ANZCTR - Registration

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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

6/02/2023

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]

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

Sedation at the end of life

Condition category

Condition code

Neurological

Other neurological disorders

Anaesthesiology

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-Crossover to standard care or escalation if consent withdrawn, or clinical concerns, side effects require crossover, treatment proves ineffective.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]

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]

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]

Assessments performed daily until the end of life, expected maximum duration of treatment of 10 days.

Secondary outcome [1]

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]

Assessments performed daily until the end of life, expected maximum duration of treatment of 10 days.

Secondary outcome [2]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Recruiting

Date of first participant enrolment

Anticipated

30/01/2021

Actual

30/04/2021

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]

Port Kembla Hospital - Warrawong

Recruitment hospital [2]

Wollongong Hospital - Wollongong

Recruitment hospital [3]

Shoalhaven Hospital - Nowra

Recruitment postcode(s) [1]

2502 - Warrawong

Recruitment postcode(s) [2]

2500 - Wollongong

Recruitment postcode(s) [3]

2541 - Nowra

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Illawarra Shoalhaven Local Health District

Address [1]

67-71 King Street District Executive Office Suite 2, Level 2, Warrawong NSW 2505

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Joint University of Wollongong and Illawarra Shoalhaven Local Health District Health and Medical Human Research Ethics Committee

Ethics committee address [1]

The University of Wollongong
Northfields Avenue, Wollongong, NSW 2500

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/09/2020

Approval date [1]

05/11/2020

Ethics approval number [1]

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

Dr Benjamin Thomas

Address

Port Kembla Hospital
89-91 Cowper Street
Warrawong NSW 2502

Country

Australia

Phone

+61 0242238380

Fax

benjamin.thomas@health.nsw.gov.au

Contact person for public queries

Name

Benjamin Thomas

Address

Port Kembla Hospital
89-91 Cowper Street
Warrawong NSW 2502

Country

Australia

Phone

+61 0242238380

Fax

benjamin.thomas@health.nsw.gov.au

Contact person for scientific queries

Name

Benjamin Thomas

Address

Port Kembla Hospital
89-91 Cowper Street
Warrawong NSW 2502

Country

Australia

Phone

+61 0242238380

Fax

benjamin.thomas@health.nsw.gov.au

Data sharing statement

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

No/undecided IPD sharing reason/comment

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

No additional documents have been identified.

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