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Trial registered on ANZCTR


Registration number
ACTRN12622001532796
Ethics application status
Approved
Date submitted
1/12/2022
Date registered
12/12/2022
Date last updated
12/12/2022
Date data sharing statement initially provided
12/12/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A multicentre, cluster randomised, double cross over pragmatic clinical trial comparing the safety and efficacy of enteral olanzapine with quetiapine in critically ill patients with hyperactive delirium
Scientific title
A multicentre, cluster randomised, double cross over pragmatic clinical trial comparing the safety and efficacy of enteral olanzapine with quetiapine in critically ill patients with hyperactive delirium
Secondary ID [1] 308466 0
Nil known
Universal Trial Number (UTN)
Trial acronym
CALM-ICU
Linked study record

Health condition
Health condition(s) or problem(s) studied:
critical illness 328270 0
hyperactive delirium 328271 0
Condition category
Condition code
Neurological 325315 325315 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This multicentre, cluster randomised, double cross over, pragmatic clinical trial will compare the safety and efficacy of enteral (tablet) olanzapine with quetiapine in critically ill patients with hyperactive delirium. The double cross over design means that we will randomise ICUs (instead of individual patients) to the open label use of olanzapine or quetiapine over four treatment periods, with each treatment period being a three-month block. Dosage of anti-psychotic (using allocated anti-psychotic for that treatment period) will be left to discretion of treating clinician. Usual daily doses of olanzapine would be 20mg or less (in divided doses). Usual daily doses of quetiapine would be 200mg or less (in divided doses). Medication charts are reviewed daily.

The plan for study drug administration is that the patient exclusively receives the allocated enteral anti-psychotic for the first three doses of pharmacological hyperactive delirium treatment (including doses administered as part of the regular regime or when required) before other agents are considered as part of hyperactive delirium ‘usual care’ (with the exception of the alternative anti-psychotic i.e. no use of olanzapine if the ICU is currently randomised to the quetiapine arm). Usual care is in accordance with (the ICU section of) hospital delirium guidelines where quetiapine and olanzapine are potential therapies.

Duration of study treatment will be until death, discharge from ICU, 14 days after commencing treatment, or the treating Intensivist believes the patient no longer requires the use of an anti-psychotic to treat hyperactive delirium, whichever comes first. If clinicians deem the study drug (olanzapine or quetiapine) should continue after ICU, this is allowed according to clinical judgement.

There will be no ‘washout’ between the crossover periods, but patients who remain in ICU at a point of crossover will remain on the treatment they were originally assigned.
Intervention code [1] 324906 0
Treatment: Drugs
Comparator / control treatment
Enteral olanzapine will be the comparator treatment
Control group
Active

Outcomes
Primary outcome [1] 333180 0
Alive delirium/coma free days.

A patient will be regarded as delirium/coma free for that calendar day if:
- They are alive and discharged from ICU OR
- They are alive in the ICU with:
- the Richmond Agitation - Sedation Scale (RASS) score being -2 or greater all day AND
- the Confusion Assessment Method for the ICU (CAM-ICU) assessment found to be negative (each time the assessment has been completed that calendar day)

Please note:
- All ICU patients have a CAM-ICU/RASS score recorded at least twice a day as part of standard clinical care at participating sites
- 'Delirium free days' commence once the patient is NOT delirious again throughout the 14-day study period
- If clinicians deem the study drug (olanzapine or quetiapine) should continue after ICU, this is allowed according to clinician judgement.
- This data is obtained from the electronic medical record by trained staff.
Timepoint [1] 333180 0
Censored at 14 days after study enrolment.
Secondary outcome [1] 416065 0
Mortality, assessed using the patient's electronic medical record
Timepoint [1] 416065 0
Censored to hospital discharge
Secondary outcome [2] 416066 0
Delirium days, assessed using the patient's electronic medical record
Timepoint [2] 416066 0
Duration of patient's ICU stay
Secondary outcome [3] 416067 0
ICU length of stay, assessed using the patient's electronic medical record
Timepoint [3] 416067 0
Patient discharge from ICU
Secondary outcome [4] 416068 0
Hospital length of stay, assessed using the patient's electronic medical record
Timepoint [4] 416068 0
Patient discharge from hospital
Secondary outcome [5] 416069 0
Duration of mechanical ventilation in those who were ventilated at randomisation, assessed using the patient's electronic medical record
Timepoint [5] 416069 0
Measured throughout the entire duration of the patient's stay in ICU
Secondary outcome [6] 416070 0
Adverse drug events, assessed using the patient's electronic medical record and 'Riskman' reporting. Examples of possible adverse events include extrapyramidal side effects (EPSE), neuroleptic malignant syndrome (NMS) and electrocardiogram (ECG) changes.
Timepoint [6] 416070 0
Measured throughout the entire duration of the patient's stay in ICU
Secondary outcome [7] 416071 0
Compliance outcome: the number of enteral doses of allocated study drug per patient assessed using the patient's electronic medical record
Timepoint [7] 416071 0
Measured daily throughout the entire duration of the patient's stay in ICU
Secondary outcome [8] 416072 0
Compliance outcome: the number of enteral doses of 'non-study' anti-psychotic administered per patient (i.e. olanzapine if the ICU has been allocated quetiapine for the three-month period) assessed using the patient's electronic medical record
Timepoint [8] 416072 0
Measured daily throughout the entire duration of the patient's stay in ICU
Secondary outcome [9] 416073 0
Compliance outcome: the number of doses of intravenous (IV) or intramuscular (IM) olanzapine administered and total amount (in mg) on the calendar day, assessed using the patient's electronic medical record
Timepoint [9] 416073 0
Measured daily throughout the entire duration of the patient's stay in ICU
Secondary outcome [10] 416074 0
Compliance outcome: The number of doses of clonidine administered per patient (enteral or IV bolus) or number of hours (infusion) on the calendar day; total amount of clonidine will also be recorded (in microg) for the day, assessed using the patient's electronic medical record
Timepoint [10] 416074 0
Measured daily throughout the entire duration of the patient's stay in ICU
Secondary outcome [11] 416075 0
Compliance outcome: The number of doses of haloperidol administered per patient (enteral or IV bolus) and total amount of haloperidol (in mg) on the calendar day, assessed using the patient's electronic medical record
Timepoint [11] 416075 0
Measured daily throughout the entire duration of the patient's stay in ICU
Secondary outcome [12] 416076 0
Compliance outcome: the number of hours per patient that dexmedetomidine infusion is administered on the calendar day. Total amount of dexmedetomidine will also be recorded (in microg) for the day, assessed using the patient's electronic medical record
Timepoint [12] 416076 0
Measured daily throughout the entire duration of the patient's stay in ICU
Secondary outcome [13] 416077 0
Compliance outcome: the number of doses of benzodiazepine (specify individual agent) administered per patient (enteral or IV bolus) or number of hours (infusion) on the calendar day. Total amount of benzodiazepine will also be recorded (in mg) for the day, assessed using the patient's electronic medical record
Timepoint [13] 416077 0
Measured daily throughout the entire duration of the patient's stay in ICU
Secondary outcome [14] 416539 0
Compliance outcome: the total amount of 'non-study' anti-psychotic administered in mg per patient (i.e. olanzapine if the ICU has been allocated quetiapine for the three-month period) on the calendar day, assessed using the patient's electronic medical record.
Timepoint [14] 416539 0
Measured daily throughout the entire duration of the patient's stay in ICU
Secondary outcome [15] 416540 0
Compliance outcome: the total amount of study drug in mg per patient per calendar day, assessed using the patient's electronic medical record
Timepoint [15] 416540 0
Measured daily throughout the entire duration of the patient's stay in ICU

Eligibility
Key inclusion criteria
A patient in one of the three participating ICU's will be eligible if they are 18 years of age or older and require pharmacological treatment for hyperactive delirium as indicated by administration of an anti-psychotic (during their initial ICU admission).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they were regularly taking an anti-psychotic medication prior to hospital admission or they have an allergy to either olanzapine or quetiapine.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The double cross over design will randomise entire ICUs (as opposed to individual patients) to the open label use of olanzapine or quetiapine for three months (first treatment period). During the second treatment period the ICU will be allocated to the alternative treatment. This will comprise one sequence period. At the start of the second sequence (third treatment period) the cluster can remain on the alternative treatment or change back to the original allocated therapy before alternating again for the final three-month block (fourth treatment period). The treatment order will be randomised with the possible order being ABAB, BABA, ABBA or BAAB (with the two treatment options the sites could be allocated = A and B).
This simple randomisation was completed using computer software (computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All data will be assessed for normality. Baseline comparisons were performed using chi-square tests for equal proportion, student t-tests for normally distributed data and Wilcoxon rank sum tests otherwise with results reported as n (%), mean (standard deviation) or median (interquartile range) respectively. The primary outcome (alive delirium/coma free days censored at 14 days) will be analysed using quantile regression with clustered at an ICU level and adjustment for randomization time period and order of administration of treatment, with results reported as difference of medians (95%CI). Sensitivity analysis will be adopted using mixed linear modelling adjusting for period and order with robust standard errors clustered at an ICU level and results reported as difference of means (95%CI). Binomial secondary outcomes (mortality & any adverse event) will be compared between treatment arms using generalised estimating equations with adjustment for time period and order of administration of the treatments, with an exchangeable working correlation matrix and robust standard errors using the ICU as the clustering unit. Duration of mechanical ventilation along with ICU and hospital length of stay will be compared between treatment arms using Cox regression with robust standard errors clustered at ICU level to estimate cause-specific hazard ratios (95%CI) with results summarized as medians (interquartile range) and presented as cumulative incidence functions with death treated as a competing risk. All analysis will be performed using SAS Version 9.4 (SAS Institute Inc., Cary, NC, USA) and a two sided p-value of 0.05 was used to indicate statistical significance for the primary outcome. No adjustment will be made for multiplicity in secondary outcomes and as such all secondary outcome findings will be considered to be hypothesis generating.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
14/12/2022
Actual
Date of last participant enrolment
Anticipated
29/03/2024
Actual
Date of last data collection
Anticipated
28/06/2024
Actual
Sample size
Target
1200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23625 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 23626 0
The Alfred - Melbourne
Recruitment hospital [3] 23627 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 39044 0
3050 - Royal Melbourne Hospital
Recruitment postcode(s) [2] 39046 0
3004 - Melbourne
Recruitment postcode(s) [3] 39047 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 312708 0
Charities/Societies/Foundations
Name [1] 312708 0
The Australian and New Zealand Intensive Care Foundation
Country [1] 312708 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
300 Grattan Street, Parkville VIC 3050
Country
Australia
Secondary sponsor category [1] 314331 0
None
Name [1] 314331 0
Address [1] 314331 0
Country [1] 314331 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312009 0
Royal Melbourne Hospital Human Research Ethics Committee
Ethics committee address [1] 312009 0
Ethics committee country [1] 312009 0
Australia
Date submitted for ethics approval [1] 312009 0
Approval date [1] 312009 0
26/10/2021
Ethics approval number [1] 312009 0

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

Contacts
Principal investigator
Name 123158 0
Ms Melissa Ankravs
Address 123158 0
Royal Melbourne Hospital
300 Grattan Street, Parkville Victoria 3050
Country 123158 0
Australia
Phone 123158 0
+61 3 9342 9240
Fax 123158 0
Email 123158 0
melissa.ankravs@mh.org.au
Contact person for public queries
Name 123159 0
Melissa Ankravs
Address 123159 0
Royal Melbourne Hospital
300 Grattan Street, Parkville Victoria 3050
Country 123159 0
Australia
Phone 123159 0
+61 3 9342 9240
Fax 123159 0
Email 123159 0
melissa.ankravs@mh.org.au
Contact person for scientific queries
Name 123160 0
Melissa Ankravs
Address 123160 0
Royal Melbourne Hospital
300 Grattan Street, Parkville Victoria 3050
Country 123160 0
Australia
Phone 123160 0
+61 3 9342 9240
Fax 123160 0
Email 123160 0
melissa.ankravs@mh.org.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 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.