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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

27/10/2023

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]

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

Condition category

Condition code

Mental Health

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]

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]

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]

Week 4 (Day 28) Follow-up

Secondary outcome [1]

Sustained change in the researcher-rated MADRS compared with baseline MADRS

Timepoint [1]

Week 8 (Day 56) and Week 26 (Day 182) Follow-ups

Secondary outcome [2]

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]

Days 1, 8, 15 and 22.

Secondary outcome [3]

Change in self-rated depression symptoms using the self-rated Quick Inventory of Depression Symptomatology (QIDS).

Timepoint [3]

Week 4 (Day 28) and Week 8 (Day 56) Follow-ups

Secondary outcome [4]

Remission of depression defined as MADRS score less than or equal to 10.

Timepoint [4]

Week 4 (Day 28) and Week 8 (Day 56) Follow-ups

Secondary outcome [5]

Change in suicidal ideation using the self-report Suicidal Ideation Screen (SIS).

Timepoint [5]

Week 4 (Day 28) and Week 8 (Day 56) Follow-ups

Secondary outcome [6]

Absence of suicidal thoughts, defined as a MADRS Suicidality Item score of 0.

Timepoint [6]

Week 4 (Day 28) And Week 8 (Day 56) Follow-ups

Secondary outcome [7]

Absence of a suicide attempt – defined as a score of 0 on the Columbia Suicide Severity Rating Scale (CSSRS) ‘actual attempt’ criterion.

Timepoint [7]

Week 4 (Day 28) and Week 8 (Day 56) Follow-ups

Secondary outcome [8]

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]

Week 4 (Day 28) and Week 8 (Day 56) Follow-ups.

Secondary outcome [9]

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]

Week 4 (Day 28) Follow-up.

Secondary outcome [10]

Change in anxiety scores using the Generalized Anxiety Disorder 7-item (GAD-7) scale.

Timepoint [10]

Week 4 (Day 28) and Week 8 (Day 56) Follow-up.

Secondary outcome [11]

Change in quality of life scores using the Assessment of Quality of Life (AQoL-8D).

Timepoint [11]

Week 4 (Day 28) and Week 8 (Day 56) Follow-ups.

Secondary outcome [12]

Change in social and occupational functioning using the Social and Occupational Functioning Assessment Scale (SOFAS).

Timepoint [12]

Week 4 (Day 28) and Week 8 (Day 56) Follow-ups.

Secondary outcome [13]

Exploratory outcome: To assess the safety of low-dose subcutaneous ketamine by analysing changes in cognitive function (Cogstate).

Timepoint [13]

Week 4 (Day 28) Follow-up.

Secondary outcome [14]

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]

Week 4 (Day 28) Follow-up.

Secondary outcome [15]

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]

Days 0, 7, 114, 21, 28, 56, 182.

Secondary outcome [16]

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]

Treatment Days 0, 7, 14, 21.

Secondary outcome [17]

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]

Week 4 (Day 28), Week 8 (Day 28) and Week 26 (Day 182) follow-ups.

Secondary outcome [18]

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]

Week 4 (Day 28) Follow-up.

Secondary outcome [19]

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]

Week 4 (Day 28) Follow-up

Secondary outcome [20]

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]

Day 0 and Day 28.

Secondary outcome [21]

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]

Week 4 (Day 28) Follow up.

Secondary outcome [22]

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]

Treatment days 0, 7, 14 and 21.

Secondary outcome [23]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Active, not recruiting

Date of first participant enrolment

Anticipated

20/05/2019

Actual

1/07/2019

Date of last participant enrolment

Anticipated

30/11/2023

Actual

11/09/2023

Date of last data collection

Anticipated

11/03/2024

Actual

Sample size

Target

140

Accrual to date

Final

110

Recruitment in Australia

Recruitment state(s)

NSW,QLD,VIC

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council of Australia

Address [1]

16 Marcus Clarke St
Canberra ACT 2601

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health Human Research Ethics Committee

Ethics committee address [1]

Melbourne Health Human Research Ethics Committee
Royal Melbourne Hospital City Campus
RMH, Victoria, 3050
Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

28/08/2018

Approval date [1]

13/11/2018

Ethics approval number [1]

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

Prof Christopher Davey

Address

Level 1 North Block
Royal Melbourne Hospital
300 Grattan Street
Parkville VIC 3050
Australia

Country

Australia

Phone

+61 3 8344 5509

Fax

[email protected]

Contact person for public queries

Name

Christopher Davey

Address

Level 1 North Block
Royal Melbourne Hospital
300 Grattan Street
Parkville VIC 3050
Australia

Country

Australia

Phone

+61 3 8344 5509

Fax

[email protected]

Contact person for scientific queries

Name

Christopher Davey

Address

Level 1 North Block
Royal Melbourne Hospital
300 Grattan Street
Parkville VIC 3050
Australia

Country

Australia

Phone

+61 3 8344 5509

Fax

[email protected]

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)?

Data will be available Immediately following publication, for an indefinite time

Available to whom?

Data will potentially be available to researchers from not-for profit organisations, commercial organisations or other based in any location. All data requests will be considered by the data custodian and the primary sponsor on a case-by-case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted. For further information, see Orygen data sharing policy

Available for what types of analyses?

To any type of analyses. Assessed on a case-by-case basis

How or where can data be obtained?

Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health). Search for the ACTRN number in the catalogue to find datasets associated with this trial.

What supporting documents are/will be available?

Doc. No.	Type	Email	Attachment
5340	Study protocol		377513-(Uploaded-27-10-2023-12-49-23)-Study-related document.pdf
5341	Statistical analysis plan	[email protected]
5342	Informed consent form	[email protected]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	The Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder.	2023	https://dx.doi.org/10.1186/s13063-023-07631-3

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically