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

• ClinicalTrials.gov Identifier: NCT03256162
• Recruitment Status: Completed
• First Posted: August 21, 2017
• Results First Posted: January 18, 2020
• Last Update Posted: January 18, 2020
• Sponsor: St Patrick's Hospital, Ireland
• Information provided by (Responsible Party): Prof Declan McLoughlin, St Patrick's Hospital, Ireland

Tracking Information

• First Submitted Date: August 2, 2017
• First Posted Date: August 21, 2017
• Results First Submitted Date: January 2, 2020
• Results First Posted Date: January 18, 2020
• Last Update Posted Date: January 18, 2020
• Actual Study Start Date: September 7, 2017
• Actual Primary Completion Date: September 21, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 15, 2020)

The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24) [ Time Frame: 15 weeks ]

The HRSD assesses severity of depressive symptoms and is commonly used to measure depression severity. It was initially a 17-item format with the optional addition of 4 items making up the 21-item version. In addition to the original 21 items, the 24-item HRSD includes items on helplessness, hopelessness and worthlessness; its score range is 0-77, with higher scores reflecting greater burden of depressive symptoms. Response to antidepressant treatment is defined as achieving ≥60% decrease from baseline HRSD-24 and score ≤16. Remission criteria are ≥60% decrease in HRSD from baseline and score ≤10. Criteria for relapse are ≥10 point increase in HRSD-24 compared to responder baseline score plus HRSD ≥16; in addition, increase in the HRSD should be maintained one week later. Participants will have a baseline (T0) HRSD-24 score. This will be repeated 1 week after each of 4 once-weekly infusions (T1-4) and follow-up measures after another 5 (T9) and 11 (T15) weeks, week 15 is reported.

Original Primary Outcome Measures (submitted: August 16, 2017)

The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24) [ Time Frame: 15 weeks ]

The HRSD assesses severity of depressive symptoms and is commonly used to measure depression severity. It was initially a 17-item format with the optional addition of 4 items making up the 21-item version. In addition to the original 21 items, the 24-item HRSD includes items on helplessness, hopelessness and worthlessness; its score range is 0-77, with higher scores reflecting greater burden of depressive symptoms. Response to antidepressant treatment is defined as achieving ≥60% decrease from baseline HRSD-24 and score ≤16. Remission criteria are ≥60% decrease in HRSD from baseline and score ≤10. Criteria for relapse are ≥10 point increase in HRSD-24 compared to responder baseline score plus HRSD ≥16; in addition, increase in the HRSD should be maintained one week later. Participants will have a baseline (T0) HRSD-24 score. This will be repeated one week after each of four once-weekly infusions (T1-4) and follow-up measures after another five (T9) and 11 (T15) weeks.

Current Secondary Outcome Measures (submitted: January 15, 2020)

• The Quick Inventory of Depressive Symptoms, Self-report Version (QIDS-SR16) [ Time Frame: 15 weeks ]
  The QIDS-SR16 is a validated self-report measure of depressive symptoms. This consists of 16 questions rated 0-3. Its score range is 0-48, with higher scores reflecting greater burden of depressive symptoms. Participants will have a baseline (T0) QIDS-SR16 score. This will be repeated one week after each of four once-weekly infusions (T1-4) and follow-up measures after another five (T9) and 11 (T15) weeks. Week 15 scores are reported.
• The Clinician-Administered Dissociative States Scale (CADSS) [ Time Frame: 4 weeks ]
  The CADSS measures dissociative symptoms. It will be administered before, during and after infusions in order to capture the range of possible subjective side effects of either agent. This consists of 23 questions and scores for each question range from 0-4. The maximum score is 92 with higher scores indicating more dissociative symptoms. Participants will have the CADSS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
• The Brief Psychiatric Rating Scale (BPRS) [ Time Frame: 4 weeks ]
  The BPRS measures psychotomimetic effects. The investigators will use the positive symptoms subscale of the Brief Psychiatric Rating Scale. The 4-item positive symptoms subscale measures suspiciousness, hallucinations, unusual thought content, and conceptual disorganisation. Each question is scored between 0-7. The maximum score in this 4-item questionnaire is 28. Higher scores indicate more severe psychotic symptoms. Participants will have the BPRS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
• Young Mania Rating Scale (YMRS; Mood Item) [ Time Frame: 4 weeks ]
  Investigators will use the mood item of them YMRS to assess for psychotomimetic effects. This item is rated 0-4. The higher scores reflect elevated mood. Participants will have the YMRS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
• The Patient-Rated Inventory of Side Effects (PRISE) [ Time Frame: 4 weeks ]
  The PRISE will be used to document other general adverse events by patients before, during and after infusions. This is a patient self-report used to qualify side effects by identifying and evaluating the tolerability of each symptom. It is a 9 item assessment of the side effects 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 rates whether or not the symptoms are tolerable or distressing. Data below represent the number of participants from which there was an endorsement of each listed event. Participants will have the PRISE performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
• The Montreal Cognitive Assessment (MoCA) [ Time Frame: 15 weeks ]
  The MOCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. It is scored out of a maximum of 30. The higher scores indicate better cognition. The MOCA will be performed at baseline, one day after infusions 1 and 4 and 12 weeks after the final infusion.

Original Secondary Outcome Measures (submitted: August 16, 2017)

• The Quick Inventory of Depressive Symptoms, Self-report Version (QIDS-SR16) [ Time Frame: 15 weeks ]
  The QIDS-SR16 is a validated self-report measure of depressive symptoms. This consists of 16 questions rated 0-3. Its score range is 0-48, with higher scores reflecting greater burden of depressive symptoms. Participants will have a baseline (T0) QIDS-SR16 score. This will be repeated one week after each of four once-weekly infusions (T1-4) and follow-up measures after another five (T9) and 11 (T15) weeks.
• The Clinician-Administered Dissociative States Scale (CADSS) [ Time Frame: 4 weeks ]
  The CADSS measures dissociative symptoms. It will be administered before, during and after infusions in order to capture the range of possible subjective side effects of either agent. This consists of 23 questions and scores for each question range from 0-4. The maximum score is 92 with higher scores indicating more dissociative symptoms. Participants will have the CADSS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
• The Brief Psychiatric Rating Scale (BPRS) [ Time Frame: 4 weeks ]
  The BPRS measures psychotomimetic effects. The investigators will use the positive symptoms subscale of the Brief Psychiatric Rating Scale. The 4-item positive symptoms subscale measures suspiciousness, hallucinations, unusual thought content, and conceptual disorganisation. Each question is scored between 0-7. The maximum score in this 4-item questionnaire is 28. Higher scores indicate more severe psychotic symptoms. Participants will have the BPRS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
• Young Mania Rating Scale (YMRS; Mood Item) [ Time Frame: 4 weeks ]
  Investigators will use the mood item of them YMRS to assess for psychotomimetic effects. This item is rated 0-4. The higher scores reflect elevated mood. Participants will have the YMRS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
• The Patient-Rated Inventory of Side Effects (PRISE) [ Time Frame: 4 weeks ]
  The PRISE will be used to document other general adverse events by patients before, during and after infusions. This is a patient self-report used to qualify side effects by identifying and evaluating the tolerability of each symptom. It is a 9 item assessment of the side effects 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 rates whether or not the symptoms are tolerable or distressing. Participants will have the PRISE performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
• The Montreal Cognitive Assessment (MoCA) [ Time Frame: 15 weeks ]
  The MOCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. It is scored out of a maximum of 30. The higher scores indicate better cognition. The MOCA will be performed at baseline, one day after infusions 1 and 4 and 12 weeks after the final infusion.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ketamine as an Adjunctive Therapy for Major Depression
• Official Title: Ketamine as an Adjunctive Therapy for Major Depression - a Randomised Controlled Pilot Trial: The KARMA-Dep Trial
• Brief Summary: Randomised, controlled, parallel-group, pilot clinical trial of ketamine vs. midazolam as an adjunctive therapy for depression. The main purpose of the pilot study is to assess trial processes to help inform a future definitive trial.
• Detailed Description: Pragmatic, randomised, controlled, parallel-group, pilot 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 20 participants who will be eligible for this study and randomly allocate 10 patients to each group. The participants will undergo usual inpatient care as prescribed by their treating team for the index acute depressive episode. Both participants and assessors will be blind to treatment allocation. Consented participants will be randomly allocated in a 1:1 ratio to a four week course of either once-weekly ketamine or midazolam infusions. Block randomisation will be independently performed. Physical, psychotomimetic and cognitive outcomes will be monitored before, during and after infusions. Blood samples will be taken at four time-points in the first infusion session and before the final infusion for neuroplasticity biomarker studies. Both groups will continue treatment as usual. Participates will also be followed up over a three month period.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Other

Condition

• Major Depressive Episode
• Unipolar Depression
• Bipolar Depression

Intervention

• Drug: Ketamine
  A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.
  Other Name: Ketalar
• Drug: Midazolam
  A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
  Other Name: Hypnovel

Study Arms

• Experimental: Ketamine
  Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist.
  Intervention: Drug: Ketamine
• Active Comparator: Midazolam
  Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist.
  Intervention: Drug: Midazolam

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 25, 2018): 25
• Original Estimated Enrollment (submitted: August 16, 2017): 20
• Actual Study Completion Date: September 21, 2018
• Actual Primary Completion Date: September 21, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ≥18 years old
• Hamilton Rating Scale for Depression-24 item version (HRSD-24) score of ≥21
• Voluntary admission for treatment of an acute depressive episode
• Meet Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-V) criteria for a major depressive disorder (MDD) and bipolar affective disorder (current episode depression)

Exclusion Criteria:

• Current involuntary admission
• Medical condition rendering unfit for ketamine/midazolam
• 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 or inability to confirm use of adequate contraception during the trial
• Breastfeeding women

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Ireland

Administrative Information

• NCT Number: NCT03256162
• Other Study ID Numbers: 01/17; 2016-004764-18 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Prof Declan McLoughlin, St Patrick's Hospital, Ireland
• Study Sponsor: St Patrick's Hospital, Ireland
• Collaborators: Not Provided

Investigators

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

• PRS Account: St Patrick's Hospital, Ireland
• Verification Date: January 2020