Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001499875
Ethics application status
Approved
Date submitted
7/09/2021
Date registered
4/11/2021
Date last updated
23/05/2022
Date data sharing statement initially provided
4/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Dexmedetomidine versus standard of care for the management of severe agitation in patients at end of life.
Scientific title
A randomized feasibility study comparing dexmedetomidine with standard of care drug therapy in the management of agitation patients with a palliative diagnosis in a hospice setting.
Secondary ID [1] 305253 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Agitation 323527 0
Condition category
Condition code
Neurological 321087 321087 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1
Dexmedetomidine infusion as per department guidelines (as per Waikato DHB Subcutaneous dexmedetomidine infusion guideline) starting at 0.4 mcg/kg/hr subcutaneously via continuous ambulatory delivery device (CADD-solis) or Alaris infusion pump, titrated to acceptable symptom control. Titration to a maximum of 1.4mcg/kg/hr over a duration fo 72 hours (treatment may continue beyond 72 hours, but data will not be collected after this time point)
Arm 2
Standard of care, which, for the purposes of this study, refers to the use of antipsychotic and/or benzodiazepine medication as per the treating clinician with reference to department guidelines

Treatment Failure and Subsequent Management:
Treatment failure is defined as the addition of, or change to, drug therapy different to the initial starting strategy. If agitation is not adequately controlled (i.e., RASS-PAL score of 0 to -2 is not achieved), the treating clinician can initiate other treatment as clinically appropriate, including treatment included in the other study arm. This would be deemed a failure of the original treatment arm. The patient will not be withdrawn from the study if treatment failure occurs, data on second-line therapy will continue to be collected.
Assessment Tools:
Agitation in the palliative care setting will be assessed using the Richmond-Agitation-Sedation Scale (RASS-PAL). This is a validated tool used to assess levels of agitation and sedation, modified for palliative care inpatients..
Use of the scale allows consistent measurement of sedation level in line with the aim to achieve a RASS-PAL score of </=0 in the management of problematic agitation.

All patients will have appropriate care in other respects, as per the treating clinician, including:
- Analgesia;
- Attempts to reverse any underlying cause of agitation, if consistent with the patient’s goals of care (e.g., antibiotics for an infection causing agitation, if the patients accepts this);
- Usual non-pharmacological management of agitation (e.g., low stimulus environment, safety partner if required).
- Attention to pressure areas and elimination;
- The patient’s usual medication, if consistent with their goals of care and remains appropriate to the clinical situation.

Participants will be assessed routinely (nursing ratio maximum of 1:2), data will be collected as follows:

In the first 24 hours after starting treatment, data collected will include:
• hourly RASS-PAL assessment;
• 4-hourly vital signs (if clinically appropriate);
• adverse effects (modified-CTCAE);
• bolus medications given (drug, dose, rationale, effect).
Data collected from 24-72 hours will include:
• 4-hourly RASS-PAL assessment;
• adverse effects (modified-CTCAE);
• bolus medications given (drug, dose, rationale, effect).
Intervention code [1] 321644 0
Treatment: Drugs
Comparator / control treatment
Standard of care, which, for the purposes of this study, refers to the use of antipsychotic and/or benzodiazepine medication as per the treating clinician with reference to Waikato DHB Palliative Care department guidelines.

Maximum doses of antipsychotic and benzodiazepine medications include:
haloperidol 5mg/24 hours
levomepromazine 300mg/24 hours
phenobarbitone 2000mg/24 hours
Midazolam 100mg/24 hours
clonazepam 3mg/24 hours

In the first 24 hours after starting treatment, data collected will include:
• hourly RASS-PAL assessment;
• 4-hourly vital signs (if clinically appropriate);
• adverse effects (modified-CTCAE);
• bolus medications given (drug, dose, rationale, effect).
Data collected from 24-72 hours will include:
• 4-hourly RASS-PAL assessment;
• adverse effects (modified-CTCAE);
• bolus medications given (drug, dose, rationale, effect).
Control group
Active

Outcomes
Primary outcome [1] 328870 0
The mean time to achieving a RASS-PAL score </= 0.
Compare time infusion was started with time RASS-PAL score </= 0 achieved; this will be achieved by reviewing medical records, electronic prescribing programme (Medi-map) and data recorded on case report forms.
Timepoint [1] 328870 0
Study duration of 72 hours from initiation of treatment
Secondary outcome [1] 400685 0
Duration of time at RASS-PAL </= 0 using the primary strategy;
determined by review of medical records and case report forms
RASS-PAL
Timepoint [1] 400685 0
72 hours from initiation of treatment
Secondary outcome [2] 401357 0
Mean time for second-line therapy to achieve a RASS-PAL score </= 0.
Data is collected through review of medical notes, nurse records, completed case record forms, as per our research protocol.
Hourly RASS-Pal score will be taken for 24 hours then 4 hourly for the next 48 hours (total 72 hours from initiation of treatment.
Timepoint [2] 401357 0
72 hours from initiation of treatment
Secondary outcome [3] 401360 0
Second-line therapy used in each group;
Data is collected through review of medical notes, nurse records, completed case record forms, review of electronic prescribing platform, as per our research protocol.
Timepoint [3] 401360 0
72 hours from initiation of treatment
Secondary outcome [4] 401362 0
Tolerability and adverse effects of dexmedetomidine infusion.
1. Examples of known possible adverse effects are provided in the research protocol, patient information leaflet and precedex medsafe datasheet.

Dexmedetomidine is generally well tolerated, side effects which can occur include:
• Hypotension
• Hypertension
• Dry mouth/thirst
• Bradycardia
• Nausea
• Fever


2. Adverse effect will graded using the common terminology criteria for adverse events (as per research protocol)
Timepoint [4] 401362 0
72 hours from initiation of treatment
Secondary outcome [5] 401363 0
Proportion of patients with RASS-PAL scores >0 over the first 48 hours;
Data is collected through review of medical notes, nurse records, completed case record forms, review of electronic prescribing platform, as per our research protocol.
Timepoint [5] 401363 0
48 hours from initiation of treatment
Secondary outcome [6] 402185 0
Time to treatment failure (TTF), defined as the time from treatment initiation to the addition of, or change to, drug therapy different to the initial treatment strategy;
Data is collected through review of medical notes, nurse records, completed case record forms, review of electronic prescribing platform, as per our research protocol.
Timepoint [6] 402185 0
72 hours from initiation of treatment

Eligibility
Key inclusion criteria
• Palliative diagnosis with a prognosis of 6 months or less;
• Patient has agitation requiring pharmacological management (RASS-PAL greater than or equal to +2);
• 18 years and over.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Patients with known AV block in the absence of functioning pacemaker;
• Bradycardia (baseline heart rate less than 55 beats per minute);
• Patients with end-stage heart failure with documented ejection fraction <20%;
• Hypotension (systolic blood pressure < 90mmHg);
• Patients with a chronic mental health history who are taking long-term antipsychotic medication.
• Non-English speaking

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)

Sequentially-numbered, sealed envelopes will be kept at the site, and opened in order to allocate treatment arm for each consented participant.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This trial will use permuted block randomisation to allocate each participant to one of the two treatment arms: Arm 1 = dexmedetomidine; Arm 2 = SOC. Sequentially-numbered, sealed envelopes will be kept at the site, and opened in order to allocate treatment arm for each consented participant.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size:
Based on the likely number of participants able to be recruited in 12 months, in order to inform recruitment estimates for subsequent larger studies.
Based on an audit undertaken by investigators, this study has 66% power with 2-sided alpha=0.05 to detect the difference in mean time to achieving a RASS-PAL score </= 0 in 20 randomised participants. If the adjusted mean in the dexmedetomidine group is used, the same number of randomised participants gives 99% power to detect this difference with 2-sided alpha=0.05.

Statistical analysis:
Primary endpoint will be analysed by the student t test.
Secondary endpoints will be analysed by the student t test for quantitative outcomes, and the Kaplan-Meier method for time-to-event outcomes.
Descriptive statistics will be used for participant demographics, second-line therapy, tolerability and adverse effects.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/12/2021
Actual
Date of last participant enrolment
Anticipated
1/12/2022
Actual
Date of last data collection
Anticipated
5/12/2022
Actual
Sample size
Target
20
Accrual to date
0
Final
Recruitment outside Australia
Country [1] 24103 0
New Zealand
State/province [1] 24103 0
Waikato

Funding & Sponsors
Funding source category [1] 309622 0
Charities/Societies/Foundations
Name [1] 309622 0
Waikato Medical Research Foundation Grant
Country [1] 309622 0
New Zealand
Primary sponsor type
Individual
Name
Dr Lana Ferguson
Address
Palliative Care Department
Waikato District Health Board
Pembroke Street
Hamilton 3204
New Zealand
Country
New Zealand
Secondary sponsor category [1] 310640 0
None
Name [1] 310640 0
NA
Address [1] 310640 0
NA
Country [1] 310640 0
Other collaborator category [1] 281977 0
Individual
Name [1] 281977 0
Prof. Michael Jameson
Address [1] 281977 0
Cancer and Blood Research Trial Unit
Waikato District Health Board
Pembroke Street
Hamilton 3204
New Zealand
Country [1] 281977 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309397 0
Health and Disability Ethics Committee New Zealand
Ethics committee address [1] 309397 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 309397 0
New Zealand
Date submitted for ethics approval [1] 309397 0
20/09/2021
Approval date [1] 309397 0
17/02/2022
Ethics approval number [1] 309397 0
11051

Summary
Brief summary
The purpose of this pilot study determine if dexmedetomidine provides more rapid control of all-cause agitation than standard of care (SOC) drug therapy for patients at end of life.
The study hypothesis is that dexmedetomidine achieves more rapid and sustained control of all cause agitation than current SOC.

While several overseas centres are using dexmedetomidine, there is currently no published randomised controlled trial evaluating the efficacy or superiority of dexmedetomidine over current SOC. The results of this and subsequent collaborative trials with NZ and overseas palliative care colleagues have the potential to significantly change the current management and SOC for patients with agitation in the palliative care setting, both in New Zealand and internationally.
Trial website
nil.
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114010 0
Dr Lana Ferguson
Address 114010 0
Palliative Care Department
Waikato District Health Board
Pembroke street
Hamilton 3204
Country 114010 0
New Zealand
Phone 114010 0
+64 27 2507962
Fax 114010 0
Email 114010 0
lana.ferguson2@waikatodhb.health.nz
Contact person for public queries
Name 114011 0
Dr Lana Ferguson
Address 114011 0
Palliative Care Department
Waikato District Health Board
Pembroke street
Hamilton 3204
Country 114011 0
New Zealand
Phone 114011 0
+64 7 8388899
Fax 114011 0
Email 114011 0
lana.ferguson2@waikatodhb.health.nz
Contact person for scientific queries
Name 114012 0
Dr Lana Ferguson
Address 114012 0
Palliative Care Department
Waikato District Health Board
Pembroke street
Hamilton 3204
Country 114012 0
New Zealand
Phone 114012 0
+64 7 8388899
Fax 114012 0
Email 114012 0
lana.ferguson2@waikatodhb.health.nz

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 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.