Ketamine as an Adjunctive Therapy for Major Depression (2) (KARMA-Dep2)

Ketamine as an Adjunctive Therapy for Major Depression - A Randomised Controlled Trial: [KARMA-Dep (2)]

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.

Study Overview

• Status: Recruiting
• Conditions: Bipolar Depression; Unipolar Depression; Major Depressive Episode
• Intervention / Treatment: Drug: Ketamine; Drug: Midazolam

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.

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Declan M McLoughlin, PhD; Phone Number: 3385 00353 (0)1 2493385; Email: d.mcloughlin@tcd.ie

Study Locations

• Ireland
  • Dublin, Ireland, D8
    • Recruiting
    • St Patrick's Univeristy Hospital
    • Contact: Declan M McLoughlin, PhD; Phone Number: 3385 00353 (0)1 2493385; Email: d.mcloughlin@tcd.ie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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 remitters, relapse at follow-up time points is defined as a MADRS score of ≥18.	28 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	4 weeks
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).	4 weeks
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).	4 week
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).	4 weeks
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.	28 weeks
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.	28 weeks
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.	28 weeks
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.	28 weeks
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 infusions, and the 6- and 12-week follow-up timepoints.	16 weeks
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.	28 weeks
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 final infusion sessions, and at the 12 and 24 weeks follow-up time points.	28 weeks
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 or until final visit.	28 weeks

Collaborators and Investigators

• Sponsor: University of Dublin, Trinity College
• Investigators: Principal Investigator: Declan M McLoughlin, PhD, University of Dublin, Trinity College and St Patrick's Mental Health Services

Publications and helpful links

Helpful Links

• Research Team Website

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2021
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 20, 2021
• First Submitted That Met QC Criteria: June 20, 2021
• First Posted (Actual): June 25, 2021

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: ketamine; glutamate
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Depression; Depressive Disorder; Bipolar Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Ketamine; Midazolam
• Other Study ID Numbers: CRFSPN004; 2019-003109-92 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No