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Trial registered on ANZCTR


Registration number
ACTRN12621000052831
Ethics application status
Approved
Date submitted
5/11/2020
Date registered
21/01/2021
Date last updated
21/01/2021
Date data sharing statement initially provided
21/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
DREAMS: Comparing dexmedetomidine versus midazolam at the end of life for sedative and anti-agitation effects
Scientific title
Dexmedetomidine versus midazolam for end of life agitation and sedation in palliative care patients
Secondary ID [1] 303051 0
Nil
Universal Trial Number (UTN)
Trial acronym
DREAMS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Distress at the end of life 319638 0
Sedation at the end of life 319639 0
Condition category
Condition code
Neurological 317579 317579 0 0
Other neurological disorders
Anaesthesiology 318059 318059 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For patients approaching the end of life suffering distress, dexmedetomidine (arm 1) or midazolam (arm 2) will be administered as a continuous subcutaneous infusion, with rescue doses of the infusion medication available. Patients will be randomised at consent to arm 1 or arm 2. Effects of midazolam and dexmedetomidine will be assessed by treating clinicians utilising assessment of sedation (Richmond Agitation Sedation Scale - Palliative type, RASS-PAL), as well assessment of delirium (using Memorial Delirium Assessment Score, MDAS). Patient comfort will be assessed via questionnaire completed by family / carers.


Both arms:
-Analgesia will be provided at clinician’s prescription
-Reversible causes of distress and agitation at end of life will be treated in line with goals of care
-Bowel and bladder function will be assessed and normalised as possible
-Investigational agent will be delivered via continuous subcutaneous infusion pump (syringe driver) in a unique device with no admixture
-Maximum duration of infusion will be until death (expected maximum 7 days)
-Crossover to standard care or escalation if consent withdrawn, or clinical concerns, side effects require crossover, treatment proves ineffective. Standard care will be determined in line with the EAPC framework for terminal sedation, https://bmcpalliatcare.biomedcentral.com/articles/10.1186/1472-684X-9-20


Interventional arm is Dexmedetomidine Arm, “Arm 1”:

Arm 1 Infusion:
Dexmedetomidine 12mcg/kg via subcutaneous infusion, rounded up to nearest 10mcg, over 24 hours.

Arm 1 Rescue:
Dexmedetomidine 0.5mcg/kg, given as required, up to every 2 hours subcutaneously, rounded up to nearest 10mcg. Rescue doses will be given if symptoms are not adequately controlled with medication infusion.

Doses will be pre-calculated on a per-patient basis by the trial team.
Intervention code [1] 319001 0
Treatment: Drugs
Comparator / control treatment
Control arm is Midazolam Arm, “Arm 2”:

Arm 2 Infusion:
Midazolam 0.25mg/kg via subcutaneous infusion, rounded up to nearest 1mg, over 24 hours.

Arm 2 Rescue:
Midazolam 2.5mg given as required, up to every 2 hours subcutaneously. Rescue doses will be given if symptoms are not adequately controlled with medication infusion.

Doses will be pre-calculated on a per-patient basis by the trial team.
Control group
Active

Outcomes
Primary outcome [1] 325622 0
The outcome assessed is sedation, as assessed by the Richmond Agitation Sedation Score Palliative Subtype (RASS-PAL).

Goal is to determine whether one drug is 10% less sedative (RASS-PAL score of 1 higher) than the other agent.

Timepoint [1] 325622 0
Assessments performed daily until the end of life, expected maximum duration of treatment of 10 days.
Secondary outcome [1] 388593 0
Amount of restlessness on dexmedetomidine and midazolam, as measured by family utilising the Comfort Score (scores in the mild range, <4/10, the majority of the time).
Timepoint [1] 388593 0
Assessments performed daily until the end of life, expected maximum duration of treatment of 10 days.
Secondary outcome [2] 388594 0
Average MDAS score to assess level of delirium for patients on dexmedetomidine infusion.
MDAS of 13+ equates to moderate to severe delirium
MDAS of 6-12 equates to mild delirium
MDAS of 5 or below equates to no delirium
Timepoint [2] 388594 0
Assessments performed daily until the end of life, expected maximum duration of treatment of 10 days.

Eligibility
Key inclusion criteria
-Admitted to hospital
-English speaking, or suitable availability of an interpreter for trial procedures
-Consent obtained to inclusion
-Deteriorate towards end of life care requiring sedatives for comfort, as diagnosed by the assessment of the expert treating palliative clinician, and remaining inpatient for end of life care.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Non-English speaking, or no interpreter availability
-Known severe left ventricular dysfunction (defined as an ejection fraction of <20% on known echocardiography, in patients with a prior history of heart failure. as available within the past 12 months either via inpatient or outpatient scans within the last 12 months

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)
Not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Based on an expected between group difference of 1 unit with a SD of 1.26 it is estimated that 26 subjects will be required per group to achieve statistical significance at an alpha of 0.05 and 80% power, as calculated by the Statistical Consulting Centre, University of Wollongong.

Recruitment
Recruitment status
Not yet 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
Recruitment hospital [1] 17967 0
Port Kembla Hospital - Warrawong
Recruitment hospital [2] 17968 0
Wollongong Hospital - Wollongong
Recruitment hospital [3] 17969 0
Shoalhaven Hospital - Nowra
Recruitment postcode(s) [1] 31841 0
2502 - Warrawong
Recruitment postcode(s) [2] 31842 0
2500 - Wollongong
Recruitment postcode(s) [3] 31843 0
2541 - Nowra

Funding & Sponsors
Funding source category [1] 307150 0
Government body
Name [1] 307150 0
Illawarra Shoalhaven Local Health District
Address [1] 307150 0
67-71 King Street District Executive Office Suite 2, Level 2, Warrawong NSW 2505
Country [1] 307150 0
Australia
Primary sponsor type
Individual
Name
Dr Benjamin Thomas
Address
Port Kembla Hospital, 89-91 Cowper Street Warrawong New South Wales 2502
Country
Australia
Secondary sponsor category [1] 307738 0
None
Name [1] 307738 0
Address [1] 307738 0
Country [1] 307738 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307263 0
Joint University of Wollongong and Illawarra Shoalhaven Local Health District Health and Medical Human Research Ethics Committee
Ethics committee address [1] 307263 0
The University of Wollongong
Northfields Avenue, Wollongong, NSW 2500
Ethics committee country [1] 307263 0
Australia
Date submitted for ethics approval [1] 307263 0
01/09/2020
Approval date [1] 307263 0
05/11/2020
Ethics approval number [1] 307263 0
2020/ETH01943

Summary
Brief summary

Patients near the end of life may suffer from an array of distressing symptoms, including pain, nausea, agitation, confusion and distress. Many patients will be delirious, with up to 88% of palliative care inpatients suffering a terminal delirium. When patients are distressed at the end of life, and other targeted symptomatic management has been unsuccessful, or when patients are struggling with confusion or distress, the treatment offered may be sedation, in order to relieve symptoms of anxiety, restlessness, emotional anguish and distress.

Patients who require sedation at the end of life often appear comfortable to treating clinicians, but the loss of biographical life and interaction is often difficult and distressing to family and loved ones, and to patients themselves. Whilst comfort does appear to be maintained, the use of alternative sedation to allow meaningful biographical interaction with a patients loved ones could be considered desirable, especially if comfort could be preserved.

Dexmedetomidine is an imidazole alpha-2 receptor agonist utilised commonly in the intensive care and anaesthetic environments. Dexmedetomidine was investigated in a clinical trial setting at the Port Kembla Palliative Care Unit (Joint University of Wollongong and Illawarra Shoalhaven Local Health District Human Research Ethics Committee (2018/247) as a potential therapeutic option for terminal delirium and rousable sedation, with results showing a trend to interactive sedation and decreased delirium.

Standard care for distress at the end of life has typically involved benzodiazepine infusions, in Australia the most commonly utilised is midazolam. Despite this, the evidence base for benzodiazepine infusions at the end of life is not robust, with usage predominantly predicated on professional consensus and guidelines. Small-scale observational studies and retrospective analysis have been performed, but there is minimal evidence in the literature for actual efficacy trials, especially in patients treated with midazolam in the terminal phase of life.

Given the gap in knowledge, the investigators propose a randomised controlled trial into the use of dexmedetomidine versus midazolam via continuous subcutaneous infusion (CSCI) in patients for sedation at the end of life. The subcutaneous (SC) route is chosen for this study as the preferred route of delivery as this conforms to the current standard of care for medication infusions given within the ISLHD for palliative care patients, and in NSW.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106614 0
Dr Benjamin Thomas
Address 106614 0
Port Kembla Hospital
89-91 Cowper Street
Warrawong NSW 2502
Country 106614 0
Australia
Phone 106614 0
+61 0242238380
Fax 106614 0
Email 106614 0
benjamin.thomas@health.nsw.gov.au
Contact person for public queries
Name 106615 0
Dr Benjamin Thomas
Address 106615 0
Port Kembla Hospital
89-91 Cowper Street
Warrawong NSW 2502
Country 106615 0
Australia
Phone 106615 0
+61 0242238380
Fax 106615 0
Email 106615 0
benjamin.thomas@health.nsw.gov.au
Contact person for scientific queries
Name 106616 0
Dr Benjamin Thomas
Address 106616 0
Port Kembla Hospital
89-91 Cowper Street
Warrawong NSW 2502
Country 106616 0
Australia
Phone 106616 0
+61 0242238380
Fax 106616 0
Email 106616 0
benjamin.thomas@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results