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Ketamine for Relapse Prevention in Recurrent Depressive Disorder (KINDRED)

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ClinicalTrials.gov Identifier: NCT02661061
Recruitment Status : Terminated (Inadequate recruitment)
First Posted : January 22, 2016
Last Update Posted : August 2, 2018
Sponsor:
Information provided by (Responsible Party):
Prof Declan McLoughlin, St Patrick's Hospital, Ireland

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.

Condition or disease Intervention/treatment Phase
Depression Relapse Recurrent Depressive Disorder Major Depressive Disorder Drug: Ketamine Drug: Midazolam Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
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
Official Title: Ketamine for Relapse Prevention in Recurrent Depressive Disorder: a Randomised, Controlled, Pilot Trial: the KINDRED Trial
Study Start Date : December 2015
Actual Primary Completion Date : May 23, 2018
Actual Study Completion Date : May 23, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: Ketamine
A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart.
Other Name: Ketalar

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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.


  2. 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.




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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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02661061


Locations
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Ireland
St Patrick's University Hospital
Dublin, Ireland, 8
Sponsors and Collaborators
St Patrick's Hospital, Ireland
Investigators
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Principal Investigator: Declan McLoughlin Trinity College Dublin

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Responsible Party: Prof Declan McLoughlin, Professor, St Patrick's Hospital, Ireland
ClinicalTrials.gov Identifier: NCT02661061     History of Changes
Other Study ID Numbers: 20/15
2015-002020-37 ( EudraCT Number )
First Posted: January 22, 2016    Key Record Dates
Last Update Posted: August 2, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: None envisaged: data will be anonymised
Keywords provided by Prof Declan McLoughlin, St Patrick's Hospital, Ireland:
ketamine
glutamate
relapse prevention
Additional relevant MeSH terms:
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Ketamine
Disease
Recurrence
Depression
Depressive Disorder
Depressive Disorder, Major
Pathologic Processes
Behavioral Symptoms
Mood Disorders
Mental Disorders
Disease Attributes
Midazolam
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