed at every visit. All AEs and SAEs will be reported and followed up until resolved.
Concomitant Medication
All medications taken one month prior to participant screening will be recorded. At all other visits, concomitant medication taken since last visit will be documented. Adherence to prohibited/contraindicated medication requirements will be assessed and documented at each infusion visit.
Full Information
NCT ID
NCT04939649
First Posted
June 20, 2021
Last Updated
February 10, 2023
Sponsor
University of Dublin, Trinity College
1. Study Identification
Unique Protocol Identification Number
NCT04939649
Brief Title
Ketamine as an Adjunctive Therapy for Major Depression (2)
Acronym
KARMA-Dep2
Official Title
Ketamine as an Adjunctive Therapy for Major Depression - A Randomised Controlled Trial: [KARMA-Dep (2)]
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 13, 2021 (Actual)
Primary Completion Date
October 1, 2023 (Anticipated)
Study Completion Date
April 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Dublin, Trinity College
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
Pragmatic, randomised, controlled, parallel-group, superiority trial of ketamine vs. midazolam as an adjunctive therapy for depression. The main purpose of the trial is to assess the mood-rating score difference between ketamine and midazolam from before the first infusion to 24 hours after the final infusion, supplemented by a 95% confidence interval. There will also be a 24-week follow-up after the final infusion session.
Detailed Description
Pragmatic, randomised, controlled, parallel-group, superiority trial. Trial participants will be patients admitted to St Patrick's University Hospital for treatment of a major depressive episode. The investigators aim to recruit up to 104 participants who will be eligible for this study and randomly allocate 52 patients to each group. Both participants and assessors will be blind to treatment allocation. Eligible consented participants will be randomly allocated in a 1:1 ratio to a course of up to eight infusions of either ketamine or midazolam twice weekly over up to four weeks. Block randomisation will be independently performed. Physical, psychotomimetic and cognitive outcomes will be monitored before, during and after infusions. During the allocated infusions and follow-up period patients will be monitored for treatment-related adverse events relating to both mental and physical health. Participants will also be followed-up for 24 weeks after the end of the initial randomised treatment and assessment period lasting up to four weeks, in order to identify if and when relapse occurs. During the trial, both groups will continue usual inpatient care as prescribed by their treating team.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Episode, Unipolar Depression, Bipolar Depression
Keywords
ketamine, glutamate
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
104 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Ketamine
Arm Type
Experimental
Arm Description
Participants will receive up to a four-week course of twice-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist.
Arm Title
Midazolam
Arm Type
Active Comparator
Arm Description
Participants will receive up to a four-week course of twice-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist.
Intervention Type
Drug
Intervention Name(s)
Ketamine
Other Intervention Name(s)
Ketalar
Intervention Description
A sub-anaesthetic dose of ketamine will be administered for up to a four-week course of twice-weekly infusions.
Intervention Type
Drug
Intervention Name(s)
Midazolam
Other Intervention Name(s)
Hypnovel
Intervention Description
A sub-anaesthetic dose of midazolam will be administered for up to a four-week course of twice-weekly infusions.
Primary Outcome Measure Information:
Title
Montgomery Asberg Depression Rating Scale-10 item version (MADRS)
Description
The MADRS is a validated, 10-item, observer-rated scale that measures the symptoms and severity of depression. The primary outcome measure will be the change from baseline in the MADRS score to 24 hours after the eighth/final infusion.
MADRS will be completed at screening (prior to randomisation), before and after all infusion sessions (at the following timepoints: -40 (±20) mins before the infusion begins; +60 (±10) mins and +120 (±10) mins after the infusion begins; +24 (±1) hours after the infusion ends) and at the 6, 12 and 24 weeks follow-up time points. Sleep and appetite scores will be carried over from -40 minutes to +60 minutes, +120 minutes, and 24 hours after each infusion.
Response to treatment is defined as a ≥50% improvement from baseline MADRS score. Remission is defined as achieving a MADRS score ≤10. For those deemed to be treatment "responders", relapse at follow-up time points is defined as maintaining <50% improvement in MADRS score from baseline MADRS score.
Time Frame
28 weeks
Secondary Outcome Measure Information:
Title
The Clinician-Administered Dissociative States Scale (CADSS)
Description
The CADSS will measure dissociative symptoms, as a possible subjective side effect of either ketamine or midazolam. The CADSS consists of 23 items and scores for each item range from 0 to 4. The CADSS measures dissociative symptoms in the following domains: identity, proprioception, time perception, colour and depth perception, and other modalities. The maximum score is 92, with higher scores indicating more dissociative symptoms.
The CADSS will be completed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).
Time Frame
4 weeks
Title
The Brief Psychiatric Rating Scale (BPRS)
Description
The positive symptoms subscale of the BPRS will be used to measure psychotomimetic effects of either ketamine or midazolam. This 4-item positive symptoms subscale measures suspiciousness, hallucinations, unusual thought content, and conceptual disorganisation. Each item is scored between 0 and 7. The maximum score is 28, with higher scores indicating more severe psychotic symptom.
Participants will complete the BPRS three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).
Time Frame
4 weeks
Title
Young Mania Rating Scale (YMRS; mood item)
Description
The YMRS is an observer-rated assessment tool for severity of mania and hypomania. The single mood item of the YMRS, rated from 0 to 4 (representing a range from normal mood to frank euphoria), will be used to assess for possible mood elevation during the infusion sessions. Higher scores reflect more elevated mood.
Participants will have the YMRS performed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).
Time Frame
4 week
Title
Observer's Assessment of Alertness/Sedation; responsiveness subscale (OAA/S-R)
Description
The OAA/S-R is an observer-rated assessment that will be used to measure levels of sedation experienced by participants during either ketamine or midazolam infusion. The OAA/S-R ranges in score from 1 to 5, where 1 denotes deep sleep (i.e. no response to mild prodding or shaking) and 5 denotes fully alert.
The OAA/S-R will be completed three times at each infusion session: before (-30 (±10) mins before the infusion begins), during (+30 (±5) mins after the infusion begins) and after (+60 (±10) mins after the infusion begins, i.e. 20 (±10) mins after the infusion ends).
Time Frame
4 weeks
Title
20-item Physician Withdrawal Checklist (PWC-20)
Description
The PWC-20 will be used to assess for potential withdrawal symptoms during and after completion of the allocated course of ketamine/midazolam infusions. The PWC-20 is a brief checklist and each item is rated from 0 (not present) to 3 (severe). PWC-20 scores range from 0 to 60, with higher scores indicating more withdrawal symptoms with greater severity.
The PWC-20 will be completed at screening (prior to randomisation), 24 (±1) hours after the end of the fourth and final/eighth infusions, and the 6- and 12-week follow-up timepoints.
Time Frame
16 weeks
Title
The Quick Inventory of Depressive Symptoms, self-report version (QIDS-SR)
Description
The QIDS-SR is a validated, self-report measure of depressive symptoms. The QIDS-SR consists of 16 items, with each item rated on a scale from 0 to 3. Total scores range from 0 to 48, with higher scores reflecting greater burden of depressive symptoms.
The QIDS-SR will be completed at screening (prior to randomisation), before and after all infusion sessions (at the following timepoints: -40 (±20) mins before the infusion begins; +60 (±10) mins and +120 (±10) mins after the infusion begins; +24 (±1) hours after the infusion ends) and at the 6, 12 and 24 weeks follow-up time points. Sleep and appetite items 1,2,3,4,6,7,8 & 9 on the QIDS-SR will be carried over from -40 minutes before each infusion to +60 minutes, +120 minutes & 24 hours after each infusion in line with the methodology of previous literature. Item 17 for medication adherence will also be carried over from -40 minutes before each infusion to +60 minutes, +120 minutes and 24 hours after each infusion.
Time Frame
28 weeks
Title
Patient-Rated Inventory of Side Effects (PRISE)
Description
The PRISE is a 9-item, self-report measure that will document general adverse events experienced by patients during each infusion, by identifying and evaluating the tolerability of each adverse event. The PRISE assesses adverse events in the following symptom domains; Gastrointestinal, Heart, Skin, Nervous System, Eyes/Ears, Genital/Urinary, Sleep, Sexual Functioning, and Other. Each domain has multiple symptoms which can be endorsed. For each domain the patient rate whether or not the symptoms are tolerable or distressing.
The PRISE will be completed at screening (prior to randomisation), after all infusion sessions (+120 (±10) mins after the infusion begins), and at the 6, 12 and 24 weeks follow-up time points.
Time Frame
28 weeks
Title
The Montreal Cognitive Assessment (MoCA)
Description
The MoCA is a rapid screening instrument for mild cognitive dysfunction. It assesses the following cognitive domains: attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. The maximum score is 30, with higher scores indicating better cognition.
The MoCA will be completed at screening (prior to randomisation), at +120 (±10) mins after the infusion begins during the first and eighth/final infusion sessions, and at the 12 and 24 weeks follow-up time points.
Time Frame
28 weeks
Title
EuroQol-5 dimensions-5 level scale for health status (EQ-5D-5L)
Description
Health-related quality-of-life will be measured using the EQ-5D-5L. The EQ-5D-5L consists of the EQ-5D descriptive system, and the EQ visual analogue scale (EQ VAS).
The EQ-5D descriptive system includes the following five dimensions that assess an individual's self-rated health status: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is rated on a 5-point Likert scale. The digits related to each response to the five dimensions are combined into a 5-digit number, which describes the patient's health state.
The EQ VAS includes a vertical visual analogue as a quantitative measure of subjectively rated health, with endpoints labelled as 'Best imaginable health status' and 'Worst imaginable health status'.
The EQ-5D-5L will be administered at screening (prior to randomisation) and at the 6-, 12- and 24-week follow up time periods.
Time Frame
28 weeks
Title
Client Service Receipt Inventory (CSRI)
Description
The CSRI will calculate healthcare costs using the following data: sociodemographic information, usual living situation, employment status and income levels and the care services and supports used by participants. Currently prescribed medicines will also be recorded.
Healthcare costs will be estimated using the CSRI at baseline and at the 6-, 12- and 24-week follow-up timepoints.
Time Frame
28 weeks
Title
Adverse events (AE) and serious adverse events (SAE) review
Description
AEs and SAEs will be reviewed at every visit. All AEs and SAEs will be reported and followed up until resolved.
Time Frame
28 weeks
Title
Concomitant Medication
Description
All medications taken one month prior to participant screening will be recorded. At all other visits, concomitant medication taken since last visit will be documented. Adherence to prohibited/contraindicated medication requirements will be assessed and documented at each infusion visit.
Time Frame
28 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
≥18 years old.
Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 20 at screening and start of the first infusion.
Voluntary admission for treatment of an acute depressive episode
Meet DSM-5 criteria for a major depressive disorder or bipolar affective disorder (current episode depression). Diagnosis of a major depressive disorder or bipolar affective disorder (DSM-5) will be confirmed by the structured diagnostic Mini International Neuropsychiatric Interview (MINI; updated Version 7 for DSM-5).
Exclusion Criteria:
Current involuntary admission.
Medical condition rendering unfit for ketamine/midazolam.
Currently taking any of the contraindicated medications that may alter the pharmacokinetics of ketamine.
Active suicidal intention.
Dementia.
Lifetime history of schizophrenia or schizoaffective disorder; active anorexia nervosa or bulimia nervosa in the past 12 months; alcohol or other substance use disorder (with the exception of nicotine) in the previous six months; any DSM-5 disorder other than a major depressive episode (unipolar or bipolar) as the primary presenting problem.
Electroconvulsive Therapy (ECT) administered within the last two months.
Pregnancy, breastfeeding or considering becoming pregnancy whilst on the trial for up to 12 weeks after last dose or inability to confirm use of adequate contraception during the trial.
Breastfeeding women.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Declan M McLoughlin, PhD
Phone
00353 (0)1 2493385
Ext
3385
Email
d.mcloughlin@tcd.ie
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Declan M McLoughlin, PhD
Organizational Affiliation
University of Dublin, Trinity College and St Patrick's Mental Health Services
Official's Role
Principal Investigator
Facility Information:
Facility Name
St Patrick's Univeristy Hospital
City
Dublin
ZIP/Postal Code
D8
Country
Ireland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Declan M McLoughlin, PhD
Phone
00353 (0)1 2493385
Ext
3385
Email
d.mcloughlin@tcd.ie
12. IPD Sharing Statement
Plan to Share IPD
No
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Ketamine as an Adjunctive Therapy for Major Depression (2)
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