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Trial registered on ANZCTR


Registration number
ACTRN12619000683134
Ethics application status
Approved
Date submitted
3/05/2019
Date registered
7/05/2019
Date last updated
16/10/2019
Date data sharing statement initially provided
7/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Study of Ketamine for Youth Depression
Scientific title
Study of Ketamine for Youth Depression
Secondary ID [1] 298125 0
None
Universal Trial Number (UTN)
U1111-1232-6927
Trial acronym
SKY-D
Linked study record
n/a

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder 312656 0
Condition category
Condition code
Mental Health 311152 311152 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention in SKY-D is low-dose ketamine, administered once a week for 4 weeks. All treatments will be administered using subcutaneous injection. The starting dose (Level 1) of ketamine is 0.6mg/kg. Participants with inadequate treatment response will be provided with an increased dose, up to a maximum dose of 0.9mg/kg of ketamine. Those who are unable to tolerate the starting dose will have their dosage reduced for subsequent treatments to a minimum of 0.5mg/kg of ketamine (Level 0). Ability to tolerate dose will be determined based on participant subjective report and objective observations taken over four hours for the first treatment, and two hours for treatments 2, 3 and 4.
Intervention code [1] 314345 0
Treatment: Drugs
Comparator / control treatment
The control treatment in SKY-D is low-dose midazolam, administered once a week for 4 weeks. All treatments will be administered using subcutaneous injection. The starting dose of midazolam is 0.03mg/kg. Participants with inadequate treatment response will be provided with an increased dose, up to a maximum dose of 0.045mg/kg of midazolam. Those who are unable to tolerate the starting dose will have their dosage reduced for subsequent treatments to a minimum of 0.025mg/kg of midazolam.
Control group
Active

Outcomes
Primary outcome [1] 319927 0
The primary outcome is change in depression scores, defined as a reduction in the researcher-rated MADRS at 4 weeks compared with baseline MADRS.
Timepoint [1] 319927 0
Week 4 (Day 28) Follow-up
Secondary outcome [1] 369906 0
Sustained change in the researcher-rated MADRS compared with baseline MADRS
Timepoint [1] 369906 0
Week 8 (Day 56) and Week 26 (Day 182) Follow-ups
Secondary outcome [2] 369907 0
Change in the researcher-rated MADRS at 24 hours after each of the four treatment sessions, compared with the pre-administration MADRS before each session
Timepoint [2] 369907 0
Days 1, 8, 15 and 22.
Secondary outcome [3] 370055 0
Change in self-rated depression symptoms using the self-rated Quick Inventory of Depression Symptomatology (QIDS).
Timepoint [3] 370055 0
Week 4 (Day 28) and Week 8 (Day 56) Follow-ups
Secondary outcome [4] 370056 0
Remission of depression defined as MADRS score less than or equal to 10.
Timepoint [4] 370056 0
Week 4 (Day 28) and Week 8 (Day 56) Follow-ups
Secondary outcome [5] 370057 0
Change in suicidal ideation using the self-report Suicidal Ideation Screen (SIS).
Timepoint [5] 370057 0
Week 4 (Day 28) and Week 8 (Day 56) Follow-ups
Secondary outcome [6] 370058 0
Absence of suicidal thoughts, defined as a MADRS Suicidality Item score of 0.
Timepoint [6] 370058 0
Week 4 (Day 28) And Week 8 (Day 56) Follow-ups
Secondary outcome [7] 370059 0
Absence of a suicide attempt – defined as a score of 0 on the Columbia Suicide Severity Rating Scale (CSSRS) ‘actual attempt’ criterion.
Timepoint [7] 370059 0
Week 4 (Day 28) and Week 8 (Day 56) Follow-ups
Secondary outcome [8] 370060 0
Researcher-rated response to treatment, defined as a Clinical Global Impression–Improvement (CGI-I) score of less than or equal to 2 (“much” or “very much” improved).
Timepoint [8] 370060 0
Week 4 (Day 28) and Week 8 (Day 56) Follow-ups.
Secondary outcome [9] 370061 0
Participant-rated response to treatment, defined as a Patient Global Impression – Improvement (PGI-I) score of less than or equal to 2 (“much” or “very much” improved).
Timepoint [9] 370061 0
Week 4 (Day 28) Follow-up.
Secondary outcome [10] 370062 0
Change in anxiety scores using the Generalized Anxiety Disorder 7-item (GAD-7) scale.
Timepoint [10] 370062 0
Week 4 (Day 28) and Week 8 (Day 56) Follow-up.
Secondary outcome [11] 370063 0
Change in quality of life scores using the Assessment of Quality of Life (AQoL-8D).
Timepoint [11] 370063 0
Week 4 (Day 28) and Week 8 (Day 56) Follow-ups.
Secondary outcome [12] 370064 0
Change in social and occupational functioning using the Social and Occupational Functioning Assessment Scale (SOFAS).
Timepoint [12] 370064 0
Week 4 (Day 28) and Week 8 (Day 56) Follow-ups.
Secondary outcome [13] 370066 0
Exploratory outcome: To assess the safety of low-dose subcutaneous ketamine by analysing changes in cognitive function (Cogstate).
Timepoint [13] 370066 0
Week 4 (Day 28) Follow-up.
Secondary outcome [14] 370067 0
Exploratory outcome: To assess the safety of low-dose subcutaneous ketamine by analysing changes in clinical blood parameters (include Full Blood Examination, Electrolytes, Urea and Creatinine, Liver Function Test, and Thyroid Function Test).
Timepoint [14] 370067 0
Week 4 (Day 28) Follow-up.
Secondary outcome [15] 370068 0
Exploratory outcome: To assess the safety of low-dose subcutaneous ketamine by analysing adverse effects, as measured using the Ketamine Side Effect Tool.
Timepoint [15] 370068 0
Days 0, 7, 114, 21, 28, 56, 182.
Secondary outcome [16] 370069 0
Exploratory outcome: To assess the safety of low-dose subcutaneous ketamine by analysing psychotomimetic effects, using the Brief Psychiatric Rating Scale and Clinician Administered Dissociative Symptoms Scale.
Timepoint [16] 370069 0
Treatment Days 0, 7, 14, 21.
Secondary outcome [17] 370070 0
Exploratory outcome: To assess the safety of low-dose subcutaneous ketamine by analysing abuse liability as assessed using the Alcohol, Smoking and Substance Involvement Screening Tool and the Brief Substance Craving Scale.
Timepoint [17] 370070 0
Week 4 (Day 28), Week 8 (Day 28) and Week 26 (Day 182) follow-ups.
Secondary outcome [18] 370071 0
Exploratory outcome: To investigate biomarkers of ketamine's effect using pre- and post-treatment assessment of magnetic resonance spectroscopy to examine brain spectra of glutamate, glutamine and glutathione.
Timepoint [18] 370071 0
Week 4 (Day 28) Follow-up.
Secondary outcome [19] 370072 0
Exploratory outcome: To investigate biomarkers of ketamine's effect using pre- and post-treatment assessment of functional magnetic resonance imaging tasks to identify baseline predictors of treatment response, and brain correlates of response.
Timepoint [19] 370072 0
Week 4 (Day 28) Follow-up
Secondary outcome [20] 370073 0
Exploratory outcome: To investigate biomarkers of ketamine's effect using pre- and post-treatment assessment of blood samples to conduct pharmacokinetic analysis of plasma concentrations of ketamine and its major active metabolites, and analyse biomarkers related to treatment response (e.g., brain derived neurotrophic factor)
Timepoint [20] 370073 0
Day 0 and Day 28.
Secondary outcome [21] 370074 0
Exploratory outcome: To investigate functional markers of ketamine's effect using pre- and post-treatment assessment of objective (actigraphy) and subjective (Pittsburgh Sleep Quality Index) measures of sleep to assess whether sleep is a mechanism underlying ketamine’s rapid anti-depressant effects, and whether sleep effects predict treatment response to ketamine.
Timepoint [21] 370074 0
Week 4 (Day 28) Follow up.
Secondary outcome [22] 370075 0
Exploratory outcome: To investigate functional markers of ketamine's effect using acute drug effects (assessed using the Hood Mysticism Scale and the Drug Effects Questionnaire) to assess whether such effects predict treatment response.
Timepoint [22] 370075 0
Treatment days 0, 7, 14 and 21.
Secondary outcome [23] 370076 0
Exploratory outcome: To assess whether early anti-depressant response to ketamine (measured by the MADRS at 24 hours after each treatment) is a potential predictor of sustained anti-depressant response (measured by the MADRS at weeks 4, 8 and 26).
Timepoint [23] 370076 0
Week 4 (Day 28), Week 8 (Day 56), and Week 26 (Day 182) Follow-ups.

Eligibility
Key inclusion criteria
• Age 16–25 years inclusive at the time of providing informed consent;
• Current MDD as assessed using the Structured Clinical Interview for DSM-5 (SCID-5);
• MADRS score greater than or equal to 22 – equivalent to moderate-to-severe depression – within 7 days (Day -7 to Day -1) of the first treatment visit;
• Treatment with either a stable dose of an antidepressant or no antidepressant medication for greater than or equal to 2 weeks;
• Ability to provide written informed consent (including both adequate intellectual capacity and fluency in the English language).
Minimum age
16 Years
Maximum age
25 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Severe disturbance such that the young person would be unable to comply with the requirements of informed consent or comply with the study protocol, as determined by the trial doctor;
• History of psychosis or bipolar disorder (assessed with SCID-5);
• Any unstable medical or neurologic condition, or medical or pharmaceutical contraindication to ketamine or midazolam use (as indicated in the Product Information forms for ketamine and midazolam);
• Any history of a ketamine use disorder of any severity, or presence of a substance use disorder of at least moderate severity (DSM-5) within the preceding 6 months, as determined by the trial doctor;
• Females who are pregnant or currently breastfeeding, or who are not using effective contraception.
• Participation in any other clinical intervention trial from SKY-D baseline to the Week 8 follow-up.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This study uses a double blind design, such that allocation is concealed to the person who determines eligibility. Allocation will be determined using the online Research Project Management System (RPMS) that has been developed at Orygen, which conceals the allocation sequence.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be developed by a statistician independent of the trial. Randomisation will be stratified by trial site and age (under 21 years, and 21 years and over). Random permutated blocks will be used.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary analyses will be based on the intention-to-treat (ITT) inclusion of all participants randomised. Wherever applicable we will use generalised linear mixed models to analyse both efficacy and safety outcomes, as these models have a number of features relevant to this study: (i) tolerance of missing data; (ii) allowance of both normally distributed outcomes (e.g., MADRS scores) and non-normal outcomes (e.g., binary measures such as remission) in the models; and (iii) incorporation of random effects to allow for inter-individual differences, especially for longitudinal data and site effects.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC

Funding & Sponsors
Funding source category [1] 302656 0
Government body
Name [1] 302656 0
National Health and Medical Research Council of Australia
Address [1] 302656 0
16 Marcus Clarke St
Canberra ACT 2601
Country [1] 302656 0
Australia
Primary sponsor type
Other
Name
Orygen, the National Centre of Excellence in Youth Mental Health
Address
35 Poplar Rd (Locked Bag 10)
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 302576 0
None
Name [1] 302576 0
Address [1] 302576 0
Country [1] 302576 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303278 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 303278 0
Melbourne Health Human Research Ethics Committee
Royal Melbourne Hospital City Campus
RMH, Victoria, 3050
Australia
Ethics committee country [1] 303278 0
Australia
Date submitted for ethics approval [1] 303278 0
28/08/2018
Approval date [1] 303278 0
13/11/2018
Ethics approval number [1] 303278 0
HREC/42984/MH-2018

Summary
Brief summary
The primary aim of this research project is to determine if a 4-week course of low-dose subcutaneous ketamine is an effective treatment for young people
(males and females aged 16-25 years) with moderate-to-severe depression. Participants will be randomised to receive either low-dose subcutaneous ketamine or a blinded control treatment that is therapeutically inactive (midazolam), given once a week for 4 weeks. Change in depression scores will be assessed at the end of the treatment phase at week 4, with further assessment at weeks 8 and 26 to assess whether treatment effects are sustained. We hypothesise that ketamine will be an effective treatment for moderate-to-severe depression in young people.
Trial website
n/a
Trial related presentations / publications
n/a
Public notes
n/a

Contacts
Principal investigator
Name 93110 0
A/Prof Christopher Davey
Address 93110 0
Orygen, The National Centre of Excellent in Youth Mental Health
Locked Bag 10 (35 Poplar Rd)
Parkville VIC 3052
Australia
Country 93110 0
Australia
Phone 93110 0
+61 3 9966 9151
Fax 93110 0
Email 93110 0
christopher.davey@orygen.org.au
Contact person for public queries
Name 93111 0
A/Prof Christopher Davey
Address 93111 0
Orygen, The National Centre of Excellent in Youth Mental Health
Locked Bag 10 (35 Poplar Rd)
Parkville VIC 3052
Australia
Country 93111 0
Australia
Phone 93111 0
+61 3 9966 9151
Fax 93111 0
Email 93111 0
christopher.davey@orygen.org.au
Contact person for scientific queries
Name 93112 0
A/Prof Christopher Davey
Address 93112 0
Orygen, The National Centre of Excellent in Youth Mental Health
Locked Bag 10 (35 Poplar Rd)
Parkville VIC 3052
Australia
Country 93112 0
Australia
Phone 93112 0
+61 3 9966 9151
Fax 93112 0
Email 93112 0
christopher.davey@orygen.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after deidentification.
When will data be available (start and end dates)?
Immediately following publication and for a further 3 years.
Available to whom?
Investigators whose proposed use of the data has been approved by an independent
review committee.
Available for what types of analyses?
To achieve aims outlined in the approved protocol
How or where can data be obtained?
Proposals can be submitted up to three years following article publication. Initial
contact should be directed to an Executive Officer at Orygen, The National Centre
of Excellence in Youth Mental Health, located in Parkville, Victoria. Phone +61 (0)
3 9966 9574 or via https://www.orygen.org.au/Contact/ContactUs#
ContactForm.
Note: To gain access to the data requesters must sign a data access agreement.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
How or where can supporting documents be obtained?
Type [1] 5340 0
Study protocol
Citation [1] 5340 0
Link [1] 5340 0
Email [1] 5340 0
Other [1] 5340 0
We aim to publish the study protocol in a peer reviewed journal.
Attachment [1] 5340 0
Type [2] 5341 0
Statistical analysis plan
Citation [2] 5341 0
Link [2] 5341 0
Email [2] 5341 0
research@orygen.org.au
Other [2] 5341 0
Attachment [2] 5341 0
Type [3] 5342 0
Informed consent form
Citation [3] 5342 0
Link [3] 5342 0
Email [3] 5342 0
research@orygen.org.au
Other [3] 5342 0
Attachment [3] 5342 0
Summary results
No Results