Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000485235p
Ethics application status
Submitted, not yet approved
Date submitted
9/03/2018
Date registered
4/04/2018
Date last updated
4/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of graduated return to high-intensity exercise on time to return to play in the context of sports-related concussions.
Scientific title
A pilot study to determine the effect of the early introduction of graduated return to either low or high-intensity exercise in the early recovery phase of concussion on symptoms and time to return to play.
Secondary ID [1] 294271 0
Nil known
Universal Trial Number (UTN)
U1111-1210-5730
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sports-related concussion 306954 0
Mild Traumatic Brain Injury 307056 0
Condition category
Condition code
Neurological 306050 306050 0 0
Other neurological disorders
Injuries and Accidents 306167 306167 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The graduated return to high-intensity exercise (intervention) arm will involve athletes doing a daily two-stage aerobic exercise regime. This will begin on the first day with a ten-minute walk and, if this does not lead to a worsening of symptoms, will be followed by ten minutes of exercise at an increased intensity (e.g. brisk walk). On the second day, the first ten minute period will be matching that of the second ten minute period from the previous day. If this does not lead to worsening of concussion symptoms they will increase the intensity again for the second ten minutes. If an increase in intensity leads to a worsening of symptoms, the patient will be instructed to return to the intensity that they last used which lead to no increase in symptoms. If the symptom exacerbation continues then the participant will be instructed to rest for the rest of the day. This will continue from day 3 post-injury until the patients report being symptom-free, or day 14 (whichever occurs first). For all participants who are aged 13-18, they will report to the clinic on injury day 14, whether or not they become symptom-free earlier.
The exercise will be unsupervised, individual exercise which will be following a protocol administered by Dr Hamish Osborne, a qualified sports physician. It is not feasible to have athletes under daily supervision for exercise, and there is no evidence to suggest that it is unsafe to let the athletes exercise alone.
All patients will be reviewed clinically every 14 days until resolution of symptoms or sooner during that 14-day cycle if their symptoms resolve. Adults will have the repeated battery of physiological testing done at 14 days or sooner if symptoms resolve. Those still with symptoms at 14 days will be retested on resolution of symptoms or at 42 days whichever is sooner. Adolescent patients will be retested at resolution of symptoms or 42 days whichever is sooner.
Participants will be asked to keep a short exercise diary. This will entail them simply stating the times at which they exercise and providing a simple summary of it (e.g. how did it feel? Did it feel any different from previous days? If so, how is it different?)
The initial intervention is only occurring for the first 14 days. However, from here, if they are medically cleared, they will progress on to complete the rest of the standardised graduated return to play protocol, as stipulated by ACC (regardless of group). If they are not yet medically cleared, Dr Osborne will advise them on how they can manage their symptoms.
Intervention code [1] 300573 0
Rehabilitation
Intervention code [2] 300641 0
Treatment: Other
Comparator / control treatment
The graduated return to low-intensity exercise arm will be given the current post-concussion recovery advice, as dictated by the Accident Compensation Corporation (ACC). This involves slowly increasing levels of activity from walking to light jogging over the period of days 3-14 post-injury. The exercise will be unsupervised, individual exercise which will be following a protocol administered by Dr Hamish Osborne, a qualified sports physician. It is not feasible to have athletes under daily supervision for exercise, and there is no evidence to suggest that it is unsafe to let the athletes exercise alone.
All patients will be reviewed clinically every 14 days until resolution of symptoms or sooner during that 14-day cycle if their symptoms resolve. Adults will have the repeated battery of physiological testing done at 14 days or sooner if symptoms resolve. Those still with symptoms at 14 days will be retested on the resolution of symptoms or at 42 days whichever is sooner. Adolescent patients will be retested at the resolution of symptoms or 42 days whichever is sooner.
The initial intervention is only occurring for the first 14 days. However, from here, if they are medically cleared, they will progress on to complete the rest of the standardised graduated return to play protocol, as stipulated by ACC (regardless of group). If they are not yet medically cleared, Dr Osborne will advise them on how they can manage their symptoms.
Participants will be asked to keep a short exercise diary. This will entail them simply stating the times at which they exercise and providing a simple summary of it (e.g. how did it feel? Did it feel any different from previous days? If so, how is it different?)

Control group
Active

Outcomes
Primary outcome [1] 305112 0
The number of adult patients who both report being symptom-free, and are medically cleared to return to play, prior to the 14-day mark will be measured.
This is being assessed by a combination of patient report and assessment by Dr Osborne in a follow-up clinical session
Timepoint [1] 305112 0
14 days
Primary outcome [2] 305113 0
The mean time to recovery across all age groups between the control and experimental groups will be compared. Recovery is measured as the point at which a patient is able to exercise at a high intensity, and is completely clear of symptoms. This point of recovery will be assessed by Dr Hamish Osbonre, after the patients self-report as being symptom free.
Timepoint [2] 305113 0
These will be measured across the whole period of the study, with a maximum timepoint being 42 days.
Secondary outcome [1] 344199 0
The initial cerebral blood flow, cerebral O2 metabolism, blood pressure, quantitative olfactory scores will be compared to scores taken again during follow up sessions. These sub-symptomatic markers will be compared to the measurable patient symptoms and will provide insight into whether a symptomatic improvement also means a physiological one, or whether or not any of these measures could serve as useful biomarkers of concussion state/recovery. The sub-symptomatic markers measured will be considered one secondary outcome, as they are being interpreted together, and will be taken together in a single battery of tests.
The measurements will be taken using the following tools:
- Cerebral blood flow will be measured using a transcranial Doppler
- Cerebral O2 metabolism will be measured using near-infrared spectroscopy
- Quantitative olfactory scores will be tested using the Combined Olfactory Test.
- Measurable symptoms of concussion will be tested using the Sports Concussion Assessment Tool 5
Timepoint [1] 344199 0
All patients will be reviewed clinically every 14 days till resolution of symptoms or sooner during that 14-day cycle if their symptoms resolve. Adults will have the repeated battery of physiological testing done at 14 days or sooner if symptoms resolve. Those still with symptoms at 14 days will be retested on the resolution of symptoms or at 42 days whichever is sooner. Adolescent patients will be retested at the resolution of symptoms or 42 days whichever is sooner.
Secondary outcome [2] 344447 0
The Buffalo Concussion Treadmill Test (BCTT) point of exhaustion will be compared to the follow-up levels in patients to check for any changes over time. This will be used to measure the patient's ability to tolerate exercise. The BCTT scores will be taken at the same timepoints as the initial sub-symptomatic battery of tests (mentioned above) and will be interpreted in conjunction with these other markers.
As a part of the BCTT protocol, resting and active heart rate (HR) and blood pressure measurements will be taken using an automatic, chest strapped, wireless HR monitor as well as an automatic sphygmomanometer.
Timepoint [2] 344447 0
All patients will be reviewed clinically every 14 days till resolution of symptoms or sooner during that 14-day cycle if their symptoms resolve. Adults will have the repeated battery of physiological testing done at 14 days or sooner if symptoms resolve. Those still with symptoms at 14 days will be retested on the resolution of symptoms or at 42 days whichever is sooner. Adolescent patients will be retested at the resolution of symptoms or 42 days whichever is sooner.

Eligibility
Key inclusion criteria
Patients diagnosed with a sports-related concussion in the Emergency Department at Dunedin Public Hospital or at the Otago Sports Injury Clinic
Able to give informed consent or, if under 18 years of age, gain written consent from legal guardian (as well as signing a consent form for themselves).
Be able to attend three follow up sessions in outpatient concussion clinic.
Minimum age
13 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Co-occurring orthopaedic injury which impairs ability to exercise

Any other contraindications or risk factors to exercise (e.g. cardiac conditions).

Co-occurring mental health concerns or learning disabilities that would prevent them from understanding instructions or completing a graduated return to learning/school regime in a normally expected amount of time.

Diagnosis of a severe TBI, or a concussion severe enough to result in an admission to hospital.

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 issued by Dr Hamish Osborne to patients upon consulation,
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The number of subjects was based on the feasibility of what can be recruited in the time period of the study. From the 1st of May 2017 to 31st of August 2017 there were 49 patients diagnosed with a concussion in Dunedin ED as a direct result of competitive sports. We have now also got an agreement to be allowed to recruit patients from Otago Sports Injury Clinic (OSIC), who see injured athletes over weekends during the sporting season from April-September. OSIC often see and diagnose sporting concussions (diagnosed by their clinic doctor) without sending them to the hospital (reducing chances of double ups in the statistics). We see it feasible to recruit a minimum of 40 patients to the study across the two centres in the four-month recruitment period. This would not be sufficient for a significant non-inferiority measure of the primary outcome. This study will be run as a pilot study where the means between the groups time to recovery will be compared. It will be used to further support the safety and larger scale investigation of the use of high-intensity exercise in recently concussed athletes. It will also look to detect changes in the sub-symptomatic markers being investigated and determine their further utility as they have not yet been investigated as markers of concussion recovery.
The statistics are not published but were found by searching diagnostic codes indexed to patient records. These were retrieved without the use or divulging of sensitive, or identifiable parts of patients records (e.g. name, NHI number, past medical history, etc.).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2018
Actual
Date of last participant enrolment
Anticipated
31/08/2018
Actual
Date of last data collection
Anticipated
15/10/2018
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment outside Australia
Country [1] 9666 0
New Zealand
State/province [1] 9666 0
Otago

Funding & Sponsors
Funding source category [1] 298908 0
University
Name [1] 298908 0
University of Otago
Country [1] 298908 0
New Zealand
Primary sponsor type
Individual
Name
Dr Hamish Osborne
Address
Dunedin School of Medicine
PO Box 56
Dunedin 9054
New Zealand
Country
New Zealand
Secondary sponsor category [1] 298146 0
None
Name [1] 298146 0
Address [1] 298146 0
Country [1] 298146 0
Other collaborator category [1] 280007 0
Individual
Name [1] 280007 0
Dr Sierra Beck
Address [1] 280007 0
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
New Zealand
Country [1] 280007 0
New Zealand
Other collaborator category [2] 280008 0
Individual
Name [2] 280008 0
Professor Jim Cotter
Address [2] 280008 0
School of Physical Education, Sport and Exercise Sciences
University of Otago
P.O. Box 56
Dunedin 9054
New Zealand
Country [2] 280008 0
New Zealand

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 299849 0
Health and Disability Ethics Committees NZ
Ethics committee address [1] 299849 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 299849 0
New Zealand
Date submitted for ethics approval [1] 299849 0
29/03/2018
Approval date [1] 299849 0
Ethics approval number [1] 299849 0

Summary
Brief summary
A sports-related concussion (SRC) is defined as a traumatic brain injury (TBI) induced by biomechanical forces which results in a functional, rather than structural injury. This is reflected by the fact that standard clinical imaging is normal while a graduated set of clinically measurable concussion symptoms manifest within seconds to hours (McCrory et al., 2017). Other measurable changes have been found previously; such as acute and chronic changes in cerebral blood flow (CBF), cerebral oxygen consumption, neurovascular coupling (NVC), and autoregulation of blood pressure (BP) (Werner & Engelhard, 2007; Wright, Smirl, Bryk, & van Donkelaar, 2017). Furthermore, there is recent unpublished work from the Dunedin School of Medicine which shows a relationship between rugby players having a history of concussions and an impaired olfactory ability (Osborne etal 2016, Perez, 2017).
It has long been shown that graduated exercise to high intensity is a useful tool for rehabilitating delayed symptoms of concussion, in both the short-term and the long term (Leddy et al., 2018; Leddy et al., 2010; Leddy & Willer, 2013; Silverberg & Iverson, 2013). However, it is only since the most recent international guidelines were published last year that the advice has now changed from “complete rest until you’re recovered” to incorporating “low levels of activity into early recovery” (McCrory et al., 2017; McCrory et al., 2013). Nevertheless, it is the increasing of levels of activity that has been shown to cause the resolution of symptoms compared with resting (Leddy et al., 2018; Leddy & Willer, 2013).
The following proposed research is a pilot study which aims to show that the early introduction of graduated return to either low or high intensity exercise is safe and not worse than the outcomes published in the consensus statement of the 5th international conference on concussion in sport (McCrory et al., 2017). Patients with sport related concussion will be recruited and baseline tests done of symptoms of concussion, balance, smell, CBF, cerebral oxygen consumption and exercise induced symptom tolerance. Players will be randomised to either graduated return to low intensity or high intensity physical activity till symptoms resolve and then they will be reassessed with the battery of tests. The hypothesis that the set of symptoms found at the beginning should have resolved by the end, both clinically and also with the other sub-symptomatic physiological tests.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81766 0
Mr Luke Barker
Address 81766 0
University of Otago
Dunedin School of Medicine
PO Box 56
Dunedin 9054
Country 81766 0
New Zealand
Phone 81766 0
+64 3 474 0999 extn 58556
Fax 81766 0
Email 81766 0
luke.barker@otago.ac.nz
Contact person for public queries
Name 81767 0
Dr Hamish Osborne
Address 81767 0
University of Otago
Dunedin School of Medicine
PO Box 56
Dunedin 9054
Country 81767 0
New Zealand
Phone 81767 0
+64 3 474 0999 extn 58556
Fax 81767 0
Email 81767 0
hamish.osborne@otago.ac.nz
Contact person for scientific queries
Name 81768 0
Mr Luke Barker
Address 81768 0
University of Otago
Dunedin School of Medicine
PO Box 56
Dunedin 9054
Country 81768 0
New Zealand
Phone 81768 0
+64 3 474 0999 extn 58556
Fax 81768 0
Email 81768 0
luke.barker@otago.ac.nz

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