Trial Review

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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] 296058 0
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 309611 0
Advanced life limiting illnesses 309753 0
Condition category
Condition code
Mental Health 308427 308427 0 0
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] 312395 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307393 0
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] 307393 0
End of study
Secondary outcome [1] 351813 0
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] 351813 0
Throughout the 8 weeks of study period for participant
Secondary outcome [2] 351814 0
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] 351814 0
t0, t30min, t1hr, t1.5hr, t2hr, t4h, t6hr post each dose of ketamine commencement
Secondary outcome [3] 351815 0
Psychotomimetic symptoms (Brief Psychiatric Rating Scale)
Timepoint [3] 351815 0
t0, t1hr, t2hr, t4h, t6hr (4 hour post ketamine infusion completion) post each dose of ketamine commencement
Secondary outcome [4] 351816 0
Dissociative symptoms (Clinician-Administered Dissociative State Scale)
Timepoint [4] 351816 0
t0, t1hr, t2hr, t4h, t6hr (4 hour post ketamine infusion completion) post each dose of ketamine commencement
Secondary outcome [5] 351817 0
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] 351817 0
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] 351818 0
Numeric Pain Rating Scale
Timepoint [6] 351818 0
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] 351819 0
Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF)
Timepoint [7] 351819 0
t0min, t3 days, and t7days (t7 days would be t0min if repeat ketamine infusion is given).
Secondary outcome [8] 351820 0
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] 351820 0
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?
No
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
32
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 11829 0
Calvary Health Care Sydney Ltd - Kogarah
Recruitment hospital [2] 11830 0
Braeside Hospital - Prairiewood
Recruitment hospital [3] 11831 0
Sacred Heart Hospice - Darlinghurst
Recruitment hospital [4] 11832 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 23956 0
2217 - Kogarah
Recruitment postcode(s) [2] 23957 0
2176 - Prairiewood
Recruitment postcode(s) [3] 23958 0
2010 - Darlinghurst
Recruitment postcode(s) [4] 23959 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 300645 0
Hospital
Name [1] 300645 0
Sacred Heart Hospital
Country [1] 300645 0
Australia
Funding source category [2] 300740 0
Hospital
Name [2] 300740 0
Calvary Hospital
Country [2] 300740 0
Australia
Funding source category [3] 300741 0
Hospital
Name [3] 300741 0
Braeside Hospital
Country [3] 300741 0
Australia
Funding source category [4] 300742 0
Hospital
Name [4] 300742 0
Liverpool Hospital
Country [4] 300742 0
Australia
Primary sponsor type
University
Name
University of Technology Sydney
Address
15 Broadway, Ultimo NSW 2007
Country
Australia
Secondary sponsor category [1] 300178 0
None
Name [1] 300178 0
Address [1] 300178 0
Country [1] 300178 0
Other collaborator category [1] 280351 0
Individual
Name [1] 280351 0
Colleen Loo
Address [1] 280351 0
Black Dog Institute, Hospital Road, Prince of Wales Hospital, Randwick NSW 2031
Country [1] 280351 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301434 0
South Western Sydney Local Health District (Liverpool)
Ethics committee address [1] 301434 0
Ethics committee country [1] 301434 0
Australia
Date submitted for ethics approval [1] 301434 0
12/10/2018
Approval date [1] 301434 0
18/02/2019
Ethics approval number [1] 301434 0
HREC/18/LPOOL/466

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86982 0
Dr Wei Lee
Address 86982 0
University of Technology Sydney, 15 Broadway, Ultimo NSW 2007
Country 86982 0
Australia
Phone 86982 0
+61 2 9514 4862
Fax 86982 0
Email 86982 0
[email protected]
Contact person for public queries
Name 86983 0
Linda Brown
Address 86983 0
Palliative Care Clinical Studies Collaborative (PACCSC),
University of Technology Sydney,
Level 3, 235 Jones St, Ultimo, NSW 2007
Country 86983 0
Australia
Phone 86983 0
+61 2 9514 4862
Fax 86983 0
Email 86983 0
[email protected]
Contact person for scientific queries
Name 86984 0
Wei Lee
Address 86984 0
University of Technology Sydney, 15 Broadway, Ultimo NSW 2007
Country 86984 0
Australia
Phone 86984 0
+61 2 9514 4862
Fax 86984 0
Email 86984 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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
SourceTitleYear of PublicationDOI
EmbaseStudy protocol for SKIPMDD: Subcutaneous ketamine infusion in palliative care patients with advanced life limiting illnesses for major depressive disorder (phase II pilot feasibility study).2021https://dx.doi.org/10.1136/bmjopen-2021-052312
N.B. These documents automatically identified may not have been verified by the study sponsor.