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History of Changes for Study: NCT04939649
Ketamine as an Adjunctive Therapy for Major Depression (2) (KARMA-Dep2)
Latest version (submitted September 15, 2021) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 June 20, 2021 None (earliest Version on record)
2 September 1, 2021 Study Status and Eligibility
3 September 15, 2021 Study Status
Comparison Format:

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Study NCT04939649
Submitted Date:  June 20, 2021 (v1)

Open or close this module Study Identification
Unique Protocol ID: CRFSPN004
Brief Title: Ketamine as an Adjunctive Therapy for Major Depression (2) (KARMA-Dep2)
Official Title: Ketamine as an Adjunctive Therapy for Major Depression - A Randomised Controlled Trial: [KARMA-Dep (2)]
Secondary IDs: 2019-003109-92 [EudraCT Number]
Open or close this module Study Status
Record Verification: June 2021
Overall Status: Recruiting
Study Start: June 28, 2021
Primary Completion: October 1, 2023 [Anticipated]
Study Completion: April 1, 2024 [Anticipated]
First Submitted: June 20, 2021
First Submitted that
Met QC Criteria:
June 20, 2021
First Posted: June 25, 2021 [Actual]
Last Update Submitted that
Met QC Criteria:
June 20, 2021
Last Update Posted: June 25, 2021 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: University of Dublin, Trinity College
Responsible Party: Principal Investigator
Investigator: Prof Declan McLoughlin
Official Title: Professor
Affiliation: University of Dublin, Trinity College
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: No
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module 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 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 four-week course of either twice-weekly ketamine or midazolam infusions. 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 four-week randomised treatment and assessment period, 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.
Open or close this module Conditions
Conditions: Major Depressive Episode
Unipolar Depression
Bipolar Depression
Keywords: ketamine
glutamate
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation: Randomized
Enrollment: 104 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Ketamine
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.
Drug: Ketamine
A sub-anaesthetic dose of ketamine will be administered for up to a four-week course of twice-weekly infusions.
Other Names:
  • Ketalar
Active Comparator: Midazolam
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.
Drug: Midazolam
A sub-anaesthetic dose of midazolam will be administered for up to a four-week course of twice-weekly infusions.
Other Names:
  • Hypnovel
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Montgomery Asberg Depression Rating Scale-10 item version (MADRS)
[ Time Frame: 28 weeks ]

The MADRS is a validated, 10-item, observer-rated scale that measures the symptoms and severity of depression. Each item is rated from 0 to 6, with higher MADRS scores indicating greater depression severity. The primary outcome measure will be the change from baseline in the MADRS score to 24 hours after the eighth/final infusion.

These assessments will be completed at screening (prior to randomisation), before and after all infusion sessions (at the following timepoints: -40 (±10) 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.

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:
1. The Clinician-Administered Dissociative States Scale (CADSS)
[ Time Frame: 4 weeks ]

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).

2. The Brief Psychiatric Rating Scale (BPRS)
[ Time Frame: 4 weeks ]

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).

3. Young Mania Rating Scale (YMRS; mood item)
[ Time Frame: 4 week ]

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).

4. Observer's Assessment of Alertness/Sedation; responsiveness subscale (OAA/S-R)
[ Time Frame: 4 weeks ]

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).

5. 20-item Physician Withdrawal Checklist (PWC-20)
[ Time Frame: 16 weeks ]

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.

6. The Quick Inventory of Depressive Symptoms, self-report version (QIDS-SR)
[ Time Frame: 28 weeks ]

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 (±10) 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.

7. Patient-Rated Inventory of Side Effects (PRISE)
[ Time Frame: 28 weeks ]

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.

8. The Montreal Cognitive Assessment (MoCA)
[ Time Frame: 28 weeks ]

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.

9. EuroQol-5 dimensions-5 level scale for health status (EQ-5D-5L)
[ Time Frame: 28 weeks ]

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.

10. Client Service Receipt Inventory (CSRI)
[ Time Frame: 28 weeks ]

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.

11. Adverse events (AE) and serious adverse events (SAE) review
[ Time Frame: 28 weeks ]

AEs and SAEs will be reviewed at every visit. All AEs and SAEs will be reported and followed up until resolved.
12. Concomitant Medication
[ Time Frame: 28 weeks ]

All medications taken 2 months 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.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
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 or significantly reduce ECT seizure threshold.
  • Active suicidal intention.
  • Dementia.
  • History of Axis 1 diagnosis other than major depression.
  • 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.
Open or close this module Contacts/Locations
Central Contact Person: Declan M McLoughlin, PhD
Telephone: 00353 (0)1 2493385 Ext. 3385
Email: d.mcloughlin@tcd.ie
Study Officials: Declan M McLoughlin, PhD
Principal Investigator
University of Dublin, Trinity College and St Patrick's Mental Health Services
Locations: Ireland
St Patrick's Univeristy Hospital
[Recruiting]
Dublin, Ireland, D8
Contact:Contact: Declan M McLoughlin, PhD 00353 (0)1 2493385 Ext. 3385 d.mcloughlin@tcd.ie
Open or close this module IPDSharing
Plan to Share IPD: No
Open or close this module References
Citations:
Links: Description: Research Team Website
Available IPD/Information:

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