Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001355864
Ethics application status
Approved
Date submitted
23/08/2021
Date registered
7/10/2021
Date last updated
5/12/2022
Date data sharing statement initially provided
7/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of soccer heading on the brain.
Scientific title
Investigating the neural effects of subconcussive head impacts in athletes: A pilot RCT using advanced neuroimaging techniques
Secondary ID [1] 305038 0
None
Universal Trial Number (UTN)
U1111-1268-7034
Trial acronym
Biomarkers of SUbconcussive IMpacts in SPort (BUMP)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Subconcussive Head Impacts 323208 0
Condition category
Condition code
Injuries and Accidents 320796 320796 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A Subconcussive Soccer Heading Task (SSHT)

A JUGS Soccer Machine will be used to launch FIFA regulation size 5 soccer balls inflated to 13 psi at a speed of 40 km·h-1. Participants will perform 20 soccer headers at 1-minute intervals from a distance of 12 meters. The clinical trial coordinator will instruct participants to hit the ball with their forehead and aim at a target 15 meters in front of them. The launch angle will initially be set at 40° to the horizontal; however, a ‘practice’ launch, during which participants will observe the trajectory of the ball (without heading it), will be performed (and repeated if required) to calibrate this to each individual’s preference.

Intervention fidelity will be measured via personalised Impact Monitoring Mouthguard sensors (Prevent Biometrics, Edina, MN, USA)

The intervention will be administered on one occasion, only; with participants randomly allocated to complete the intervention or comparator condition first (see below). The intervention task will take 20 minutes to complete, with 3 hours for further assessments and 30 minutes for travel between the intervention site and data collection site. Each condition will be separated by a washout period of at least 7 days.
Intervention code [1] 321493 0
Diagnosis / Prognosis
Comparator / control treatment
Kicking Task

The control condition will be administered exactly as the intervention except that participants will be instructed to kick, rather than head, the soccer balls. The launch angle will also be reduced to aid kicking. The control task will take 20 minutes to complete, with 3 hours for further assessments and 30 minutes for travel between the task site and data collection site.
Control group
Active

Outcomes
Primary outcome [1] 328679 0
Brain structure assessed via Diffuse Tensor Imaging (DTI) measuring fractional anisotropy
Timepoint [1] 328679 0
~30-90 mins post SSHT and kicking task
Primary outcome [2] 328680 0
Brain function assessed via functional Magnetic Resonance Imaging (fMRI) measuring resting state functional connectivity
Timepoint [2] 328680 0
~30-90 mins post SSHT and kicking task
Primary outcome [3] 328681 0
Brain chemistry assessed via Magnetic Resonance Spectroscopy (MRS) measuring concentrations of glutamate
Timepoint [3] 328681 0
~30-90 mins post SSHT and kicking task
Secondary outcome [1] 399928 0
Primary Outcome: Brain chemistry assessed via Magnetic Resonance Spectroscopy (MRS) measuring concentrations of creatine
Timepoint [1] 399928 0
~30-90 mins post SSHT and kicking task
Secondary outcome [2] 399929 0
Primary Outcome: Brain chemistry assessed via Magnetic Resonance Spectroscopy (MRS) measuring concentrations of myo-insitol
Timepoint [2] 399929 0
~30-90 mins post SSHT and kicking task
Secondary outcome [3] 399930 0
Primary Outcome: Brain chemistry assessed via Magnetic Resonance Spectroscopy (MRS) measuring concentrations of N-acetylasparate
Timepoint [3] 399930 0
~30-90 mins post SSHT and kicking task
Secondary outcome [4] 399931 0
Primary Outcome: Brain chemistry assessed via Magnetic Resonance Spectroscopy (MRS) measuring concentrations of glutamine
Timepoint [4] 399931 0
~30-90 mins post SSHT and kicking task
Secondary outcome [5] 399932 0
Primary Outcome: Brain structure assessed via Diffuse Tensor Imaging (DTI) measuring mean diffusivity
Timepoint [5] 399932 0
~30-90 mins post SSHT and kicking task
Secondary outcome [6] 399933 0
Primary Outcome: Brain function assessed via Arterial Spin Labelling (ASL) measuring cerebral blood flow.
Timepoint [6] 399933 0
~30-90 mins post SSHT and kicking task
Secondary outcome [7] 399934 0
High frequency resting electrical activity (over the entire frequency band - as well as within the infra-slow, theta, alpha, beta and delta bands) will be assessed via electroencephalography (EEG).
Timepoint [7] 399934 0
Assessed immediately post primary outcome scans (~75mins post SSHT and kicking task)
Secondary outcome [8] 399935 0
High frequency connectivity in major brain networks including the executive control network will be assessed via electroencephalography (EEG).
Timepoint [8] 399935 0
Assessed immediately post primary outcome scans (~75mins post SSHT and kicking task)
Secondary outcome [9] 399936 0
Plasma concentrations of Neurofilament-Light (NF-L) analysed using the Simoa™ Platform
Timepoint [9] 399936 0
Blood draw taken at baseline and 24hrs post SSHT and kicking task
Secondary outcome [10] 399937 0
While plasma NF-L samples will be collected at four time points (i.e., Baseline, Immediately Post, 2-hours Post and 24-hours Post SSHT and kicking task) the following samples will only be subjected to analysis if the research team are successful in seeking additional funding:
Timepoint [10] 399937 0
blood draw taken immediately post and 2hrs post SSHT and kicking task.
Secondary outcome [11] 399938 0
Plasma purified exosome NF-L concentrations analysed using the Simoa™ Platform.
Timepoint [11] 399938 0
Blood draw taken at baseline and 24hrs post SSHT and kicking task
Secondary outcome [12] 399939 0
While plasma purified exosome NF-L samples will be collected at four time points (i.e., Baseline, Immediately Post, 2-hours Post and 24-hours Post SSHT and kicking task) the following samples will only be subjected to analysis if the research team are successful in seeking additional funding:
Timepoint [12] 399939 0
blood draw taken immediately post and 2hrs post SSHT and kicking task.
Secondary outcome [13] 399940 0
Serum samples assessing inflammatory response using the Human Cytokine / Chemokine Array assay (i.e. GM-CSF, IFN-gamma, IL-1ß, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12(p40), IL-12(p70), IL-13, MCP-1, TNF-alpha).
Timepoint [13] 399940 0
Blood draw taken at baseline and 24hrs post SSHT and kicking task.
Secondary outcome [14] 400858 0
While serum samples assessing inflammatory response (i.e. GM-CSF, IFN-gamma, IL-1ß, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12(p40), IL-12(p70), IL-13, MCP-1, TNF-alpha) will be collected at four time points (i.e., Baseline, Immediately Post, 2-hours Post and 24-hours Post SSHT and kicking task) the following samples will be subjected to analysis if the research team are successful in seeking additional funding:
Timepoint [14] 400858 0
blood draw taken immediately post and 2hrs post SSHT and kicking task.
Secondary outcome [15] 400859 0
The paired associates learning (PAL) task from the CANTAB range will be administered and assessed for number of errors, the number of trials required to locate the pattern(s) correctly, memory scores and stages completed
Timepoint [15] 400859 0
Assessed at Baseline, Immediately Post, 2-hours Post and 24-hours Post SSHT and kicking task.
Secondary outcome [16] 400860 0
The paired associates learning (PAL) task from the CANTAB range will be administered and assessed for number of errors.
Timepoint [16] 400860 0
Assessed at Baseline, Immediately Post, 2-hours Post and 24-hours Post SSHT and kicking task.
Secondary outcome [17] 400861 0
The PAL task from the CANTAB range will be administered and assessed for the number of trials required to locate the pattern(s) correctly.
Timepoint [17] 400861 0
Assessed at Baseline, Immediately Post, 2-hours Post and 24-hours Post SSHT and kicking task.
Secondary outcome [18] 400862 0
The PAL task from the CANTAB range will be administered and assessed for memory scores.
Timepoint [18] 400862 0
Assessed at Baseline, Immediately Post, 2-hours Post and 24-hours Post SSHT and kicking task.
Secondary outcome [19] 400863 0
The PAL task from the CANTAB range will be administered and assessed for number of stages completed.
Timepoint [19] 400863 0
Assessed at Baseline, Immediately, Post, 2-hours Post and 24-hours Post SSHT and kicking task.
Secondary outcome [20] 400864 0
Linear acceleration of each soccer header assessed via peak linear acceleration (PLA) using an Impact Monitor Mouthguard by Prevent BiometricsTM.

Timepoint [20] 400864 0
Assessed continuously during the 20 mins of SSHT.
Secondary outcome [21] 400865 0
Rotational acceleration of each soccer header assessed via peak linear acceleration (PLA) using an Impact Monitor Mouthguard by Prevent BiometricsTM.
Timepoint [21] 400865 0
Assessed continuously during the 20 mins of SSHT.
Secondary outcome [22] 400866 0
Heart rate (beats/min) will be measured via Polar H10 HR Sensor.
Timepoint [22] 400866 0
Assessed shortly pre- and post- each successful soccer header in the SSHT and kick in the kicking task.
Secondary outcome [23] 400867 0
Participants will rate how well (or successfully) they believe they performed each header on an 11-point scale ranging from –5 (‘very poorly’; i.e., it felt technically incorrect and the ball was poorly positioned on the head) to +5 (‘very well’, i.e., it felt technically correct and the ball was well positioned on the head.
Timepoint [23] 400867 0
Assessed immediately after each header in the SSHT.
Secondary outcome [24] 400868 0
Participants will rate the strength of each header on a scale ranging from 1 (‘very low’) to 5 (‘very high’).
Timepoint [24] 400868 0
Assessed immediately after each header in the SSHT.

Eligibility
Key inclusion criteria
- Healthy individuals
- More than or equal to 5 years of soccer heading experience; that is, more than or equal to 5 full seasons of play and(or) training (with heading) the most recent of which was completed in the last 2 years.
- Proficient in English and able to provide informed consent
Minimum age
18 Years
Maximum age
35 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
(a) A self-reported head, neck, face and/or eye injury (including concussion; as assessed via the Concussion History Questionnaire in the last 12 months
(b) A current, self-reported sports injury (any type)
(c) A self-reported history of neurological disorders (e.g., seizure disorders, closed head injuries with loss of consciousness >15-minutes, spinal cord injury, stroke)
(d) Implantation of a cochlear device, cardiac pacemaker, intracardiac lines, medical fusion device, neurostimulator or metal plates (in the head)
(e) Use of dental braces or eyeglasses (contact lenses permitted)
(f) A contraindication to MRI (that is not already excluded in another criterion) (i.e., body and(or) facial piercings that cannot easily be removed, a drug infusion pump that cannot easily be removed)
(g) A history of a major psychiatric disorder within the previous 12 months, as per the Diagnostic and Statistical Manual of Mental Disorders (DSM)-V criteria or at the medical doctor’s discretion, except, mild to moderate depression (score <20 on the Beck Depression Inventory [BDI] or mild to moderate anxiety (score <16 on the Beck Anxiety Inventory [BAI]
(h) A history of attempted suicide or current suicide ideation as determined by a score >0 on Question 9 of the Patient Health Questionnaire (PHQ)-9
(i) Inability to avoid soccer heading or any other activity involving head impacts (e.g., contact sports) 7-days prior to and while participating in this project
(j) Inability to refrain from consuming alcohol (24 hours) and caffeine (12 hours) prior to each experimental trial
(k) Inability to refrain from using anti-inflammatory medications (4-days) prior to each experimental trial (e.g., non-steroidal anti-inflammatories [NSAIDs], such as Ibuprofen, Naproxen, Diclofenac; and corticosteroids, such as Prednisolone).
(l) Inability to refrain from using central nervous system (CNS) active drugs (i.e., cocaine, cannabis, amphetamines, methamphetamine, benzodiazepines, methadone, opioids, oxycodone, barbiturates) 7-days prior to and while participating in this project as confirmed by a negative urine drug screen (UDS) (DrugCheck® NxStep Onsite Urine Test Cup)
(m) Pregnant or lactating. All female volunteers of childbearing potential will be required to complete a urine pregnancy test (Human Chorionic Gonadotrophin [hCG] Cassette, AlereTM). Females of childbearing potential must also agree to use a reliable form of contraception while participating in this project.
(n) Current use of platelet active agents such as aspirin, ticagrelor, clopidogrel and prasugrel, warfarin and direct oral anticoagulants (DOACs)

Study design
Purpose of the study
Diagnosis
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)
Block randomisation using a random number generator
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Neuroimaging data will be analysed as described elsewhere1-4.
Secondary outcomes will be compared across Treatment (i.e., SSHT vs. control) and Time (as applicable) using standard tests of statistical significance (i.e., superiority analyses) such as linear mixed-effects models. Planned comparisons will also be performed to compare:
• Plasma and exosome NF-L concentrations between treatments 24-hours Post-Intervention
• Serum inflammatory markers between treatments 2-hours Post-Intervention
• Measures of cognitive function between treatments 2-hours Post-Intervention
Statistical significance will be accepted as p<0.05.

References:
1. Di Pietro, F., Lee, B. and Henderson, L.A., 2020. Altered resting activity patterns and connectivity in individuals with complex regional pain syndrome. Human Brain Mapping, 41(13), pp.3781-3793.
2. Meylakh, N., Marciszewski, K.K., Di Pietro, F., Macefield, V.G., Macey, P.M. and Henderson, L.A., 2020. Altered regional cerebral blood flow and hypothalamic connectivity immediately prior to a migraine headache. Cephalalgia, 40(5), pp.448-460.
3. Kobuch, S., Fatouleh, R.H., Macefield, J.M., Henderson, L.A. and Macefield, V.G., 2020. Differences in regional grey matter volume of the brain are related to mean blood pressure and muscle sympathetic nerve activity in normotensive humans. Journal of hypertension, 38(2), pp.303-313.
4. Lee, B., Henderson, L.A., Rae, C.D. and Di Pietro, F., 2020. CRPS is not associated with altered sensorimotor cortex GABA or glutamate. Eneuro, 7(1).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/11/2021
Actual
25/11/2021
Date of last participant enrolment
Anticipated
30/09/2022
Actual
6/10/2022
Date of last data collection
Anticipated
31/10/2022
Actual
4/11/2022
Sample size
Target
15
Accrual to date
Final
15
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 309426 0
Charities/Societies/Foundations
Name [1] 309426 0
Lambert Initiative for Cannabinoid Therapeutics
Country [1] 309426 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
The University of Sydney
Camperdown, NSW 2006
Country
Australia
Secondary sponsor category [1] 310468 0
None
Name [1] 310468 0
Address [1] 310468 0
Country [1] 310468 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309228 0
The University of Sydney Human Research Ethics Committee
Ethics committee address [1] 309228 0
Ethics committee country [1] 309228 0
Australia
Date submitted for ethics approval [1] 309228 0
11/06/2021
Approval date [1] 309228 0
16/08/2021
Ethics approval number [1] 309228 0
2021/515

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

Contacts
Principal investigator
Name 113418 0
Prof Luke Henderson
Address 113418 0
Brain and Mind Centre
94 Mallet Street, Camperdown
NSW 2050
Country 113418 0
Australia
Phone 113418 0
+612 9351 7063
Fax 113418 0
Email 113418 0
[email protected]
Contact person for public queries
Name 113419 0
Nathan Delang
Address 113419 0
Brain and Mind Centre,
Level 6 M02F, Rm 611, 94 Mallett St, Camperdown,
NSW, 2050
Country 113419 0
Australia
Phone 113419 0
+61402716729
Fax 113419 0
Email 113419 0
[email protected]
Contact person for scientific queries
Name 113420 0
Nathan Delang
Address 113420 0
Brain and Mind Centre,
Level 6 M02F, Rm 611, 94 Mallett St, Camperdown,
NSW, 2050
Country 113420 0
Australia
Phone 113420 0
+61402716729
Fax 113420 0
Email 113420 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only
When will data be available (start and end dates)?
All data will be retained for greater than or equal to 20 years, following publication of the primary findings
Available to whom?
Case-by-case basis at the discretion of Primary Sponsor
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Access subject to approvals by Principal Investigator (Luke Henderson; [email protected])


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.