ANZCTR - Registration

Did you know?

The ANZCTR now automatically displays published trial results and simplifies the addition of trial documents such as unpublished protocols and statistical analysis plans.

These enhancements will offer a more comprehensive view of trials, regardless of whether their results are positive, negative, or inconclusive.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

Trial registered on ANZCTR

Registration number

ACTRN12618001586202

Ethics application status

Approved

Date submitted

14/09/2018

Date registered

25/09/2018

Date last updated

23/05/2022

Date data sharing statement initially provided

23/07/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Low dose individually-tailored subcutaneous ketamine infusion for the treatment of depression in palliative care patients

Scientific title

Subcutaneous ketamine infusion in palliative care patients with advanced life limiting illnesses for major depressive disorder: A phase II pilot feasibility study

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1220-2848

Trial acronym

SKIPMDD

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Major Depressive Disorder

Advanced life limiting illnesses

Condition category

Condition code

Mental Health

Depression

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Individually tailored subcutaneous infusion of ketamine, at weekly intervals by response, commencing with 0.1-0.4mg/kg over 2 hours, up to 4 doses (4 weeks) with the maximal dose of 0.4mg/kg. This is followed by 4 weeks of follow up.

Commencement and titration of a typical antidepressant for depression by the treating clinical team’s choice if clinically appropriate (given 48 hours apart from ketamine administration).

Study data with its accuracy, and protocol compliance will be monitored by members of the Trial Management Committee or their delegates. Monitoring may include review of CRFs, patient’s clinical records, and being onsite to monitor protocol compliance and perform other relevant procedures.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Study feasibility measures of absolute numbers (including accrual rate per month throughout multiple centres) and proportions of palliative care patients, who are screened for depression, meet the study eligibility criteria, give consent, are treated with subcutaneous ketamine, and complete the study with repeated weekly dosing (according to response) for 4 weeks with a further 4 weeks of follow up (A total of 8 weeks)

Timepoint [1]

End of study

Secondary outcome [1]

Serious side effects (Common Terminology Criteria for Adverse Effect 4.0)

These are defined as effects which are:
- life-threatening at the time of the event or leads to death
- results in inpatient hospitalisation or prolonging the current hospital admission
- ends in persistent and/or significant disability or incapacity
- are likely to become serious if left untreated in the opinion of the investigator

Importantly, if the cause of the above outcomes is due to primary progression of disease, the medical occurrence is not considered as a serious side effect.

(There is no generalised CTCAE grading for all side effect that defines "serious side effect", as what constitutes a "clinically severe" side effect from the CTCAE grading differs between symptomatology e.g. Any grade of seizure is considered as severe vs = Grade 3 drowsiness)

Timepoint [1]

Throughout the 8 weeks of study period for participant

Secondary outcome [2]

Vital signs:
Oxygen saturation by pulse oximeter
Blood pressure by automatic or manual sphygmomanometer
Pulse rate by clinical examination or pulse oximeter
Respiratory rate by clinical examination
Temperature by ear thermometer

Timepoint [2]

t0, t30min, t1hr, t1.5hr, t2hr, t4h, t6hr post each dose of ketamine commencement

Secondary outcome [3]

Psychotomimetic symptoms (Brief Psychiatric Rating Scale)

Timepoint [3]

t0, t1hr, t2hr, t4h, t6hr (4 hour post ketamine infusion completion) post each dose of ketamine commencement

Secondary outcome [4]

Dissociative symptoms (Clinician-Administered Dissociative State Scale)

Timepoint [4]

t0, t1hr, t2hr, t4h, t6hr (4 hour post ketamine infusion completion) post each dose of ketamine commencement

Secondary outcome [5]

Change in Montgomery-Asberg Depression Rating Scale (MADRS) (Positive response defined as reduction by 50% of the baseline score; remission defined as score less or equal to 9)

Timepoint [5]

Measured at time points of t 0 min, 6 hours, then 1, 3, and 7 days post each ketamine, and weekly if no repeat ketamine administration up to 8 weeks.

Secondary outcome [6]

Numeric Pain Rating Scale

Timepoint [6]

At t0min, t6hr and t1day, t2 days, t3 days, t7days after each ketamine infusion then weekly if no repeat ketamine infusion up to 8 weeks post initial ketamine

Secondary outcome [7]

Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF)

Timepoint [7]

t0min, t3 days, and t7days (t7 days would be t0min if repeat ketamine infusion is given).

Secondary outcome [8]

Reasons potential participants are unable to complete each of the stages above after screening (including reasons patients are ineligible for the study) - assessed by interview on participant contact in person or through phone by the research team

Timepoint [8]

Throughout the study

Eligibility

Key inclusion criteria

Patients known to the palliative care services in the acute hospital, palliative care units or in the community with advanced life limiting illness and major depressive disorder in Australia (inclusive of those with very limited prognosis with Australia-modified Karnofsy Performance Scale [AKPS] 30 or less, and those with severe depression with MADRS 35 or more)

Inclusion criteria
• Adult males or females known to palliative care service with age greater than or equal to 18 yrs
• Palliative intent of treatment due to irreversible medical illnesses
• Patient Health Questionnaire-2 (PHQ-2) score greater than or equal to 3, and
• Major Depressive Disorder defined by Endicott Criteria diagnosed by trained personnel (e.g. psychiatry team, psychologist or trained research team member) with:
• MADRS Score greater than or equal to 16
• Willing and able to comply with all study requirements,
• Signed, written informed consent for the study

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Exclusion criteria
• Australian-modified Karnofsky Performance scale (AKPS) score less than or equal to 10
• Having curative intent to treatment
• Palliative intent life prolonging measures such as target therapies, radiotherapy or intravenous antibiotics is acceptable
• Methylphenidate use in the last 4 weeks
• Changes to antidepressant doses in the last 2 weeks prior to the commencement of ketamine
• Ketamine use in the last 4 weeks
• Previous significant adverse effect or hypersensitivity to ketamine
• Concurrent phenobarbitone use
• Factors of increased risk of intracranial pressure:
i. Recent ischaemic or haemorrhagic cerebral vascular accident in the last 1 month
ii. Brain tumours with symptoms and signs of increased intracranial pressure
iii. Seizure in the last 6 months
iv. Head trauma with symptoms of increased intracranial pressure
v. Hydrocephalus
vi. Uncontrolled nausea (Greater than or equal to grade 3 despite 1 line of antiemetic), vomiting and headache (e.g. from cerebral metastases, trauma)
vii. Greater than or equal to grade 3 despite one line of antiemetics
• Factors of increased risk of sympathomimetic response (hypertension and tachycardia) with associated complications
i. Uncontrolled hypertension with systolic blood pressure greater than or equal to 160
ii. Tachycardia with heart rate greater than or equal to 120 per minute.
iii. Symptomatic ischaemic heart disease (e.g. exertional angina) and decompensated heart failure with NYHA class III and IV symptoms
iv. Uncontrolled Hyperthyroidism (Low TSH with high T3 and/or T4)
v. Diagnosis and history of Prophyria
• Factors of increased risk of intraocular pressure with its complications
i. Glaucoma
ii. Open eye injury / Acute globe injury
• Severe hepatic impairment: Bilirubin greater than or equal to 3 times upper limit of normal; AST and/or ALT > 5 times upper limit of normal - clinically determined to be due to hepatic impairment
• Severe renal impairment (Creatinine clearance <15ml/min by Cockroft Gault Equation)
• Other mental disorders apart from major depression (lifetime history schizophrenia/bipolar/mania)
• Recent substance misuse as determined by the treating and research clinicians

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Single arm, multicentre, pilot feasibility study with individual dose tailoring design up to 8 weeks (4 weeks ketamine administration period and 4 weeks of follow up monitoring), for up to 2 years of recruitment

Phase

Phase 2

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

For this pilot phase 2 feasibility study, using a 2-tailed test (assuming ketamine can have a response less than placebo in the literature), aiming for a power of 80% and type 1 error (a) of 0.05, assuming a constant proportion of 0.1 (as in the literature, placebo may cause 10% of positive response) and a conservative effect size of 0.2 (ketamine causing only a positive response in 30%), we will need a minimum sample size of 33 over the trial period of up to 24 months (just < 1.5 participants per month up to 24 months).

Outcomes will be analysed using descriptive statistics. The prevalence of participants with positive response and remission on the MADRS score will be further stratified by various participant characteristics, including low AKPS score of less than or equal to 30 with clinical opinion of prognosis of days to weeks and high MADRS score of greater than or equal to 35 (to reflect severe depression). A one sample proportion Z test and 95% confidence interval will be performed to assess for ketamine activity.

Recruitment

Recruitment status

Stopped early

Data analysis

Data collected is being analysed

Reason for early stopping/withdrawal

Participant recruitment difficulties
Other reasons/comments

Other reasons

COVID-19 related impact making participant recruitment very difficult.

Date of first participant enrolment

Anticipated

29/07/2019

Actual

16/09/2019

Date of last participant enrolment

Anticipated

Actual

27/04/2021

Date of last data collection

Anticipated

Actual

25/05/2021

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Calvary Health Care Sydney Ltd - Kogarah

Recruitment hospital [2]

Braeside Hospital - Prairiewood

Recruitment hospital [3]

Sacred Heart Hospice - Darlinghurst

Recruitment hospital [4]

Liverpool Hospital - Liverpool

Recruitment postcode(s) [1]

2217 - Kogarah

Recruitment postcode(s) [2]

2176 - Prairiewood

Recruitment postcode(s) [3]

2010 - Darlinghurst

Recruitment postcode(s) [4]

2170 - Liverpool

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Sacred Heart Hospital

Address [1]

170 Darlinghurst Road, Darlinghurst, NSW 2010

Country [1]

Australia

Funding source category [2]

Hospital

Name [2]

Calvary Hospital

Address [2]

91-111 Rocky Point Road, Kogarah, NSW 2217

Country [2]

Australia

Funding source category [3]

Hospital

Name [3]

Braeside Hospital

Address [3]

340 Prairie Vale Road, Prairiewood, NSW 2176

Country [3]

Australia

Funding source category [4]

Hospital

Name [4]

Liverpool Hospital

Address [4]

Goulburn Street & Elizabeth Street, Liverpool, NSW 2170

Country [4]

Australia

Primary sponsor type

University

Name

University of Technology Sydney

Address

15 Broadway, Ultimo NSW 2007

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Individual

Name [1]

Colleen Loo

Address [1]

Black Dog Institute, Hospital Road, Prince of Wales Hospital, Randwick NSW 2031

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

South Western Sydney Local Health District (Liverpool)

Ethics committee address [1]

Locked Bag 7103, LIVERPOOL BC, NSW, 1871

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

12/10/2018

Approval date [1]

18/02/2019

Ethics approval number [1]

HREC/18/LPOOL/466

Summary

Brief summary

Depression is common in patients who have advanced life-limiting illness. There are significant time pressures for antidepressants to have rapid-onset effect in some palliative care patients. Most antidepressants, due to their slow onset of action, have limited therapeutic benefits in patients with extremely short prognoses or those with severe depression that require rapid effect while waiting for the typical antidepressants to take effect. In the psychiatry literature, subanaesthetic doses of ketamine are emerging as a novel rapid-onset antidepressant for treatment resistant major depression with high response rates, though having short-lived effect. 

There has been no similar trial done using ketamine to treat even de novo depression in the population with advanced life-limiting illness. There is a need to explore the activity of ketamine in palliative care patients, particularly those with very limited prognosis and/or severe depression that require immediate intervention where typical antidepressants are of limited utility for depression.

Further evidence may potentially allow ketamine to be used to treat severe depression in patients with very limited but uncertain prognosis (e.g. in the range of weeks) and be considered as a bridging therapy for those who have a longer prognosis for the typical antidepressants to have effects.

Prior to researchers committing to a larger phase 2/3 double blinded, cross over, randomised controlled trial, testing the activity of ketamine as antidepressant in the palliative care population, a feasibility study will be conducted with the aim to investigate: the number of patients who participate in, and subsequently complete, the ketamine intervention; the potential effects of ketamine; and the safety and tolerability of ketamine in this population.

Patients known to the palliative care services in the acute hospital, palliative care units or in the community with advanced life limiting illness and major depressive disorder in Australia will be included in this study.

The intervention is an individually tailored subcutaneous infusion of ketamine, given at weekly intervals by response, commencing with 0.1-0.4mg/kg over 2 hours, up to 4 doses (4 weeks) with the maximal dose of 0.4mg/kg. This is followed by 4 weeks of follow up.
Commencement and titration of a typical antidepressant for depression by the treating clinical team’s choice if clinically appropriate (given 48 hours apart from ketamine administration) is allowed for ethical reasons.

Primary Outcome is the number of palliative care patients completing through each stage of the study. Main secondary outcomes include serious side effects (CTCAE), psychotomimetic and dissociative symptoms (BPRS/CADSS), depression score (MADRS), quality of life score (Q-LES-Q-SF) and Numeric Pain Rating Scale.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Wei Lee

Address

University of Technology Sydney, 15 Broadway, Ultimo NSW 2007

Country

Australia

Phone

+61 2 9514 4862

Fax

wei.lee@student.uts.edu.au

Contact person for public queries

Name

Linda Brown

Address

Palliative Care Clinical Studies Collaborative (PACCSC),
University of Technology Sydney,
Level 3, 235 Jones St, Ultimo, NSW 2007

Country

Australia

Phone

+61 2 9514 4862

Fax

PaCCSC@uts.edu.au

Contact person for scientific queries

Name

Wei Lee

Address

University of Technology Sydney, 15 Broadway, Ultimo NSW 2007

Country

Australia

Phone

+61 2 9514 4862

Fax

wei.lee@student.uts.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Will require further discussion with other investigators /ethics to ensure sharing of data is compliant to HREC

What supporting documents are/will be available?

No Supporting Document Provided

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	Study protocol for SKIPMDD: Subcutaneous ketamine infusion in palliative care patients with advanced life limiting illnesses for major depressive disorder (phase II pilot feasibility study).	2021	https://dx.doi.org/10.1136/bmjopen-2021-052312

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

Trial Review

Did you know?

Documents added manually

Documents added automatically