Sub-Threshold Exercise Treatment for Adolescents With Sports Related Concussion
Phase: NA
Conditions: Brain Injury, Concussion
Sponsor: University at Buffalo

Official Title: 
Sub-Threshold Exercise Treatment for Adolescents with 
Sport-related Concussion 
NCT number: 
NCT02710123 
Document Type: 
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
10/24/2016 
 
<A Randomized Controlled Trial of Exercise Treatment for Concussion= 
Abstract 
Background: The University at Buffalo (UB) Concussion Clinic has developed a treadmill test 
(The Buffalo Concussion Treadmill Test, BCTT) that is the most systematic and only validated 
approach to the assessment of exercise tolerance in patients with concussion. We have shown 
that sub-symptom threshold aerobic exercise improves recovery in patients who are slow to 
recover. The mechanism may involve beneficial effects of exercise on neuroplasticity and upon 
the abnormal physiology of concussion (autonomic nervous system and control of cerebral 
blood flow, CBF). We want to evaluate controlled aerobic exercise as a non-pharmacological 
treatment for concussion during the acute recovery phase in adolescents. 
Methods: Subjects (13-18 years old, male and female) who sustained a concussion within the 
past 4-7 days. We chose this timeframe to make the sample as homogeneous as possible. 
Subjects will undergo the BCTT on the day of clinic presentation and will then be randomly 
assigned to daily sub-threshold aerobic or to a progressive stretching program, which is an ideal 
placebo condition because participants receive equal attention but stretching does not confer a 
cardiovascular training effect. Polar HR monitors will record their daily activity and HRs and 
subjects will report symptoms daily on a dedicated website. They will return weekly to see the 
physician who is blinded to group assignment to determine clinical recovery. 
Specific Aim: To determine the efficacy of early sub-threshold aerobic exercise treatment 
in adolescents with concussion. We hypothesize that sub-threshold aerobic exercise as 
opposed to placebo stretching will safely speed recovery in patients acutely after concussion. 
Dependent variable: Time to concussion recovery. 

Impact of the project: There is no known active intervention or medication that speeds 
recovery acutely from concussion. Rest is the most prescribed <treatment=. While a few days of 
rest are helpful, prolonged rest is actually detrimental to recovery. We are the first group in the 
world to use the physiological effects of sub-threshold aerobic exercise to safely treat humans 
with delayed recovery from concussion. There are no data on the use of exercise treatment in 
the acute phase of concussion recovery although we have completed an RCT that showed it is 
safe to test exercise tolerance (on the BCTT using our pre-determined stopping criterion) early 
(within one week) after concussion. The logical next step is to use sub-threshold exercise in 
those with exercise intolerance shortly after injury to see if it speeds recovery; theoretically 
because of the beneficial effects of aerobic exercise on autonomic function, CBF control, and 
neuroplasticity. If successful, this would represent a paradigm shift in the way concussion is 
assessed and treated. Such an approach may also prevent some of the 20% of adolescents 
who would have gone on to experience post-concussion syndrome. We have already enrolled 
21 subjects into each group but we need funding to extend this pilot study to satisfy our sample 
size of 54 in each group in order to obtain an effect size to apply to NIH for a multicenter RCT of 
early exercise intervention in adolescent concussion. Child and adolescent concussion is an 
emerging interest area for NIH (Dr. Leddy was an invited panel member of the recent NIH 
Pediatric Concussion Workshop held at the NIH on October 13-14, 2016). 
Investigators:  PI Dr. John Leddy, MD: Professor of Clinical Orthopaedics and Rehabilitation 
Sciences. 
Dr. Barry Willer, PhD: Professor of Psychiatry. 
Dr. Jeffrey Miecznikowski, PhD: Professor of Biostatistics 
 
Dr. Scott Darling, MD: Volunteer faculty – Department of Orthopaedics. 
5 Key words: exercise, aerobic, concussion, treatment, physiology 
Background/Significance  
Concussion is a physiological brain injury that has systemic effects.1 One of these effects is 
exercise intolerance, which is defined as inability to exercise to the level predicted for a given 
age. In previous work we showed that exercise intolerance is an objective sign of ongoing 
physiological dysfunction after concussion.2 Using the principle of exercise intolerance as an 
objective sign of concussion, we developed a standard treadmill test- the Buffalo Concussion 
Treadmill Test (BCTT)- that is the only functional test thus far shown to safely3 and reliably4 
diagnose physiological dysfunction in concussion, help to differentiate it from other conditions 
with similar subjective symptoms (e.g., cervical and vestibular injury, depression, migraines),5 
and quantify the clinical severity and exercise capacity of concussed patients.3, 4  The BCTT is 
now used by many others throughout the world to assess concussed patients.  
 
Animal studies have shown that aerobic exercise is beneficial to cognitive recovery if 
administered three or more weeks after simulated concussion.6, 7 Other animal studies show 
that the motivation for exercise after brain injury is important. Rats forced to exercise 28-32 days 
and 35-39 days after mild traumatic brain injury (mTBI) markedly stimulated the corticotrophic 
axis and did not increase brain derived neurotrophic factor (BDNF, which is involved in neuron 
repair after injury and increases hippocampal volume and improves spatial memory8) whereas 

BDNF levels increased following voluntary exercise.9  In another study, rats forced to exercise 
soon after mTBI increased stress hormone levels whereas rats who voluntarily exercised did 
not, suggesting that exercise regimens with strong stress responses (i.e., forced exercise) may 
not be beneficial during the early post-TBI period.10 Voluntary physical exercise immediately 
after or within days of TBI has been shown in other animal studies to have beneficial effects on 
aspects of brain neuroplasticity such as: reduced interhemispheric differences in hippocampal 
formation and lateral ventricle volumes and in the density of mature neurons in the hilus of the 
dentate gyrus and the perirhinal cortex,11 increased proliferation of neuronal stem cells,12 
reduced neuronal degeneration and apoptotic cell death around the damaged area,13 increased 
Purkinje neurons and suppressed formation of reactive astrocytes,14 and better cognitive 
performance in association with decreased DNA fragmentation in the hippocampus.15 Similarly, 
human data suggest that exercise improves brain function via favorable effects on brain 
neuroplasticity16 as early as 6 weeks.17 The rapidity of the beneficial effect of exercise on the 
brain suggests that the mechanism is not reduced cerebrovascular disease risk but improved 
neuronal function. 
 
 
We were the first group to use the animal data to develop an assessment for human patients 
suffering with prolonged symptoms after concussion (called post-concussion syndrome, PCS). 
We used the BCTT to establish the symptom-exacerbation exercise threshold and prescribed 
an individualized, progressive sub-symptom threshold aerobic exercise program for patients 
with PCS. This controlled exercise program (which is akin to voluntary exercise in animals) 
safely improved recovery and helped restore function (i.e., return to sport and work) in most 
patients suffering from PCS.3, 5  
 
The results of our early studies led us to query if, in addition to relieving symptoms, exercise 
might improve the physiology of concussion, which includes abnormal autonomic nervous 
system (ANS) function and altered control of cerebral blood flow (CBF).1  In a recent controlled 
study,18 we showed that female athletes with PCS had abnormally low sensitivity to the arterial 
CO2 tension (PaCO2) that caused a relative hypoventilation during exercise that raised their 
PaCO2 levels out of proportion to exercise intensity. CBF is directly proportional to PaCO2; 
hence, elevated PaCO2 raised exercise CBF disproportionately to exercise intensity. This was 
associated with symptoms of headache and dizziness that limited their exercise tolerance to low 
levels. A program of sub-threshold aerobic exercise treatment increased their CO2 sensitivity to 
normal, which normalized exercise ventilation, PaCO2 levels, and exercise tolerance. Thus, sub-
threshold aerobic exercise had salutary effects not only on the symptoms but on the physiology 
of the concussed brain in active patients suffering with PCS. In a different study we showed that 
sub-threshold aerobic exercise treatment restored abnormal local CBF regulation (as indicated 
by brain functional MRI, fMRI, activation patterns) to normal in PCS patients whereas a placebo 
stretching program did not.19 Thus, these studies suggest that concussion symptoms and 
exercise intolerance may be related to abnormal CBF regulation and, furthermore, that 
individualized, controlled aerobic exercise treatment can restore CBF regulation and exercise 
tolerance to normal and improve outcome.  
The traditional therapy for concussion and for PCS has been rest and avoidance of activity that 
exacerbates symptoms.20  Physical deconditoning from prolonged rest can, however, impair 
control of CBF21 whereas exercise training improves CBF control22 as well as ANS balance.2 
The ability to exercise to exhaustion on a treadmill test without symptom exacerbation defines 
physiological recovery from concussion,19 which conforms to expert consensus opinion about 

recovery from concussion and readiness to return to activity.20 Individualized exercise treatment 
for PCS patients is well accepted as < 10% of subjects refuse exercise treatment.5 We have 
recently completed an RCT (paper in review) of giving the BCTT to concussed adolescents 
within 4 days from injury (range 1-9 d) and showed that it was completely safe (Figure) without 
short term increase in symptoms or delayed recovery when compared with standard 
assessment (i.e., no exercise testing).  
While adults typically recover within 10-14 days after concussion,20 adolescents may take 3-4 
weeks to recover.23, 24Since we have shown that it is safe to assess exercise capacity shortly 
after concussion (Figure), the use of sub-threshold aerobic 
exercise as a non-pharmacological treatment to speed 
recovery acutely after concussion in adolescents should be 
tested in a randomized controlled trial (RCT).  
Methods: Patients will be screened for eligibility at the UB 
Concussion Management Clinics in Buffalo and in Niagara 
Falls. Potential subjects will be identified after a standard 
clinical evaluation that consists of a thorough history and 
physical examination by physicians with extensive 
experience in concussion management. Concussion will be 
diagnosed according to international consensus definition.20 
Inclusion Criteria: Age 13-18 years; any race, ethnicity, or 
sex; concussion within 4-7 days of first clinic visit; symptom 
score >5 on the Post-Concussion Scale;25 low risk for cardiac 
disease (defined as no cardiopulmonary symptoms and meet 
no more than one risk factor for heart disease);26 submaximal 
symptom-limited threshold on the BCTT;27 willing to exercise; 
and medications, except for βeta-blockers, are acceptable.  
Exclusion Criteria: Glasgow Coma Scale (GCS) score <12 at time of injury. Justification: 
indicates moderate or severe TBI; Lesion on CT/MRI (via review of emergency room medical 
records) and/or focal neurologic deficit. Justification: indicates moderate or severe TBI; Inability 
to exercise because of orthopedic injury, significant vestibular dysfunction, visual abnormality, or 
increased cardiac risk. Justification: unsafe to perform treadmill test or undergo exercise as 
treatment; βeta-blocker use. Justification: affects autonomic function, reduces exercise capacity, 
and blunts exercise heart rate, invalidating interpretation of the treadmill test; Major depression. 
Justification: affects autonomic function, unlikely to comply with intervention; Unwilling to 
exercise. Justification: will not be compliant with intervention or control condition; and cannot 
understand English. Justification: cannot be compliant with intervention. 
Specific Aim: To determine the efficacy of early sub-threshold aerobic exercise treatment 
in patients with concussion. We hypothesize that sub-threshold aerobic exercise as opposed 
to placebo stretching will safely speed recovery in patients acutely after concussion. 
Approach (we already have IRB approval) 
Our symptom-limited graded exercise 
test (BCTT) is terminated when 
concussed subjects have an increase 
of ≥ 3 points on the VAS. We have 
shown that performing the BCTT 
within one week of concussion does 

If eligible, subjects will meet immediately with the research assistant to obtain consent. Subjects 
will fill out a validated concussion symptom checklist that has normative data.25 Subjects will be 
treadmill tested for exercise tolerance on day of enrollment (or the next day if too symptomatic, 
which we define as a score of ≥ 7 on our 1-10 VAS) using our pre-determined stopping criterion 
(symptom exacerbation).27  Subjects will be randomly assigned to sub-threshold aerobic 
exercise or to placebo (low level stretching that does not raise HR) therapy.  
Subjects will be given a Polar HR monitor that records daily activity (via accelerometer) and HR 
(via chest strap) and asked to wear it at all times at home but for shower and swimming. 
Subjects randomized to aerobic exercise will exercise at a target HR intensity (80% of the HR 
achieved on the treadmill) 20 minutes per day (on a stationary bike or treadmill under 
supervision of parent/partner, at home or in a gym). They will be instructed to stop exercise at 
symptom exacerbation or at 20 min, whichever comes first. We have shown that this is safe.3 
They will be prompted by text/email to do their exercise at the same time each day. Subjects 
randomized to placebo will be contacted by text/email each day to prompt them to stretch for 20 
minutes per day (stretching program provided via written instructions with visual examples of 
each stretch).19 Subjects will complete an activity log to document exercise times. We used a 
similar intervention in a small controlled trial of exercise vs. placebo stretching in PCS patients 
and showed that aerobic exercise improved symptoms and returned brain fMRI activation 
patterns to control levels whereas placebo stretching did not.19 After randomization, subjects will 
be seen weekly by a physician blinded to treatment group until they are declared recovered (by 
normal symptoms and physical examination). They also will have treadmill testing and have 
accelerometer/HR data downloaded weekly for up to 3 weeks (Visits 3-5). A new exercise 
prescription will be given to subjects based upon the treadmill results (a new target HR or a new 
stretching prescription). Concussion care provided by the blinded physician will be otherwise the 
same for each group. 
Research personnel administering physiological testing will be blinded to subject group 
assignment; specifically, the research assistant (RA) obtaining consent will be different from the 
person performing the physiological testing, who will be blinded to group assignment. Subjects 
will be prompted by text/email to report their symptoms daily online in the evening for up to 4 
weeks using the Post-Concussion Scale, a validated instrument with normative data for males 
and females.25 Subjects in each group will have the same amount of contact with and attention 
from the study staff. It is not possible to blind subjects to treatment but the evaluating physician 
will be blinded to group assignment. Subjects will be instructed to do only their assigned 
exercise program during the trial and to avoid all other forms of exercise. The HR monitor will 
confirm the degree of compliance with each intervention (i.e., documentation of elevated HR 
during exercise in aerobic group and no significant elevation of HR in stretching group. This 
makes stretching an ideal placebo since it is active but does not confer an aerobic training 
effect) and will provide data on daily activity. Once deemed recovered, the subject is finished 
with the study except that subjects and parents will fill out a follow-up survey at the final visit and 
a telephonic survey at six weeks from the date of injury to document degree of recovery. We 
stop the active intervention at clinical recovery because our studies have shown that subject 
retention is very low once they have recovered. We can achieve the sample size for this pilot 
study since we have a demonstrated track record of recruiting acutely concussed subjects into 

trials but we need more funding to complete this trial. We have a sports medicine clinic with a 
direct referral base from athletic trainers in local high schools who contact us immediately upon 
injury and we see them within several days of concussion.  
Dependent variable: Time to concussion recovery, which is defined as reporting a normal level 
of symptoms on the PCS scale and a normal physical examination (i.e., normal cognitive, 
cervical, vestibular, neurological and oculomotor systems) by blinded physician assessment. 
Statistical Analysis: We will analyze the mean time to concussion recovery (days) for 
significance between the aerobic exercise group and the stretching group using standard 
regression procedures at α level 0.05.  
Sample size: We used our pilot control data from a previous study of the safety of the BCTT 
(paper in revision at Clinical Journal of Sports Medicine) to estimate the standard deviation for 
the days to recovery calculated from the time of injury. Using a two sample t-test (size =0.05) 
and the estimated standard deviation for recovery time, we have an 80 percent chance to detect 
a clinically significant mean difference of 4 days in recovery time between the two groups 
(exercise vs. placebo stretching) with 54 subjects in each group.  
Impact of the project: There is no known active intervention or medication that speeds 
recovery acutely from concussion. Rest is the most prescribed <treatment= and a few days of 
rest is helpful28 but prolonged rest is actually detrimental to recovery.29 We are the first group in 
the world to use the physiological effects of sub-threshold aerobic exercise to safely treat 
humans with delayed recovery from concussion. There are no data on the use of exercise 
treatment in the acute phase of concussion recovery, although we have completed an RCT that 
showed it is safe to test exercise tolerance (using our pre-determined stopping criterion) early 
(within one week) after concussion. The logical next step is to use sub-threshold exercise in 
those with exercise intolerance shortly after injury to see if it speeds recovery; theoretically, 
because of the beneficial effects of aerobic exercise on ANS function, CBF control, and 
neuroplasticity. If successful, this would represent a paradigm shift in the way concussion is 
assessed and treated- that is, using an active as opposed to a passive approach. We need 
CTSA funding to extend our study to double our current sample size. This will allow us to obtain 
an effect size to power a larger randomized trial for an NIH grant application. 

Study Timeline (assuming a February 1, 2017 start date)
     
         Extramural Funding: Based upon the results, we will submit a grant to NIH (NINDS, 
study section BINP) to solicit funding for a larger RCT on the effect of sub-threshold aerobic 
exercise on recovery during the acute phase after concussion. We have spoken with Patrick 
Bellgowan, PhD, Program Director, Repair and Plasticity, NIH/NINDS, who says that BINP 
would be interested in this study. We will aim for submission June of 2017.  We are also 
submitting an R24 NIH multicenter trial application in February 2017 with Children’s Hospital of 
Philadelphia, Harvard Medical School and Boston Children’s Hospital, and the Mind Research 
Network in New Mexico for a study to develop consensus criteria and objective biomarkers of  
pediatric concussion that predict clinical symptoms, guide treatment decisions, and inform the 
development of new interventions. The data from this proposed CTSA project will provide critical 
pilot data to support this application, which is of interest to NINDS, study sections BINP (PO 
Patrick Bellgowan, Ph.D) and ANIE (PO Seetha Bhagavan, Ph.D).  
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Stage
(days post-
injury)
Time 1                    
(day 4-7)
Time 2                  
(day 11-14)
Time 3...                 
(day 18-21)
May 1, 2017. 
Three month 
milestones
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application
Aerobic 
Exercise
Physiological 
Testing
Physiological 
Testing
Physiological 
Testing
16 more 
subjects  
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9 more subjects  
completed. 
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54 
completed 
subjects
Stretching
Physiological 
Testing
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Testing
Physiological 
Testing
16 more 
subjects  
completed. 
. 
9 more subjects  
completed. 
Effect size 
generated.
54 
completed 
subjects

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Sample Size  
We used data from a pilot study of exercise versus stretching in concussed patients30 and 
estimated 4.2 and 7.8 as the standard deviation of the days to recovery for the aerobic exercise 
and stretching exercise groups, respectively. We used an underlying normal distribution to 
simulate time to recovery data with the above standard deviations. Using a two sample two-sided 
t-test, we calculated an 80 percent chance to detect a clinically significant mean difference of 3.7 
days in recovery time between groups with 50 participants in each group. No interim analysis 
was planned. Adverse events and near misses were recorded and evaluated by the treating 
physician.  
Data Analysis 
Analyses were based on per protocol analysis. Baseline characteristics were analyzed to 
assess cluster differences between aerobic and stretching groups. We assessed group-wise 
differences in normally distributed variables (age, total physical examination findings, total 
symptom severity scores on initial visit, and days to initial visit) using ANOVA. Chi-square test 
was used to assess group-wise differences in sex and prior concussions. The Mann-Whitney test 
was used for the main outcome measure (days to recovery), which was not normally distributed. 
This outcome was demonstrated by Kaplan-Meier curves and assessed using multivariable Cox 
proportional hazards models, which were adjusted for patient characteristics (age, sex, prior 
concussion, and time since injury) based on prior literature.34  The Mann-Whitney test was also 
used for the analysis of days to recovery from first clinical visit.  Mean daily symptom severity 
score with 95% CI for the first three weeks was considered in linear regression models and 
distributional checks of residuals were undertaken to determine the most appropriate model. 
Missing values were calculated as the average of day-before and day-after scores. A repeated 

measures ANOVA was used to assess differences in symptom recovery time between groups. 
A p-value less than 0.05 determined statistical significance and all tests were 2-sided. Statistical 
analyses were performed using STATA version 14 (College Station, Texas).