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

• ClinicalTrials.gov Identifier: NCT04939649
• Recruitment Status: Recruiting
• First Posted: June 25, 2021
• Last Update Posted: September 16, 2021
• Sponsor: University of Dublin, Trinity College
• Information provided by (Responsible Party): Prof Declan McLoughlin, University of Dublin, Trinity College

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.

Condition or disease	Intervention/treatment	Phase
Major Depressive Episode; Unipolar Depression; Bipolar Depression	Drug: Ketamine; Drug: Midazolam	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 104 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Ketamine as an Adjunctive Therapy for Major Depression - A Randomised Controlled Trial: [KARMA-Dep (2)]
• Actual Study Start Date: September 13, 2021
• Estimated Primary Completion Date: October 1, 2023
• Estimated Study Completion Date: April 1, 2024

Arms and Interventions

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 Name: 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 Name: Hypnovel

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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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.
• 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.

Contacts and Locations

Contacts

Contact: Declan M McLoughlin, PhD; 00353 (0)1 2493385 ext 3385; d.mcloughlin@tcd.ie

Locations

Ireland

St Patrick's Univeristy Hospital; Recruiting

Dublin, Ireland, D8

Contact: Declan M McLoughlin, PhD 00353 (0)1 2493385 ext 3385 d.mcloughlin@tcd.ie

Sponsors and Collaborators

University of Dublin, Trinity College

Investigators

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

More Information

Additional Information:

Research Team Website 

• Responsible Party: Prof Declan McLoughlin, Professor, University of Dublin, Trinity College
• ClinicalTrials.gov Identifier: NCT04939649
• Other Study ID Numbers: CRFSPN004; 2019-003109-92 ( EudraCT Number )
• First Posted: June 25, 2021
• Last Update Posted: September 16, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Prof Declan McLoughlin, University of Dublin, Trinity College:

ketamine; glutamate

Additional relevant MeSH terms:

Depression; Depressive Disorder; Bipolar Disorder; Behavioral Symptoms; Mood Disorders; Mental Disorders; Bipolar and Related Disorders; Midazolam; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; GABA Modulators; GABA Agents