Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000398606
Ethics application status
Approved
Date submitted
17/02/2023
Date registered
19/04/2023
Date last updated
19/04/2023
Date data sharing statement initially provided
19/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Exercise compared to passive stretching in subjects who have sustained a mild traumatic brain injury
Scientific title
A therapeutic intervention, open label study to compare the efficacy and safety of graded exercise compared to passive stretching in adults who have sustained a mild traumatic brain injury
Secondary ID [1] 309019 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Concussion 329067 0
Mild traumatic brain injury 329068 0
Condition category
Condition code
Emergency medicine 326046 326046 0 0
Other emergency care
Neurological 326231 326231 0 0
Other neurological disorders
Injuries and Accidents 326232 326232 0 0
Other injuries and accidents
Physical Medicine / Rehabilitation 326233 326233 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will then have an assessment of their exercise tolerance using the Buffalo Concussion Bike Test (BCBT) (approx. 1h). Specifically, these tests identify the heart rate (HR) at which mTBI symptom exacerbation occurs (i.e. Heart Rate Threshold [HRt]), used to establish the safe level of exercise for the consequent sub-symptom threshold aerobic exercise treatment of mTBI. Following baseline/pre-intervention procedures, randomisation will be carried out to assign to either the exercise or passive stretching interventions.

Reassessment on the abovementioned BCBT measures, including recalibrating the HRt, will be repeated weekly for 4 weeks by a research assistant/nurse who is blinded to the participants’ intervention allocation.

Participants assigned to aerobic exercise intervention will be instructed to perform aerobic exercise each day on a stationary bike, at home or in a gym at the prescribed target HR, wearing a provided HR sensor (Apple Watch: version SE) to monitor HR. Participants can walk or jog if they do not have access to exercise equipment. They will be instructed not to stretch before or after aerobic exercise. The sub-symptom threshold aerobic exercise prescription target HR will be 80% of the HR achieved at symptom exacerbation on the BCBB at the most recent visit. Participants will be instructed to stop their exercise session if their symptoms increased by 2 or more points from their pre-exercise symptom level (on a 10-point visual analogue scale) or at 20 minutes, whichever comes first. They will be told to rest apart from the prescribed exercise and not participate in other physically engaging activities. Rest will also include advice on limiting activities that exacerbate symptoms, such as excessive use of mobile phones or computers.
Intervention code [1] 325463 0
Treatment: Other
Comparator / control treatment
Participants assigned to the placebo-like passive stretching group will be instructed to follow a prescribed stretching program and given the same instructions about resting as the exercise group. This group will be provided a booklet containing a gentle, whole-body, progressive stretching program (with pictures and instructions) that does not considerably elevate HR to perform for 20min/day. The booklet has been developed specifically for this study. They will also undergo the initial, and weekly, BCBT to determine HRt, and be provided with the HR sensors.
Control group
Active

Outcomes
Primary outcome [1] 333908 0
Number of days to recovery, defined as the first symptom-free day retrospectively identified on the Rivermead Post-Concussion Symptom Questionnaire
Timepoint [1] 333908 0
30 days after allocation to study group, assessed on a daily basis
Secondary outcome [1] 418703 0
Inflammatory factor IL-1B level, measured in plasma samples
Timepoint [1] 418703 0
7, 14, 21 and 28 days post-commencement of intervention
Secondary outcome [2] 419345 0
Inflammatory factor (IL-18) level, measured in plasma samples
Timepoint [2] 419345 0
7, 14, 21 and 28 days post-commencement of intervention
Secondary outcome [3] 419346 0
Vascular endothelial growth factor levels, measured in plasma samples
Timepoint [3] 419346 0
7, 14, 21 and 28 days post-commencement of intervention
Secondary outcome [4] 419347 0
Brain derived neurotrophic factor level, measured in plasma samples
Timepoint [4] 419347 0
7, 14, 21 and 28 days post-commencement of intervention
Secondary outcome [5] 419348 0
Neurofilament light levels, measured in plasma samples
Timepoint [5] 419348 0
7, 14, 21 and 28 days post-commencement of intervention
Secondary outcome [6] 419349 0
tau levels, measured in plasma samples
Timepoint [6] 419349 0
7, 14, 21 and 28 days post-commencement of intervention
Secondary outcome [7] 419350 0
Glial fibrillary acidic protein levels, measured in plasma samples
Timepoint [7] 419350 0
7, 14, 21 and 28 days post-commencement of intervention

Eligibility
Key inclusion criteria
Participants will be patients with mild traumatic brain injury (mTBI) presenting to the Emergency Department (ED) within 48 hours of injury. Eligible patients will have a diagnosis of mTBI as per treating clinical staff. mTBI will be defined according to the WHO Collaborating Task Force on mTBI criteria, which requires an acute brain injury resulting from mechanical energy to the brain from external physical forces and (i) one or more of the following: confusion or disorientation, loss of consciousness (LOC) for 30 minutes or less, post traumatic amnesia (PTA) for less than 24 hours, and/or other transient neurological abnormalities such as focal signs or seizure; (ii) a Glasgow Coma Scale (GCS) of 13-15 after 30 minutes, or upon presentation for healthcare. Ambulance records and hospital notes will be reviewed to confirm the details of memories described by participants.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) Evidence of focal neurological deficit;
(2) Inability to exercise because of orthopaedic injury, cervical spine injury, diabetes, or known heart disease;
(3) Increased cardiac risk according to American College of Sports Medicine criteria
(4) History of moderate or severe TBI, defined as a brain injury with an associated Glasgow Coma Scale score of 12 or less;
(5) Current diagnosis of and treatment with medication for attention-deficit/hyperactivity disorder, learning disorder, depression, anxiety, or history of more than 3 prior concussions
(6) sustaining another head injury during the research period before recovery;
(7) limited English proficiency precluding completion of measures;
(8) no symptoms exceeding pre-injury levels on the Rivermead Post-Concussion Symptoms Questionnaire, or no more than 2 mild symptoms exceeding pre-injury levels at initial clinical visit; and
(9) an ability to exercise to exhaustion without symptom exacerbation on the first visit

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software, performed by an independent biostatistician
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
For all data chi-square or Fisher’s exact, test will be used to analyse categorical variables. Two-sample t-test or Mann-Whitney test will be used to analyse interval variables. Data from the exercise trial will be analysed using intention to treat principles. The equality of the survivor function will be compared across treatment groups by log-rank tests. A multivariable parametric survivor model will be constructed using Akaike information criteria to identify the best model. A test of proportions will be used to evaluate the proportion of participants with delayed recovery in each group. The effect of treatment will be further evaluated by a mixed-effects linear regression model to account for repeated measures of symptom scores. The outcome will be the daily symptom score, and the model will include the same co-variates as in the survival analyses. Missing values for symptoms will be calculated as the mean of day-before and day-after scores. A p-value<0.05 will determine statistical significance and all tests will be 2-sided.

Biomarker signatures will be examined within and between groups with repeated measures analysis across the timepoints. Diagnostic and prognostic ability of each individual measure will be assessed using AUROC analysis. Combined multimodal analysis will use logistic regression with elastic net modelling, with 5-fold cross-validation. We will randomly select 80% of the sample for model building and 20% for model validation.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2023
Actual
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/01/2025
Actual
Sample size
Target
296
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24069 0
The Alfred - Melbourne
Recruitment hospital [2] 24071 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [3] 24072 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 39577 0
3004 - Melbourne
Recruitment postcode(s) [2] 39579 0
3065 - Fitzroy
Recruitment postcode(s) [3] 39580 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 313230 0
Government body
Name [1] 313230 0
NHMRC
Country [1] 313230 0
Australia
Primary sponsor type
Hospital
Name
The Alfred
Address
55 Commercial Rd
Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 314956 0
None
Name [1] 314956 0
Address [1] 314956 0
Country [1] 314956 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312460 0
The Alfred Hospital Human Research and Ethics committee
Ethics committee address [1] 312460 0
Ethics committee country [1] 312460 0
Australia
Date submitted for ethics approval [1] 312460 0
23/06/2022
Approval date [1] 312460 0
14/11/2022
Ethics approval number [1] 312460 0
84576

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

Contacts
Principal investigator
Name 124746 0
Prof Terence O'Brien
Address 124746 0
Monash University
Level 6, 99 Commercial Rd
Melbourne VIC 3004
Country 124746 0
Australia
Phone 124746 0
+61 3 99030855
Fax 124746 0
+61 3 90762458
Email 124746 0
[email protected]
Contact person for public queries
Name 124747 0
Biswadev Mitra
Address 124747 0
Monash University
Level 3, 553 St Kilda Rd
Melbourne VIC 3004
Country 124747 0
Australia
Phone 124747 0
+61 3 9076 2782
Fax 124747 0
+61 3 9076 2699
Email 124747 0
[email protected]
Contact person for scientific queries
Name 124748 0
Terence O'Brien
Address 124748 0
Monash University
Level 6, 99 Commercial Rd
Melbourne VIC 3004
Country 124748 0
Australia
Phone 124748 0
+61 3 99030855
Fax 124748 0
+61 3 90762458
Email 124748 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The sharing of IPD has not been approved by the ethics commitete


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
18380Study protocol  [email protected] Publication TBA
18381Informed consent form    TBA
18382Ethical approval    385422-(Uploaded-17-02-2023-14-56-30)-Study-related document.pdf



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.