Ketamine for Relapse Prevention in Recurrent Depressive Disorder (KINDRED)

• ClinicalTrials.gov Identifier: NCT02661061
• Recruitment Status: Terminated
• First Posted: January 22, 2016
• Results First Posted: January 13, 2020
• Last Update Posted: January 13, 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: December 10, 2015
• First Posted Date: January 22, 2016
• Results First Submitted Date: December 18, 2019
• Results First Posted Date: January 13, 2020
• Last Update Posted Date: January 13, 2020
• Study Start Date: December 2015
• Actual Primary Completion Date: May 23, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 7, 2020)

Completion Rate for Randomised Treatment Phase [ Time Frame: 2 years ]

The outcomes for this pilot trial are process outcomes, primarily rates of recruitment and retention. Thus, the completion rate for the randomised treatment phase is the primary outcome. The study is not designed to assess efficacy.

Original Primary Outcome Measures (submitted: January 18, 2016)

Process outcomes [ Time Frame: 2 years ]

The primary outcomes for this pilot trial are process outcomes to inform a future definitive trial, e.g. completion of assessments; success of blinding. Although some attrition can be expected during the six-month follow-up period, information collected on rates and reasons for drop-out will form a valuable feasibility outcome. Non-compliance is not expected due to intravenous administration of agents. Rates of recruitment, attrition and retention will be reported.

Current Secondary Outcome Measures (submitted: January 7, 2020)

Depression Relapse Rate During Treatment and Follow-up Phase [ Time Frame: 8 months ]

Clinical outcomes are secondary in this pilot trial. The 24-item Hamilton Rating Scale for Depression (HRSD-24) was used to assess for the main clinical outcome, the relapse rate over six months. Criteria for relapse are ≥10 point increase in HRSD-24 compared to baseline score plus HRSD ≥16; in addition, increase in the HRSD should be maintained one week later (if indicated, additional follow-ups will be arranged). Hospital admission, and deliberate self-harm/suicide also constitute relapse. Relapse may also occur during the eight-week treatment phase and is captured here.

Original Secondary Outcome Measures (submitted: January 18, 2016)

• Relapse of recurrent depressive disorder: 24-item Hamilton Rating Scale for Depression scores [ Time Frame: 6 months after recruitment for individual participants, 2.5 years for total study. ]
  The primary clinical outcome is the relapse rate at six months as measured by the primary clinical measure, the 24-item Hamilton Rating Scale for Depression (HRSD-24). To enter the study patients must score ≥21 at baseline. 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 (if indicated, additional follow-ups will be arranged). During the infusion sessions in the pilot trial HRSD-24 scores will be obtained 60 minutes before the infusion begins and at +120 and +240 minutes afterwards. Baseline scores on sleep and appetite items will be maintained for repeated measures within one day. Scores on the HRSD-24 over six-months will be reported.
• Tolerability of infusion regime; performance on assessments for psychomimetic effects, physical health measures, and cognitive assessments [ Time Frame: 8 weeks for individual participants, two years for total study . ]
  We will use the following instruments before, during (+35-40 mins) and after (+240 mins) ketamine infusions: Dissociative effects: Clinician-Administered Dissociative States Scale (CADSS), Psychotomimetic effects: positive symptoms subscale of the Brief Psychiatric Rating Scale (BPRS), Mood elevation: Young Mania Rating Scale (YMRS; mood item). These instruments will be used to assess cognitive outcomes at responder baseline (prior to randomisation) and during the pilot trial: one day after the first and fourth infusions and at six-months. Addenbrooke's Cognitive Examination III (ACE-3, Forward and Backward Digit Spans, Trail Making Test (Part A + B). Physical health measures of: Heart rate, blood pressure, pulse oximetry, and ECG before and during infusions and for a further 200 minutes, and the Patient-Rated Inventory of Side Effects (PRISE) will be used to document other general adverse events by patients before, during (+35-40 mins) and after (+240 mins) infusions.

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

Descriptive Information

• Brief Title: Ketamine for Relapse Prevention in Recurrent Depressive Disorder
• Official Title: Ketamine for Relapse Prevention in Recurrent Depressive Disorder: a Randomised, Controlled, Pilot Trial: the KINDRED Trial
• Brief Summary: Randomised, controlled, parallel-group, pilot clinical trial of ketamine vs. midazolam for depression relapse prevention in persons at high risk. The main purpose of the pilot study is to assess trial processes to help inform a future definitive trial.

Detailed Description

Participants will be recruited at admission to St Patrick's University Hospital for treatment of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)-diagnosed recurrent unipolar depression and followed-up weekly to assess recovery according to standard criteria. Blood samples for epigenetic studies will be taken at baseline. Treatment-as-usual will continue throughout the entire trial. Participants who meet standardised response criteria will then be invited to be randomised to course of four two-weekly ketamine or midazolam (active comparator) 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.Trial Interventions: participants will receive four two-weekly infusions of either ketamine at 0.05mg/kg or midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Repeated infusions of ketamine have been shown to be safe and well-tolerated by patients with mental illness. Minor haemodynamic changes and psychotomimetic side-effects can occur and will be assessed regularly during infusions and for 200 minutes afterwards.

Participants will be followed up over six months to assess for relapse according to standardised criteria. This is the highest-risk period for relapse and investigators hypothesize that ketamine will provide additional neurotrophic support (assessed by the laboratory biomarker project) which will result in lower relapse rates when compared to midazolam.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A randomised, double-blind, placebo-controlled study designed to assess feasibility of recruitment, randomisation and retention.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Masking took place by sealed envelope random allocation and double blinding of participants and raters was assessed throughout. The anaesthesiologist administering infusions was aware of the allocation.

Primary Purpose: Other

Condition

• Depression
• Relapse
• Recurrent Depressive Disorder
• Major Depressive Disorder

Intervention

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

Study Arms

• Experimental: Ketamine
  Trial Interventions: participants will receive four two-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist.
  Intervention: Drug: Ketamine
• Active Comparator: Midazolam
  Trial Interventions: participants will receive four two-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: Terminated
• Actual Enrollment (submitted: July 31, 2018): 9
• Original Estimated Enrollment (submitted: January 18, 2016): 40
• Actual Study Completion Date: May 23, 2018
• Actual Primary Completion Date: May 23, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ≥18 years old
• Hamilton Rating Scale for Depression, 24-item (HRSD-24) score of ≥21
• Voluntary admission for treatment of acute depressive episode
• Meet DSM-IV criteria for recurrent depressive disorder (RDD): ≥2 previous depressive episodes with at least 2-months(consecutive) subthreshold or no symptoms in between PLUS(to enrich the sample for those at high risk for relapse) must also have experienced ≥3 major depressive episodes(including index episode) within the previous 2 years

For the randomised pilot trial, RDD patients must have:

• received antidepressant treatment for the acute depressive episode(pharmacological, psychotherapeutic or multidisciplinary)
• ≥60% decrease from baseline HRSD-24 score and score ≤16
• Standardised Mini-Mental State Examination (sMMSE) score of ≥24
• able to provide informed consent

Exclusion Criteria:

• Current involuntary admission
• Medical condition rendering unfit for ketamine/midazolam
• Active suicidal intention
• Dementia
• History of Axis 1 diagnosis other than RDD
• Electroconvulsive therapy (ECT) for treatment of current depressive episode
• Alcohol/substance abuse in previous six months
• Pregnancy or inability to confirm use of adequate contraception during the trial

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: NCT02661061
• Other Study ID Numbers: 20/15; 2015-002020-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: None envisaged: data will be anonymised

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

Investigators

• Principal Investigator: Declan McLoughlin; University of Dublin, Trinity College

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