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Trial registered on ANZCTR


Registration number
ACTRN12619000284167
Ethics application status
Approved
Date submitted
27/10/2018
Date registered
25/02/2019
Date last updated
25/02/2019
Date data sharing statement initially provided
25/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Use of the antipsychotic olanzapine to treat agitation in traumatic brain injury
Scientific title
Use of olanzapine to treat agitation in traumatic brain injury: A randomised controlled trial.
Secondary ID [1] 296442 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Traumatic brain injury 310205 0
Post-traumatic amnesia 310206 0
Agitation 310207 0
Condition category
Condition code
Neurological 308950 308950 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Olanzapine, Optimal Environmental Management: Treatment will be administered orally in capsule form initially at a dosage of 5mg/day at night. If agitation scores do not reduce after 3 days (as measured by the Agitated Behaviour Scale), the dose will be increased by 5 mg every 3 days up to a maximum daily dose of 20mg/day. Escalation will be as follows: Escalation one - 5mg morning, 5mg night; escalation two - 5mg morning, 10mg night; escalation three - 10mg morning, 10mg night. Participants will also receive optimal environmental management to minimise agitation. Treatment will continue until the patient emerges from post-traumatic amnesia, defined as the third of three consecutive days in which a score of 12 is obtained on the Westmead Post-Traumatic Amnesia Scale, or when a maximum of 6 months in a state of post-traumatic amnesia have elapsed. Each active capsule will contain 5mg olanzapine, as well as Avicel (filler) and turmeric (colouring agent).
During this trial, all participants will receive environmental management designed to minimise agitation including being located in a secure and quiet ward, avoiding restraint and overstimulation, allowing frequent rest, with dedicated, consistent staff optimising communication, reassurance and orientation. They will receive any physiotherapy, speech therapy or occupational therapy treatment on the ward. Visitors will be regulated to avoid overstimulation.
Intervention code [1] 312768 0
Treatment: Drugs
Comparator / control treatment
Placebo, Optimal Environmental Management: Treatment will be administered orally in capsule form initially at a dosage of 5mg/day at night. If agitation scores do not reduce after 3 days (as measured by the Agitated Behaviour Scale), the dose will be increased by 5 mg every 3 days up to a maximum daily dose of 20mg/day. Escalation will be as follows: Escalation one - 5mg morning, 5mg night; escalation two - 5mg morning, 10mg night; escalation three - 10mg morning, 10mg night. Placebo encapsulation will appear identical to the active treatment. Participants will also receive optimal environmental management to minimise agitation.
Placebo capsules will contain Avicel (filler) and turmeric (colouring agent).
Control group
Placebo

Outcomes
Primary outcome [1] 307914 0
Mean level of agitation as assessed by the Agitated Behaviour Scale
Timepoint [1] 307914 0
Daily across treatment period.
Secondary outcome [1] 353313 0
Mean number of agitated days as measured by the Agitated Behaviour Scale
Timepoint [1] 353313 0
Daily across treatment period
Secondary outcome [2] 353314 0
Mean agitation level at hospital discharge as measured by the Agitated Behaviour Scale.
Timepoint [2] 353314 0
At hospital discharge
Secondary outcome [3] 353315 0
Mean level of post-traumatic amnesia as measured by the Westmead Post Traumatic Amnesia Scale.
Timepoint [3] 353315 0
Daily across treatment period
Secondary outcome [4] 353316 0
Mean duration of post-traumatic amnesia as measured by the Westmead Post Traumatic Amnesia Scale.
Timepoint [4] 353316 0
Daily across treatment period
Secondary outcome [5] 353317 0
Cognitive performance as measured by mean total words recalled over five trials on the Rey Auditory Verbal Learning Test.
Timepoint [5] 353317 0
Following emergence from post-traumatic amnesia
Secondary outcome [6] 353318 0
Mean length of inpatient hospital stay in days as measured from participant's medical record.
Timepoint [6] 353318 0
From hospital admission to discharge
Secondary outcome [7] 353319 0
Level of functional independence as measured by mean score on the Functional Independence Measure
Timepoint [7] 353319 0
Hospital discharge
Secondary outcome [8] 353320 0
Composite variable, cost of olanzapine administration - Encompassing medical record indicated medication use, therapy hours, length of hospital stay, special nursing care and Post-Discharge Health Service Utilisation Care data.
Timepoint [8] 353320 0
Daily across treatment period, following emergence from post-traumatic amnesia, at hospital discharge, at three-month follow-up.
Secondary outcome [9] 367014 0
Cognitive performance as measured by mean number of items completed on the oral version of the Symbol Digit Modalities Test.
Timepoint [9] 367014 0
Following emergence from post-traumatic amnesia
Secondary outcome [10] 367015 0
Level of functional independence as measured by mean score on the Mayo Portland Adaptability Inventory-4.
Timepoint [10] 367015 0
3 month follow up
Secondary outcome [11] 367016 0
Composite outcome, cost per unit improvement on the Agitated Behaviour Scale - Cost of olanzapine and placebo administration per mean unit improvement on the Agitated Behaviour Scale.
Timepoint [11] 367016 0
Daily across treatment period, following emergence from post-traumatic amnesia, at hospital discharge, at three-month follow-up.
Secondary outcome [12] 367017 0
Composite outcome, cost per unit improvement on the Functional Independence Measure - Cost of olanzapine and placebo administration per mean unit improvement on the Functional Independence Measure.
Timepoint [12] 367017 0
Daily across treatment period, following emergence from post-traumatic amnesia, at hospital discharge, at three-month follow-up.
Secondary outcome [13] 367018 0
Composite outcome, cost per quality-adjusted life year gained - Cost of olanzapine and placebo administration per quality-adjusted life year as calculated using mean 12-Item Short Form Health Survey SF-6D utility index scores and derived using Australian weights
Timepoint [13] 367018 0
Daily across treatment period, following emergence from post-traumatic amnesia, at hospital discharge, at three-month follow-up.
Secondary outcome [14] 367019 0
Functional independence as measured by mean scores on the Functional Independence Measure Mental Component Summary subscale
Timepoint [14] 367019 0
Hospital discharge.
Secondary outcome [15] 367020 0
Functional independence as measured by mean scores on the Functional Independence Measure Physical Component Summary subscale
Timepoint [15] 367020 0
Hospital discharge.
Secondary outcome [16] 367021 0
Cognitive performance as measured by mean number of errors on the oral version of the Symbol Digit Modalities Test.
Timepoint [16] 367021 0
Following emergence from post-traumatic amnesia

Eligibility
Key inclusion criteria
1. A history of blunt head trauma with a loss of consciousness AND/OR an initial GCS of 3-14 AND/OR a period of PTA,
2. Judged to be in PTA (score < 12 on the WPTAS),
3. Judged to be in a state of clinically significant agitation (score > 21 on the ABS),
4. Aged 18-75 years, inclusive,
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of neuropsychological illness, psychotic illness or severe substance dependence,
2. Medical or pharmacological contraindications.

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)
The randomisation schedule will be supplied from independent Epworth biostatistician to a compounding pharmacist at Slade Pharmacy, Epworth HealthCare, Richmond, who will prepare sealed opaque envelopes containing the group assignment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be undertaken by an independent Epworth HealthCare accredited biostatistician employing permuted blocks of random length in line with Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines, employing a procedure such as the ralloc procedure of Stata version 15 or higher. Block sizes will not be disclosed, to facilitate concealment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Descriptive statistics will be reported using frequencies and percentages for categorical data. Percentages will be calculated based upon the number of patients for whom data are available. Continuous or dimensional variables will be summarised using means and standard deviations, with medians and interquartile ranges (difference between 25th and 75th percentiles) reported for potentially skewed data such as SF-12v2 physical and mental health scores.

For the analysis of the primary endpoint, difference in mean daily ABS scores during PTA between olanzapine and control groups, a mixed model/multilevel regression framework (Brown & Prescott, 2014), taking into account duration of PTA will be employed. Although a difference between group means corresponding to a large effect size (0.80 of the pooled group standard deviation) is expected, a clinically significant improvement is defined as a difference in group means of the mean daily ABS scores within PTA equal to at least half a pooled group standard deviation difference, the minimal clinically important difference for improvement in irritable / aggression scale scores in TBI (Malec & Hammond, 2018). In regard to secondary endpoints, regression methods appropriate to the type of outcome variable will be employed. Comparison of the two groups on dimensional secondary endpoints such as ABS at discharge and WPTAS scores will be analysed using linear regression, or median quantile regression. Median quantile regression, based upon the median and so less affected by very high or very low scores, will be employed for possibly skewed variables, such as SF-12v2 physical and mental health scores, that may not meet the assumptions of linear regression (McKenzie et al., 2015).

Secondary endpoints involving count data including number of days in PTA, number of clinically agitated days, length of stay in hospital, agitation scores on discharge and number of AEs and other measures of treatment safety will be analysed using regression models for count data (poisson or negative binomial regression as appropriate; Cameron, Purdie, Kliewer, & McClure, 2008).

All statistical tests will be two-tailed, with alpha or statistical significance level set to p < 0.05. 95% confidence intervals (CI) will be reported throughout. The number of missing observations will be reported. Analyses will assume intention to treat, with all patients analysed in the groups (olanzapine or control) that they were randomised to.

Although the amount of missing data is expected to be low, if imputation of missing data is required, the method of imputation will depend on the amount of missing data, its characteristics and whether it is the covariates and or outcome variables that are missing (Sullivan, White, Salter, Ryan, & Lee, 2018). Following suggested practice, complete case analysis will be reported along with imputation. Multiple imputation will be undertaken separately for each group, and a sensitivity analysis for the assumptions (i.e. Missing Completely at Random) performed (Sullivan et al., 2018). Full details of the imputation procedure will be reported (Mackinnon, 2010). Statistical analysis will be conducted by a professional Epworth or Epworth accredited biostatistician, blinded to group assignment, employing a standard statistical package such as Stata 15 or higher. A detailed Statistical Analysis Plan will be prepared by the biostatistician(s).

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)
VIC
Recruitment postcode(s) [1] 24484 0
3121 - Richmond

Funding & Sponsors
Funding source category [1] 301039 0
Other Collaborative groups
Name [1] 301039 0
Monash Epworth Rehabilitation Research Centre
Address [1] 301039 0
185-187 Hoddle Street, Richmond
Victoria, Australia, 3121
Country [1] 301039 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Scenic Boulevard and Wellington Road, Clayton, Victoria, Australia, 3800
Country
Australia
Secondary sponsor category [1] 301785 0
None
Name [1] 301785 0
Address [1] 301785 0
Country [1] 301785 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301794 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 301794 0
Alfred Health, 55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 301794 0
Australia
Date submitted for ethics approval [1] 301794 0
21/11/2018
Approval date [1] 301794 0
03/01/2019
Ethics approval number [1] 301794 0
663/18
Ethics committee name [2] 302678 0
Monash University Human Research Ethics Committee
Ethics committee address [2] 302678 0
Scenic Boulevard and Wellington Road, Clayton, Victoria, Australia, 3800
Ethics committee country [2] 302678 0
Australia
Date submitted for ethics approval [2] 302678 0
23/01/2019
Approval date [2] 302678 0
05/02/2019
Ethics approval number [2] 302678 0
18372

Summary
Brief summary
Following traumatic brain injury, patients frequently enter a state of post-traumatic amnesia and may become agitated. Agitation is threatening to staff and families, impacts access to treatment and is associated with longer hospital stays. Atypical antipsychotics are prevalent in the management of agitation despite a complete lack of well-designed studies underpinning their use in treating agitation in traumatic brain injury. We hypothesise that patients in post-traumatic amnesia, exhibiting agitation who are administered the atypical antipsychotic olanzapine will show lower levels of agitation than those administered placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88126 0
Prof Jennie Ponsford
Address 88126 0
Monash Epworth Rehabilitation Research Centre
185-187 Hoddle Street, Richmond
Victoria, Australia, 3121
Country 88126 0
Australia
Phone 88126 0
+610394268923
Fax 88126 0
Email 88126 0
jennie.ponsford@monash.edu
Contact person for public queries
Name 88127 0
Prof Jennie Ponsford
Address 88127 0
Monash Epworth Rehabilitation Research Centre
185-187 Hoddle Street, Richmond
Victoria, Australia, 3121
Country 88127 0
Australia
Phone 88127 0
+610394268923
Fax 88127 0
Email 88127 0
jennie.ponsford@monash.edu
Contact person for scientific queries
Name 88128 0
Prof Mark Walterfang
Address 88128 0
University of Melbourne, Parkville, Victoria, Australia, 3010
Country 88128 0
Australia
Phone 88128 0
+610393428483
Fax 88128 0
Email 88128 0
mawalt@unimelb.edu.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