KINDRED: Ketamine for Relapse Prevention in Recurrent Depressive Disorder

• Sponsor: St Patrick's Hospital, Ireland (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02661061
• Collaborator: (none)
• Enrollment: 9
• Location: 1
• Arms: 2
• Duration (Months): 29.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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.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: Dec 1, 2015
• Actual Primary Completion Date: May 23, 2018
• Actual Study Completion Date: May 23, 2018

Arms and Interventions

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 Names: 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 Names: Hypnovel

Outcome Measures

Primary Outcome Measures

1. Completion Rate for Randomised Treatment Phase [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.

Secondary Outcome Measures

1. Depression Relapse Rate During Treatment and Follow-up Phase [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St Patrick's University Hospital	Dublin		Ireland	8

Sponsors and Collaborators

• St Patrick's Hospital, Ireland

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 15, 2016

More Information

Publications

None provided.

• Responsible Party: Prof Declan McLoughlin, Professor, St Patrick's Hospital, Ireland
• ClinicalTrials.gov Identifier: NCT02661061
• Other Study ID Numbers: 20/15; 2015-002020-37
• First Posted: Jan 22, 2016
• Last Update Posted: Jan 13, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Prof Declan McLoughlin, Professor, St Patrick's Hospital, Ireland: ketamine; glutamate; relapse prevention
• Additional relevant MeSH terms: Disease; Recurrence; Depression; Depressive Disorder; Depressive Disorder, Major; Midazolam; Ketamine

Study Results

Participant Flow

Recruitment Details	Participants were inpatients at St Patrick's Mental Health Services admitted for treatment of an acute depressive episode with a previous history of depression
Pre-assignment Detail	Participants were randomised from n=28 participants in an observational phase, all of whom were receiving inpatient treatment for recurrent depressive disorder. Participants were monitored weekly for response to treatment and those who responded were invited to be randomised.

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Trial Interventions: participants will receive four two-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart.	Trial Interventions: participants will receive four two-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart.
Period Title: Overall Study
STARTED	5	4
COMPLETED	3	2
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Ketamine	Midazolam	Total
Arm/Group Description	Trial Interventions: participants will receive four two-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart.	Trial Interventions: participants will receive four two-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart.	Total of all reporting groups
Overall Participants	5	4	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 80%	4 100%	8 88.9%
>=65 years	1 20%	0 0%	1 11.1%
Sex: Female, Male (Count of Participants)
Female	2 40%	3 75%	5 55.6%
Male	3 60%	1 25%	4 44.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	5 100%	4 100%	9 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Ireland	5 100%	4 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	Completion Rate for Randomised Treatment Phase
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

All randomised participants who received one infusion were analysed (intention to treat)

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Trial Interventions: participants will receive four two-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart.	Trial Interventions: participants will receive four two-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart.
Measure Participants	5	4
Count of Participants [Participants]	3 60%	2 50%

2. Secondary Outcome

Title	Depression Relapse Rate During Treatment and Follow-up Phase
Description	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.
Time Frame	8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Trial Interventions: participants will receive four two-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart.	Trial Interventions: participants will receive four two-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart.
Measure Participants	5	4
Count of Participants [Participants]	2 40%	3 75%

Adverse Events

Time Frame	Adverse event information was collected over the entire study time frame, 29 months, from December 2015 to May 2018. Individual participants were assessed over an approximately seven-month period including their inpatient admission, eight-week randomised treatment phase, and 26-week follow-up period.
Adverse Event Reporting Description	Tolerability of the trial agents was assessed at multiple points before, during and after treatment sessions using a battery of assessments used in assessing for physical and psychotomimetic side effects of ketamine (CADSS, BPRS, PRISE and YMRS), standard in the field of ketamine clinical trials for depression, as well as assessment of physical health parameters before, during and after assessments.
Arm/Group Title	Ketamine		Midazolam
Arm/Group Description	Trial Interventions: participants will receive four two-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart.		Trial Interventions: participants will receive four two-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart.
All Cause Mortality
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/4 (0%)
Serious Adverse Events
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/5 (20%)		1/4 (25%)
Immune system disorders
Delayed hypersensitivity reaction	1/5 (20%)	1	0/4 (0%)	0
Urticaria	0/5 (0%)	0	1/4 (25%)	1

Limitations/Caveats

Recruitment and randomisation rates in this pilot trial were low, leading to small participant numbers analysed. Due to the potential for breach of confidentiality, limited participant-level information has been reported.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.