BMJ Open€¦ ·

For peer review only

The Management of Persistent Post-Concussion Symptoms in Youth:

A Randomized Control Trial Protocol

Journal: BMJ Open

Manuscript ID: bmjopen-2015-008468

Article Type: Protocol

Date Submitted by the Author: 13-Apr-2015

Complete List of Authors: Reed, Nick; Holland Bloorview Kids Rehabilitation Hospital, Bloorview Research Institute Greenspoon, Dayna; Holland Bloorview Kids Rehabilitation Hospital, Bloorview Research Institute Iverson, Grant; Harvard Medical School, Department of Physical Medicine; MassGeneral Hospital, Children's Sport Concussion Program DeMatteo, Carol; McMaster University, School of Rehabilitation Science; CanChild Centre for Childhood Disability Research, Fait, Philippe; Université du Québec à Trois-Rivières, Department of Human Kinetics Sciences; Centre de Recherche en Neuropsychologie, Gauvin-Lepage, Jérôme; McGill University, School of Physical and Occupational Therapy Hunt, Anne; Holland Bloorview Kids Rehabilitation Hospital, Bloorview Research Institute Gagnon, Isabelle; McGill University, School of Physical and Occupational Therapy; Montreal Children’s Hospital of the McGill University Health Center, Trauma

<b>Primary Subject Heading</b>:

Sports and exercise medicine

Secondary Subject Heading: Rehabilitation medicine

Keywords: Concussion, Mild Traumatic Brain Injury, Pediatrics, Exercise, Education

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Reed, N, Greenspoon, D., Iverson, G.L., DeMatteo, C., Fait, P., Gauvin-Lepage, J., Hunt, A., & Gagnon, I.

Corresponding Author: Nick Reed, PhD, MScOT, OT Reg (Ont)

Concussion Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto,

Ontario, Canada, [email protected], 416 425-6220 ext. 3861

Nick Reed, PhD, MScOT, OT Reg (Ont)Concussion Research Centre, Bloorview Research Institute, Holland Bloorview Kids

Rehabilitation Hospital; Department of Occupational Science and Occupational Therapy, University of Toronto,Toronto,

Ontario, Canada.

Dayna Greenspoon, MScOT, Concussion Research Centre, Centre for Leadership in ABI, Bloorview Research Institute,

Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.

Grant L. Iverson, PhD, Department of Physical Medicine and Rehabilitation, Harvard Medical School; Spaulding

Rehabilitation Hospital; MassGeneral Hospital for Children Sports Concussion Program; & Red Sox Foundation and

Massachusetts General Hospital Home Base Program, Boston, Massachusetts, USA

Carol DeMatteo, MSc, Dip P&OT, School of Rehabilitation Science, McMaster University; CanChild Centre for Childhood

Disability Research, Hamilton, Ontario, Canada.

Philippe Fait, PhD, ATC, CAT(C), Department of Human Kinetics Sciences, Université du Québec à Trois-Rivières (UQTR),

Quebec, Canada; Research Group on Neuromusculoskeletal Dysfunctions, UQTR, Quebec, Canada; Centre de Recherche en

Neuropsychologie, Montreal, Quebec, Canada; Clinique Cortex Medicine et Readaptation, Quebec City, Quebec, Canada

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Jérôme Gauvin-Lepage, PhD, School of Physical and Occupational Therapy, McGill University, Montreal, Canada

Anne Hunt, PhD, Concussion Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation

Hospital, Toronto, Ontario, Canada.

Isabelle J. Gagnon, PhD, School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal,

Canada; Trauma, Montreal Children’s Hospital of the McGill University Health Center, Montreal, Canada

MeSH: Concussion, Mild Traumatic Brain Injury, Pediatrics, Exercise, Education

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ABSTRACT

Introduction: Current management of concussion consists of early education, rest until symptom free, with gradual return to

school and physical activity protocols. Although this management strategy is effective for most youth who sustain a

concussion, it is not an appropriate strategy for youth with persistent post-concussion symptoms. Prolonged rest and periods of

restricted activity may place youth at risk for secondary issues and contribute to the chronicity of post-concussion symptoms.

The purpose of this study is to evaluate the efficacy of an active rehabilitation protocol for youth who are slow to recover from

concussion. It is hypothesized that an active rehabilitation intervention can reduce persistent post-concussion symptoms,

improve function, and facilitate return to activity. This article describes the research protocol.

Methods and analysis: This is a randomized clinical trial with blinded outcome measurement. Participants will be recruited

and randomly assigned to one of two treatment groups, an active rehabilitation intervention or a standard care education group.

Both groups will receive standard care education. However, the active rehabilitation group will participate in an additional low

intensity exercise program consisting of aerobic, coordination, and visualization exercises. Both the active rehabilitation and

the standard care educations interventions will be six weeks in duration. The primary outcome measure is post-concussion

symptoms. Secondary outcome measures include functional recovery (cognitive, motor, psychosocial, and emotional

functioning) and return to activity. Outcome measures will be administered pre- and post- intervention. The primary outcome

measure will also be repeated two weeks into the intervention period.

Ethics and dissemination: This study has been approved by the Holland Bloorview Kids Rehabilitation Hospital research

ethics board (REB # 13-459). The findings from this study will be shared with the general public, sport associations, relevant

brain injury organizations, and health care professionals.

Trial registration: This trial is registered with clinicaltrials.gov, registration #: NCT02257749

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INTRODUCTION

The acute management of concussion in children and youth includes early identification, education and reassurance,

along with physical and cognitive rest [1] . Return to school, often with accommodations, often occurs while the youth is

symptomatic—and some clinician-researchers have provided recommendations for this [2–4]. After post-concussion symptoms

resolve, graduated return-to-play protocols are followed [1]. International consensus suggests that for most, recovery from a

concussion is a short-lived process (80-90% experience symptom resolution within 7 to 10 days)[5]. However, there remains a

percentage of individuals who will experience persisting symptoms and will need additional care and rehabilitation. Further, it

has been suggested that children and youth are more susceptible to prolonged recovery [5]. An epidemiologic study exploring

post-concussion symptoms amongst children found that 58.5% of children remained symptomatic in the first month following

concussion, 11.0% at 3 months, and 2.3% beyond 1 year [6]. As a result, a significant number of youth who experience a

concussion will suffer from persistent symptoms. To date, little is known about interventions to manage these youth and the

research to date exploring approaches to rehabilitation specific to youth with persistent symptoms has been limited to case

reports and descriptions [7,8]. This study aims to address this gap by investigating two treatment approaches for youth who

continue to experience symptoms one-month or longer following their concussion and applies a randomized control trial

design to improve the methodological quality of the evidence, which might then justify improved approaches to rehabilitation

within this population.

Prolonged rest and extended periods of activity restriction may place youth at risk for secondary issues (e.g., physical

deconditioning, irritability, anxiety, stress, and depression) and may contribute to symptom maintenance over time [9–11]. A

further consideration is that for many youth, absolute rest is unrealistic, and youth will naturally transition back to an active

lifestyle, especially those who are only mildly symptomatic [9]. Complicating these issues is that little is known about the

optimal time period for rest and activity restriction following concussion [10,11]. It is possible that extended periods of rest

and activity restrictions contribute to the development of secondary problems including emotional consequences [11].

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Unfortunately, the authors of a systematic review examining treatment for sports-related concussions [9] found that the

literature regarding treatment approaches is severely lacking.

Regular exercise has been shown to have positive effects on well-being including mental health [12,13], improved self-

esteem [14], sleep [15–17], and memory [18,19]. It is also known to promote neuroplasticity and neurogenesis in healthy and

injured brains [20]. Leddy et al. [21] used supervised exercise protocols with adults who experienced a concussion and were

suffering from persistent post-concussion symptoms. Using a carefully controlled progressive program where participants

exercised on a treadmill 5-6 days per week at 80% of a pre-determined symptom exacerbation threshold during exercise,

participants showed significant decreases in post-concussive symptoms and recovery time [21].

Recognizing the promising nature of exercise as an approach to rehabilitation, Gagnon et al. [8] published a case series

examining the outcome of an active rehabilitation program on 16 children and adolescents with persistent post-concussion

symptoms. The active rehabilitation program consists of a combination of submaximal aerobic training, light sport-specific

coordination exercises, visualization and imagery techniques, and a home exercise program. All youth had a decrease in their

post-concussion symptoms, and successfully returned to their activities of daily living including sports participation following

the intervention. Youth reported high satisfaction with the intervention and findings from a qualitative analysis suggest

improved sense of empowerment for both youth and their parents [8]. In a second case series of 10 adolescents with persistent

symptoms, post-concussive symptoms and functioning improved after participation in the active rehabilitation intervention,

suggesting that the introduction of graded light intensity exercise in the post-acute period following concussion is feasible and

appears to have a positive benefits in uncontrolled studies [7].

Overall, the current literature examining exercise as a treatment modality post-concussion, and in particular, persistent

post-concussion symptoms, appears positive. However, this body of literature is very limited in quantity and quality, lacking

randomization and comparison groups [9]. As such, the most recent consensus statement on concussion in sport from the 4th

International Conference on Concussion in Sport Consensus Conference (2013) advocates for more research on the

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effectiveness of these approaches in order to best meet the needs of the individuals following a concussion. This study aims to

address these gaps and meet this call from the concussion clinical and research community.

The purpose of this randomized clinical trial is to examine the efficacy of an active rehabilitation protocol as compared

to a standard care comprehensive education protocol for treatment of youth with persistent post-concussion symptoms (greater

than one month post-injury). This study expands upon the work of Gagnon et al. [7,8] by implementing a more rigorous study

methodology using a two-group, prospective, randomized control design. This study examines whether a 6-week active

rehabilitation program in combination with standard care comprehensive education is more effective in reducing post-

concussive symptoms and improving functional recovery than standard care comprehensive education alone. The study

objective is to determine the efficacy of the active rehabilitation program, compared to standard care alone, with respect to (i)

reduction in post-concussion symptoms, and (ii) functional recovery as indicated by cognitive, motor, and psychological

measures. This paper presents the protocol used for this study.

METHODS

Design

This study will examine the effects of an adapted form of the active rehabilitation protocol reported by Gagnon and

colleagues [7,8,22] with youth who continue to experience symptoms for more than one month following concussion. A two-

group prospective randomized design that includes blinded outcome assessment will be used. Following a telephone screening

interview, participants will attend a baseline testing session and be randomized to the experimental (active rehabilitation plus

standard care comprehensive education) or control group (standard care comprehensive education). Participants will be told

that they are receiving one of two interventions for concussion management. Table 1 presents a summary of the study

procedure.

Table 1. Summary of Study Procedure

Time Group Session Content Method Duration

Initial Visit

(Week 0)

Standard Care &

Active Rehabilitation Groups

• Provide Overview of Study

• Consent

• Review History and Confirm Eligibility

• Standard Concussion Education

• Outcome Measurement Assessment

In-person 1.5 Hours

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Active Rehabilitation Group • Complete the Four Components of the Active Rehabilitation Intervention

• Review Home Training Protocol and Log

In-person 1 Hour

Week 1 Standard Care &

Active Rehabilitation Groups • Follow-Up on Symptoms

• Modify Active Rehabilitation Program if Necessary

Phone 10 minutes


Active Rehabilitation Groups • Outcome Measurement Assessments Phone 10 minutes

Week 3 Standard Care Group • Review Standard Education In-Person 30 minutes

Active Rehabilitation Group • Review Standard Education

• Review Active Rehabilitation Home Program Log

• Re-Assessment (increase intensity of active rehabilitation program as appropriate)

In-Person 30 minutes




Phone 10 minutes

Week 5 Active Rehabilitation Group Continues Home Program


Active Rehabilitation Groups • Final Outcome Measurements Assessments

• Intervention Wrap-Up

In-person 2 Hours

Participants and Recruitment

One hundred youth with persistent symptoms for at least one month following concussion will be recruited.

Participants will be recruited via (i) flyers posted within our research facility; (ii) advertisements on our facility’s website; (iii)

referrals from our facility’s concussion clinic; (iv) flyers sent to local community practitioners (e.g. family physicians),

community centers, and community sport organizations; and, (v) word of mouth. All recruitment materials will direct

interested potential participants (and their families) to contact the study coordinator to learn more. Potential participants will be

screened by a telephone interview to determine eligibility. Inclusion criteria are youth between the ages of 10 to 18 years old

with a confirmed diagnosis of mild traumatic brain injury or concussion; concussive injury that occurred between one and

three months prior to enrollment in the study; presence of at least one post-concussion symptom as measured by the Post-

Concussion Symptom Inventory [23] (e.g., headaches, anxiety, fatigue) for greater than four weeks; fluent in written and

spoken English and; able to demonstrate capacity to consent to participate in the study. Exclusion criteria include youth with a

previous head injury within the last six months; presence of neck pain; presence of significant musculoskeletal pain or balance

dysfunction; pre-existing co-morbidities (e.g., chronic pain, cardiac, mental health or autoimmune conditions) that prevent

participation in active rehabilitation, assessment of gait or balance, or participation in cognitive testing; concurrent

participation in other physical rehabilitation interventions for persisting post-concussion symptoms (e.g., physiotherapy,

massage therapy, chiropractic) at the time of enrollment and throughout the duration of the study.

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Ethics and Informed Consent

Ethics approval has been received from Bloorview Research Institute and Holland Bloorview Kids Rehabilitation

Hospital’s Research Ethics Board. This trial is registered with clinicaltrials.gov, registration #: NCT02257749. An in-person

meeting will be arranged with potential participants and the research coordinator to confirm study eligibility, to discuss the

study procedure in greater detail, and to obtain informed written consent. At this meeting, potential participants will be

provided with an information letter that outlines the study purpose, procedures, and time-commitment, followed by an in-

person discussion with the study’s research coordinator. The research coordinator will explain: (i) the purpose of the study; (ii)

how the randomization process works; and, (iii) a general overview of the two treatments and outcome measures. The

discussion will also include a thorough explanation of the potential risks and benefits associated with participation in the study.

The research coordinator will ensure an understanding that they can withdraw from the study at any time without question or

consequence and without any effect on the care that they or their families receive. Youth and their families will be given

unlimited time to consider implications, ask questions, and respond to the invitation to participate in the study.

Sample Size

Fifty participants will be allocated to each treatment group for a total of 100 participants. This sample size was

calculated using information from other concussion studies involving high school athletes, and children who experience

persistent post-concussion symptoms [8]. The alpha was set at .01 and power was set to .8. The difference between individuals

receiving the active rehabilitation intervention vs. the control group on the primary outcome measure, the Post-Concussion

Symptom Inventory, is expected to be 6 points with a pooled standard deviation of 6.8 [8]. Calculations suggest a sample size

of 30 children per group. Based on previous clinical and research experience, an attrition rate of 25% is expected. As a result,

this study will oversample with the aim of enrolling 50 participants per treatment group (100 participants in total).

Randomization

Participants that meet all study inclusion criteria and consent to participate within the study will be randomly allocated

to a treatment group using a stratified process. Due to previous research indicating an increase in post-concussion symptoms

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reported by females [24], stratified randomization will be used to ensure equal representation of gender across the intervention

groups. A research coordinator who is not directly involved in this study will perform randomization to ensure the research

study staff remain blinded to group allocation.

Outcome Measures

All participants will be assessed at three time points throughout the duration of the study: week 0 (in-person session

upon enrollment in the study), week 2 (over the phone), and week 6 (in-person session upon completion of the intervention).

All outcome measures will be completed by a blinded assessor to minimize the risk for bias during data collection.

Primary outcome

The primary outcome of interest is post-concussion symptoms. This outcome was chosen because post-concussion

symptoms are considered to be an essential clinical marker of recovery following concussion [5]. Symptoms will be measured

using a modified version of the Post-Concussion Symptom Inventory (PCSI) [23]. There are three available versions of the

PCSI that will be used: (i) 21-item adolescent version, ages 13 to 18 years; (ii) 18-item child version, ages 8 to 12 years; and,

(iii) 21-item parent report scale. The PCSI captures perceived presence and severity of symptoms following concussion. The

modification is to add additional symptoms relating to sleep disturbance from the Post-Concussion Scale [25], the scale upon

which the PCSI was derived. Symptoms are rated on a likert scale and are reported for before injury and after injury (current

symptoms), to track changes in symptoms over brief intervals of time. PCSI has been validated for use with parents and youth

following concussion [23]. PCSI has moderate to strong test-retest reliability (intra-class coefficients= 0.65-0.89), moderate

parent and youth concordance (r=0.44 to 0.65), and good convergent validity with a similar symptom checklist measure (r=0.8)

[23]. It also has strong internal consistency [23]. The PCSI will be administered at baseline, week 2, and upon completion of

the intervention (week 6) for both experimental and control groups.

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Secondary Outcomes

Secondary measures include assessments of cognition, motor function, behaviour, and emotions to evaluate functional

recovery across a range of performance domains. Table 2 outlines the secondary measures used according to domain, along

with the timeframe for when each secondary measures will be administered within the study protocol.

Table 2. Secondary Measures and Time Frame for their Completion

Domains

Measures

Time Frame for Completion

Week 0:

Pre-Intervention

Week 2

Week 6:

Post-Intervention

Post-Concussion Symptoms

Post-Concussion Symptom Inventory [23] X X X

Mood and Anxiety Beck Youth Inventory- 2nd Edition [26] X X

Child Behavior Checklist [27] X X

Energy Level Pediatric Quality of Life Multidimensional Fatigue Scale [28] X X

Quality of Life Pediatric Quality of Life Generic Module [29] X X

Balance Sport Concussion Assessment Tool-3rd Edition Balance Subtest [5] X X

Bruininks-Oseretsky Test of Motor Proficiency, Second Edition [30] X X

Cognition ImPACT® [31] X X

Parental Anxiety State Trait Anxiety Scale [32] X X

Physical Activity Participation Physical Activity Questionnaire for Children and Adolescents [33] X X X

Satisfaction with Intervention Pediatric Quality of Life Health Care Satisfaction Generic Module [34] X

Patient Characteristics Acute Concussion Evaluation [35] X

Goal Setting Canadian Occupational Performance Measure [36] X X

Interventions

Control Intervention: Standard Care (Comprehensive Education)

A standardized approach to delivering this concussion education and recommendations has been developed for the

purposes of this study, and is reflective of the current standard care practices of the research team members representing three

pediatric acute care and rehabilitation hospitals in Canada and the Ontario Neurotrauma Foundation’s Guidelines for

Diagnosing and Managing Pediatric Concussion [1]. The components of the standard care intervention include comprehensive

education about diagnosis of concussion, self-management strategies, and return to activity and school guidelines. Specific

curriculum topics are outlined in Box 1.

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Standard Care Education Topics

What is a Concussion?

Energy Conservation

Sleep Hygiene

Relaxation Strategies

Nutrition and Hydration

Return to School Recommendations

Return to Activity Recommendations

Self-Management Tools

Box 1. Standard Care

Standard care will be provided to all participants regardless of group allocation. This education will be provided on an

individual basis over the six-week intervention period and consists of three, 30-minute, in-person visits with an occupational

therapist on the research team (see Table 1 for summary of study procedure).

Experimental Intervention: Active Rehabilitation Intervention + Standard Care

In addition to the standard care (comprehensive education) described above, the experimental intervention involves an

active rehabilitation program that includes four components: (i) aerobic exercise; (ii) coordination exercise; (iii) visualization

exercise; and, (iv) a home program. This program is based on a protocol developed and reported by Gagnon et al. (2009) and

has been adapted to be delivered over a period of six weeks. The six week intervention duration was determined based on

findings from Gagnon et al. [8] that symptom resolution occurred after an average of 4.4 weeks (SD= 2.6 weeks) following the

commencement of the active rehabilitation program.

Once allocated to the experimental intervention (active rehabilitation), youth will complete a one-hour in-person

session (week 0) that will consist of an introduction to the active rehabilitation protocol. Youth will begin by participating in

an aerobic exercise of their choosing, either a fast-paced walk or light jog on a treadmill or stationary bicycle. Youth will wear

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a portable heart rate monitor and will be asked to exercise up to a pre-determined sub-maximal heart rate that corresponds to

50-60% of their maximum heart rate (maximum heart rate = 220 beats per minute – participant age) and/or a level 4 on the

Pictorial Children’s Effort Rating Table (PCERT) [37]. Participants will continue the aerobic exercise until post-concussion

symptoms are exacerbated or for a maximum of 15 minutes [8,37]. The time to post-concussion symptom exacerbation (or 15

minutes) becomes the time interval for the aerobic exercise component of the participant’s rehabilitation program (take home

program and in-person visits). This time interval can be adjusted (e.g., made longer up to a maximum of 15 minutes) if the

participant is able to demonstrate the ability to complete the time interval without an exacerbation of symptoms.

Upon completion of the aerobic training, youth will participate in light coordination exercises for up to 10 minutes.

These activities will be tailored to the child’s favorite sport or physical activity. For example, a North American soccer player

may be asked to complete a series of ball and footwork activities that are standard in typical practices. Heart rate will continue

to be monitored to ensure heart rate does not exceed 50-60% of their maximal capacity [8]. Because research has shown that

youth experience decreased self-efficacy in relation to their physical activity performance after mTBI [38], these exercises

combine light aerobic exercise with familiar sport activities in a monitored and supervised environment to target both self-

efficacy and physical function [8]. Participants will be closely monitored for symptom exacerbation during the coordination

exercises. If post-concussion symptoms are exacerbated, the exercises are stopped immediately [8] and procedures for

symptom exacerbation will be followed (see safety reporting and monitoring section below.)

Following the completion of coordination exercise, youth will engage in a sport-specific visualization exercise. The

purpose of this exercise is to re-associate positive experiences in relation to physical activity participation and to target self-

confidence in return to sports and physical activities. Participants will be asked to choose a specific physical activity associated

with their favourite sport for the visualization exercise. Specifically, they will be asked to choose an activity that they typically

perform successfully and that is finite in duration (e.g., footwork or dribbling drills in North American soccer) [8].

Home Program: The final part of the active rehabilitation intervention includes a daily home program. The home

program consists of daily practice of the aerobic training, coordination drills, and visualization exercises at the level pre-

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determined in the initial session in the clinic and without exacerbation of symptoms. Participants will monitor their

participation by recording their completion of each program component using a daily log designed for this purpose [8]. Parents

will be asked to facilitate completion of the daily log. Participants will be contacted by phone at weeks one, two, and four, and

they will have an in-person re-evaluation at week 3. The home program may be modified by the therapist at any of these time

points depending on the participant’s symptoms and progress. A third and final in person session will be held at week 6.

During this session, youth will be verbally instructed in the standard return to activity protocol provided they report remaining

symptom free at rest for at least one week. Youth who continue to experience persistent symptoms beyond the 6-week

intervention may be referred to the Concussion Clinic at Holland Bloorview Kids Rehabilitation Hospital for evaluation by a

physician and/or rehabilitation team.

Compliance

Participants will be aware that they can withdraw from the study at any time without penalty. Participants who choose

to withdraw from the study, regardless of their treatment group assignment (standard care only vs. active rehabilitation), will

be given the opportunity to participate in the protocol’s final data collection point (week 6). This is to ensure that important

data (such as ceased participation due to negative outcomes) is not excluded from analysis. An analysis of participants who

complete at least 80% of the intervention will also be included for exploratory purposes.

Participants will be asked to make up any missed evaluation sessions as soon as possible (preferably within 9 days of

the date the evaluation was initially scheduled). Any missed active rehabilitation and standard education sessions are required

to be made up as soon as possible. The 6-week intervention can extend to a maximum of 9 weeks secondary to missed

sessions. The participant is considered to have dropped out of the study if these criteria are not met.

Co-Intervention and Contamination

Based on our experience, it is expected that some children will be pursuing concurrent physical rehabilitation

interventions (e.g., physiotherapy, massage therapy, chiropractic) for their post-concussion symptoms. Due to the nature of the

randomized control trial design and risk for co-intervention bias, youth will be asked not to participate in any concurrent

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physical rehabilitation for post-concussion symptoms throughout the duration of the study. Participation in a concurrent

physical rehabilitation intervention would impede the study’s ability to determine the effectiveness of the active rehabilitation

intervention as a treatment for post-concussion symptoms, and therefore is considered to be exclusion criteria. A research

coordinator will inquire about co-occurring treatment at weeks 0, 3, and 6 to ensure this exclusion criterion continues to be met

throughout the duration of the study.

To monitor for contamination (participation in activity outside of the intervention protocol), youth’s activity levels will

be tracked throughout the duration of the study. Youth will be asked to log their main activities in the morning, afternoon, and

evening, rate the intensity of each activity, indicate their symptoms, and whether a change in their symptoms have occurred.

The activity log is a modified version of Gagnon, Swaine, and Forget [39] daily activity diary. It was created for the purposes

of this research project, and in response to the lack of a reliable and valid daily activity log for children with concussion that

allows for both qualitative and quantitative measurement.

Safety Reporting and Monitoring

The risk for increased fatigue and exacerbation of post-concussion symptoms will be disclosed to participants.

Although it is possible that participants may experience an exacerbation of symptoms with increased activity, there are also

risks associated with prolonged inactivity, including an increase in post-concussion symptoms [9]. Participants will be

provided with the opportunity to take rest breaks as needed during study intervention and/or data collection sessions.

Participants will be asked to report any new symptoms, or increases in frequency or intensity of post-concussion

symptoms, to the principal investigator throughout the duration of the study. The principal investigator will keep a log of all

adverse events for both treatment groups to enable comparisons upon completion of the study. Youth will be advised to stop

the active rehabilitation intervention and rest at the onset or exacerbation of symptoms. Rest should reverse symptom

exacerbation. Youth will be permitted to continue the protocol once symptoms have resolved and/or returned to baseline for at

least 24 hours. If symptoms persist and/or worsen the principal investigator will assess whether: (i) the child can continue with

the intervention; (ii) the intervention needs to be discontinued or; (iii) the intervention needs to be suspended for a specific

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period of time. These youth will be referred back to their community physicians as needed and may require medical clearance

before resuming participation in the study.

Planned Analyses

Baseline characteristics will be compared using descriptive statistics (mean, SD, 95% CIs). Differences in patient

characteristics (e.g., age, gender, mechanism of injury and presenting post-concussion symptoms) between the experimental

and control groups will be examined using t-tests (Wilcoxon Rank Sum Tests are used if the assumptions of normality and

homogeneity of variance are not met) and Chi-square tests. Any significant difference between groups will be included as

covariates in further analyses. To address aim 1, comparing changes in post-concussion symptoms (Post Concussion Symptom

Inventory) post-intervention, a two-way ANOVA (group x time [baseline, 2wks, 6 wks) with repeated measures on the time

factor will be performed (Friedman two-way analysis of variance by ranks will be used if the assumptions of normality and

homogeneity of variance are not met). The 6-week interval will be of primary interest. Similar analyses with the secondary

outcome measures will be performed for the baseline to 6-week data to address aim 2.

Dissemination

Knowledge generated from this study will be shared with health care professionals, the general public, sport

associations, and brain injury and relevant organizations, through publication of manuscripts, conference presentations, and

seminars/rounds. Further, this study will engage knowledge translation specialists to create an implementation strategy to reach

as many stakeholders and members of the youth sport community as possible.

CONCLUSION: IMPACT ON CLINICAL PRACTICE

This article describes a protocol for a randomized control trial that tests the efficacy of two interventions for the

rehabilitation of youth with persistent post-concussion symptoms: active rehabilitation plus standard care (comprehensive

education) and standard care only. Results from primary and secondary measures will improve our understanding of the

efficacy of the two interventions in relation to physical, cognitive, social-emotional, and functional recovery. Knowledge from

this study will help clinicians make informed evidence-based decisions regarding return to activity following concussion.

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CURRENT STUDY STATUS

This trial is set to begin recruitment in April/May 2015.

ACKNOWLEDGEMENTS

Funding for the pilot study informing this protocol was provided by Fonds de recherche du Québec-Santé.

COMPETING INTERESTS

Grant Iverson has been reimbursed by the government, professional scientific bodies, and commercial organizations for

discussing or presenting research relating to mild TBI and sport-related concussion at meetings, scientific conferences, and

symposiums. He has a clinical and consulting practice in forensic neuropsychology involving individuals who have sustained

mild TBIs. He has received research funding from several test publishing companies, including ImPACT Applications, Inc.,

CNS Vital Signs, and Psychological Assessment Resources (PAR, Inc.). He is a co-investigator, collaborator, or consultant on

grants relating to mild TBI funded by several organizations, including, but not limited to, the Canadian Institute of Health

Research, Alcohol Beverage Medical Research Council, Rehabilitation Research and Development (RR&D) Service of the US

Department of Veterans Affairs, Vancouver Coastal Health Research Institute, and Roche Diagnostics Canada.

Philippe Fait, is the founder and co-owner of Cortex Medicine and rehabilitation clinic.

FUNDING

Grant Iverson acknowledges sport concussion research funding from the Mooney-Reed Charitable Foundation.

CONTRIBUTIONS

IG designed the experimental intervention. NR, IG, GI, CD, PF refined the study protocol and study implementation. DG

coordinated protocol manuscript development. All authors contributed to the writing and editing of the manuscript.

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Journal: BMJ Open

Manuscript ID: bmjopen-2015-008468.R1

Article Type: Protocol

Date Submitted by the Author: 26-Jun-2015

Complete List of Authors: Reed, Nick; Holland Bloorview Kids Rehabilitation Hospital, Bloorview Research Institute Greenspoon, Dayna; Holland Bloorview Kids Rehabilitation Hospital, Bloorview Research Institute Iverson, Grant; Harvard Medical School, Department of Physical Medicine; MassGeneral Hospital, Children's Sport Concussion Program DeMatteo, Carol; McMaster University, School of Rehabilitation Science; CanChild Centre for Childhood Disability Research, Fait, Philippe; Université du Québec à Trois-Rivières, Department of Human Kinetics Sciences; Centre de Recherche en Neuropsychologie, Gauvin-Lepage, Jérôme; McGill University, School of Physical and Occupational Therapy Hunt, Anne; Holland Bloorview Kids Rehabilitation Hospital, Bloorview Research Institute Gagnon, Isabelle; McGill University, School of Physical and Occupational Therapy; Montreal Children’s Hospital of the McGill University Health Center, Trauma

<b>Primary Subject Heading</b>:

Sports and exercise medicine

Secondary Subject Heading: Rehabilitation medicine

Keywords: Concussion, Mild Traumatic Brain Injury, Pediatrics, Exercise, Education


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Reed, N., Greenspoon, D., Iverson, G.L., DeMatteo, C., Fait, P., Gauvin-Lepage, J., Hunt, A., & Gagnon, I.

Corresponding Author: Nick Reed, PhD, MScOT, OT Reg (Ont)

Concussion Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto,

Ontario, Canada, [email protected], 416 425-6220 ext. 3861

Nick Reed, PhD, MScOT, OT Reg (Ont)Concussion Research Centre, Bloorview Research Institute, Holland Bloorview Kids

Rehabilitation Hospital; Department of Occupational Science and Occupational Therapy, University of Toronto,Toronto,

Ontario, Canada.

Dayna Greenspoon, MScOT, Concussion Research Centre, Centre for Leadership in ABI, Bloorview Research Institute,

Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.

Grant L. Iverson, PhD, Department of Physical Medicine and Rehabilitation, Harvard Medical School; Spaulding

Rehabilitation Hospital; MassGeneral Hospital for Children Sports Concussion Program; & Red Sox Foundation and

Massachusetts General Hospital Home Base Program, Boston, Massachusetts, USA

Carol DeMatteo, MSc, Dip P&OT, School of Rehabilitation Science, McMaster University; CanChild Centre for Childhood

Disability Research, Hamilton, Ontario, Canada.

Philippe Fait, PhD, ATC, CAT(C), Department of Human Kinetics Sciences, Université du Québec à Trois-Rivières (UQTR),

Quebec, Canada; Research Group on Neuromusculoskeletal Dysfunctions, UQTR, Quebec, Canada; Centre de Recherche en

Neuropsychologie, Montreal, Quebec, Canada; Clinique Cortex Medicine et Readaptation, Quebec City, Quebec, Canada

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Jérôme Gauvin-Lepage, PhD, School of Physical and Occupational Therapy, McGill University, Montreal, Canada

Anne Hunt, PhD, Concussion Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation

Hospital, Toronto, Ontario, Canada.

Isabelle J. Gagnon, PhD, School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal,

Canada; Trauma, Montreal Children’s Hospital of the McGill University Health Center, Montreal, Canada

MeSH: Concussion, Mild Traumatic Brain Injury, Pediatrics, Exercise, Education

Protocol Version Date: June 26, 2015

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ABSTRACT

Introduction: Current management of concussion consists of early education, rest until symptom free, with gradual return to

school and physical activity protocols. Although this management strategy is effective for most youth who sustain a

concussion, it is not an appropriate strategy for youth with persistent post-concussion symptoms. Prolonged rest and periods of

restricted activity may place youth at risk for secondary issues and contribute to the chronicity of post-concussion symptoms.

The purpose of this study is to evaluate the efficacy of an active rehabilitation protocol for youth who are slow to recover from

concussion. It is hypothesized that an active rehabilitation intervention can reduce persistent post-concussion symptoms,

improve function, and facilitate return to activity. This article describes the research protocol.

Methods and analysis: This is a randomized clinical trial with blinded outcome measurement. Participants will be recruited

and randomly assigned to one of two treatment groups, an active rehabilitation intervention or a standard care education group.

Both groups will receive standard care education. However, the active rehabilitation group will participate in an additional low

intensity exercise program consisting of aerobic, coordination, and visualization exercises. Both the active rehabilitation and

the standard care educations interventions will be six weeks in duration. The primary outcome measure is post-concussion

symptoms. Secondary outcome measures include functional recovery (cognitive, motor, psychosocial, and emotional

functioning) and return to activity. Outcome measures will be administered pre- and post- intervention. The primary outcome

measure will also be repeated two weeks into the intervention period.

Ethics and dissemination: This study has been approved by the Holland Bloorview Kids Rehabilitation Hospital research

ethics board (REB # 13-459). The findings from this study will be shared with the general public, sport associations, relevant

brain injury organizations, and health care professionals.

Trial registration: This trial is registered with clinicaltrials.gov, registration #: NCT02257749

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INTRODUCTION

According to International Consensus, concussion is defined as “…a complex pathophysiological process affecting the

brain, induced by biomechanical forces.” (p.79) [1]. The acute management of concussion in children and youth includes early

identification, education and reassurance, along with physical and cognitive rest [2] . Return to school, often with

accommodations, often occurs while the youth is symptomatic—and some clinician-researchers have provided

recommendations for this [3–5]. After post-concussion symptoms resolve, graduated return-to-play protocols are followed [2].

International consensus suggests that for most, recovery from a concussion is a short-lived process (80-90% experience

symptom resolution within 7 to 10 days)[1]. However, there remains a percentage of individuals who will experience

persisting symptoms and will need additional care and rehabilitation. Further, it has been suggested that children and youth are

more susceptible to prolonged recovery [1]. An epidemiologic study exploring post-concussion symptoms amongst children

found that 58.5% of children remained symptomatic in the first month following concussion, 11.0% at 3 months, and 2.3%

beyond 1 year [6]. As a result, a significant number of youth who experience a concussion will suffer from persistent

symptoms. To date, little is known about interventions to manage these youth and the research to date exploring approaches to

rehabilitation specific to youth with persistent symptoms has been limited to case reports and descriptions [7,8]. This study

aims to address this gap by investigating two treatment approaches for youth who continue to experience symptoms one-month

or longer following their concussion and applies a randomized control trial design to improve the methodological quality of the

evidence, which might then justify improved approaches to rehabilitation within this population.

Prolonged rest and extended periods of activity restriction may place youth at risk for secondary issues (e.g., physical

deconditioning, irritability, anxiety, stress, and depression) and may contribute to symptom maintenance over time [9–11]. A

further consideration is that for many youth, absolute rest is unrealistic, and youth will naturally transition back to an active

lifestyle, especially those who are only mildly symptomatic [9]. Complicating these issues is that little is known about the

optimal time period for rest and activity restriction following concussion [10,11]. It is possible that extended periods of rest

and activity restrictions contribute to the development of secondary problems including emotional consequences [11].

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Unfortunately, the authors of a systematic review examining treatment for sports-related concussions [9] found that the

literature regarding treatment approaches is severely lacking.

Regular exercise has been shown to have positive effects on well-being including mental health [12,13], improved self-

esteem [14], sleep [15–17], and memory [18,19]. It is also known to promote neuroplasticity and neurogenesis in healthy and

injured brains [20]. Leddy et al. [21] used supervised exercise protocols with adults who experienced a concussion and were

suffering from persistent post-concussion symptoms. Using a carefully controlled progressive program where participants

exercised on a treadmill 5-6 days per week at 80% of a pre-determined symptom exacerbation threshold during exercise,

participants showed significant decreases in post-concussive symptoms and recovery time [21].

Recognizing the promising nature of exercise as an approach to rehabilitation, Gagnon et al. [8] published a case series

examining the outcome of an active rehabilitation program on 16 children and adolescents with persistent post-concussion

symptoms. The active rehabilitation program consists of a combination of submaximal aerobic training, light sport-specific

coordination exercises, visualization and imagery techniques, and a home exercise program. All youth had a decrease in their

post-concussion symptoms, and successfully returned to their activities of daily living including sports participation following

the intervention. Youth reported high satisfaction with the intervention and findings from a qualitative analysis suggest

improved sense of empowerment for both youth and their parents [8]. In a second case series of 10 adolescents with persistent

symptoms, post-concussive symptoms and functioning improved after participation in the active rehabilitation intervention,

suggesting that the introduction of graded light intensity exercise in the post-acute period following concussion is feasible and

appears to have a positive benefits in uncontrolled studies [7].

Overall, the current literature examining exercise as a treatment modality post-concussion, and in particular, persistent

post-concussion symptoms, appears positive. However, this body of literature is very limited in quantity and quality, lacking

randomization and comparison groups [9]. As such, the most recent consensus statement on concussion in sport from the 4th

International Conference on Concussion in Sport Consensus Conference (2013) advocates for more research on the

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effectiveness of these approaches in order to best meet the needs of the individuals following a concussion. This study aims to

address these gaps and meet this call from the concussion clinical and research community.

The purpose of this randomized clinical trial is to examine the efficacy of an active rehabilitation protocol as compared

to a standard care comprehensive education protocol for treatment of youth with persistent post-concussion symptoms (greater

than one month post-injury). This study expands upon the work of Gagnon et al. [7,8] by implementing a more rigorous study

methodology using a two-group, prospective, randomized control design. This study examines whether a 6-week active

rehabilitation program in combination with standard care comprehensive education is more effective in reducing post-

concussive symptoms and improving functional recovery than standard care comprehensive education alone. The study

objective is to determine the efficacy of the active rehabilitation program, compared to standard care alone, with respect to (i)

reduction in post-concussion symptoms, and (ii) functional recovery as indicated by cognitive, motor, and psychological

measures. This paper presents the protocol used for this study.

METHODS

Design

This study will examine the effects of an adapted form of the active rehabilitation protocol reported by Gagnon and

colleagues [7,8,22] with youth who continue to experience symptoms for more than one month following concussion. A two-

group prospective randomized design that includes blinded outcome assessment will be used. Following a telephone screening

interview, participants will attend a baseline testing session and be randomized to the experimental (active rehabilitation plus

standard care comprehensive education) or control group (standard care comprehensive education). Participants will be told

that they are receiving one of two interventions for concussion management. Table 1 presents a summary of the study

procedure. All study procedures will be conducted at a pediatric rehabilitation hospital in Toronto, Canada.

Table 1. Summary of Study Procedure

Time Group Session Content Method Duration

Initial Visit

(Week 0)

Standard Care &

Active Rehabilitation Groups

• Provide Overview of Study

• Consent

• Review History and Confirm Eligibility

• Standard Concussion Education

• Outcome Measurement Assessment

In-person 1.5 Hours

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Active Rehabilitation Group • Complete the Four Components of the Active Rehabilitation Intervention

• Review Home Training Protocol and Log

In-person 1 Hour




Phone 10 minutes


Active Rehabilitation Groups • Outcome Measurement Assessments Phone 10 minutes

Week 3 Standard Care Group • Review Standard Education In-Person 30 minutes

Active Rehabilitation Group • Review Standard Education

• Review Active Rehabilitation Home Program Log

• Re-Assessment (increase intensity of active rehabilitation program as appropriate)

In-Person 30 minutes




Phone 10 minutes

Week 5 Active Rehabilitation Group Continues Home Program


Active Rehabilitation Groups • Final Outcome Measurements Assessments

• Intervention Wrap-Up

In-person 2 Hours

Participants and Recruitment

One hundred youth with persistent symptoms for at least one month following concussion will be recruited.

Participants will be recruited via (i) referrals from our facility’s concussion clinic; and, (ii) flyers sent to local community

practitioners (e.g. family physicians, pediatricians etc.). All recruitment materials will direct interested potential participants

(and their families) to contact the study coordinator to learn more. Potential participants will be screened by a telephone

interview to determine eligibility. Inclusion criteria are youth between the ages of 10 to 18 years old with a confirmed

diagnosis of mild traumatic brain injury or concussion; concussive injury that occurred between one and three months prior to

enrollment in the study; presence of at least one post-concussion symptom as measured by the Post-Concussion Symptom

Inventory [23] (e.g., headaches, anxiety, fatigue) for greater than four weeks; fluent in written and spoken English and; able to

demonstrate capacity to consent to participate in the study. To be enrolled, the child or adolescent must have at least one

symptom that is believed to be related to the injury and has resulted in the youth not being medically cleared to fully return to

sports or other recreational activities. Exclusion criteria include youth with more than one concussion in the past six months,

presence of neck pain; presence of significant musculoskeletal pain or balance dysfunction; pre-existing co-morbidities (e.g.,

chronic pain, cardiac, mental health or autoimmune conditions) that prevent participation in active rehabilitation, assessment of

gait or balance, or participation in cognitive testing; concurrent participation in other physical rehabilitation interventions for

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persisting post-concussion symptoms (e.g., physiotherapy, massage therapy, chiropractic) at the time of enrollment and


Ethics and Informed Consent

Ethics approval has been received from Bloorview Research Institute and Holland Bloorview Kids Rehabilitation

Hospital’s Research Ethics Board. This trial is registered with clinicaltrials.gov, registration #: NCT02257749. An in-person

meeting will be arranged with potential participants and the research coordinator to confirm study eligibility, to discuss the

study procedure in greater detail, and to obtain informed written consent. At this meeting, potential participants will be

provided with an information letter that outlines the study purpose, procedures, and time-commitment, followed by an in-

person discussion with the study’s research coordinator. The research coordinator will explain: (i) the purpose of the study; (ii)

how the randomization process works; and, (iii) a general overview of the two treatments and outcome measures. The

discussion will also include a thorough explanation of the potential risks and benefits associated with participation in the study.

The research coordinator will ensure an understanding that they can withdraw from the study at any time without question or

consequence and without any effect on the care that they or their families receive. Youth and their families will be given

unlimited time to consider implications, ask questions, and respond to the invitation to participate in the study.

Sample Size

Fifty participants will be allocated to each treatment group for a total of 100 participants. This sample size was

calculated using information from other concussion studies involving high school athletes, and children who experience

persistent post-concussion symptoms [8]. The alpha was set at .01 and power was set to .8. The difference between individuals

receiving the active rehabilitation intervention vs. the control group on the primary outcome measure, the Post-Concussion

Symptom Inventory, is expected to be 6 points with a pooled standard deviation of 6.8 [8]. Calculations suggest a sample size

of 30 children per group. Based on previous clinical and research experience, an attrition rate of 25% is expected. As a result,

this study will oversample with the aim of enrolling 50 participants per treatment group (100 participants in total).

Randomization

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Participants that meet all study inclusion criteria and consent to participate within the study will be randomly allocated

to a treatment group using a stratified process. Due to previous research indicating an increase in post-concussion symptoms

reported by females [24], stratified randomization will be used to ensure equal representation of gender across the intervention

groups. A research coordinator who is not directly involved in this study will perform randomization to ensure the research

study staff remain blinded to group allocation.

Outcome Measures

All participants will be assessed at three time points throughout the duration of the study: week 0 (in-person session

upon enrollment in the study), week 2 (over the phone), and week 6 (in-person session upon completion of the intervention).

All outcome measures will be completed by a blinded assessor to minimize the risk for bias during data collection.

Primary outcome

The primary outcome of interest is post-concussion symptoms. This outcome was chosen because post-concussion

symptoms are considered to be an essential clinical marker of recovery following concussion [1]. Symptoms will be measured

using a modified version of the Post-Concussion Symptom Inventory (PCSI) [23]. There are three available versions of the

PCSI that will be used: (i) 21-item adolescent version, ages 13 to 18 years; (ii) 18-item child version, ages 8 to 12 years; and,

(iii) 21-item parent report scale. The PCSI captures perceived presence and severity of symptoms following concussion. The

modification is to add additional symptoms relating to sleep disturbance from the Post-Concussion Scale [25], the scale upon

which the PCSI was derived. Symptoms are rated on a Likert scale and are reported for before injury and after injury (current

symptoms), to track changes in symptoms over brief intervals of time. PCSI has been validated for use with parents and youth

following concussion [23]. PCSI has moderate to strong test-retest reliability (intra-class coefficients= 0.65-0.89), moderate

parent and youth concordance (r=0.44 to 0.65), and good convergent validity with a similar symptom checklist measure (r=0.8)

[23]. It also has strong internal consistency [23]. The PCSI will be administered at baseline, week 2, and upon completion of

the intervention (week 6) for both experimental and control groups.

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Secondary Outcomes

Secondary measures include assessments of cognition, motor function, behaviour, and emotions to evaluate functional

recovery across a range of performance domains. Table 2 outlines the secondary measures used according to domain, along

with the timeframe for when each secondary measures will be administered within the study protocol.

Table 2. Secondary Measures and Time Frame for their Completion

Domains

Measures

Time Frame for Completion

Week 0:

Pre-Intervention

Week 2

Week 6:

Post-Intervention

Post-Concussion Symptoms

Post-Concussion Symptom Inventory [23] X X X

Mood and Anxiety Beck Youth Inventory- 2nd Edition [26] X X

Child Behavior Checklist [27] X X

Energy Level Pediatric Quality of Life Multidimensional Fatigue Scale [28] X X

Quality of Life Pediatric Quality of Life Generic Module [29] X X

Balance Sport Concussion Assessment Tool-3rd Edition Balance Subtest [1] X X

Bruininks-Oseretsky Test of Motor Proficiency, Second Edition [30] X X

Cognition ImPACT® [31] X X

Parental Anxiety State Trait Anxiety Scale [32] X X

Physical Activity Participation Physical Activity Questionnaire for Children and Adolescents [33] X X X

Satisfaction with Intervention Pediatric Quality of Life Health Care Satisfaction Generic Module [34] X

Patient Characteristics Acute Concussion Evaluation [35] X

Goal Setting Canadian Occupational Performance Measure [36] X X

Interventions

Control Intervention: Standard Care (Comprehensive Education)

A standardized approach to delivering this concussion education and recommendations has been developed for the

purposes of this study, and is reflective of the current standard care practices of the research team members representing three

pediatric acute care and rehabilitation hospitals in Canada and the Ontario Neurotrauma Foundation’s Guidelines for

Diagnosing and Managing Pediatric Concussion [2]. The components of the standard care intervention include comprehensive

education about diagnosis of concussion, self-management strategies, and return to activity and school guidelines. Specific

curriculum topics are outlined in Box 1.

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Standard Care Education Topics

What is a Concussion?

Energy Conservation

Sleep Hygiene

Relaxation Strategies

Nutrition and Hydration

Return to School Recommendations

Return to Activity Recommendations

Self-Management Tools

Box 1. Standard Care

Standard care will be provided to all participants regardless of group allocation. This education will be provided on an

individual basis over the six-week intervention period and consists of three, 30-minute, in-person visits with an occupational

therapist on the research team (see Table 1 for summary of study procedure).

Experimental Intervention: Active Rehabilitation Intervention + Standard Care

In addition to the standard care (comprehensive education) described above, the experimental intervention involves an

active rehabilitation program that includes four components: (i) aerobic exercise; (ii) coordination exercise; (iii) visualization

exercise; and, (iv) a home program. This program is based on a protocol developed and reported by Gagnon et al. (2009) and

has been adapted to be delivered over a period of six weeks. The six week intervention duration was determined based on

findings from Gagnon et al. [8] that symptom resolution occurred after an average of 4.4 weeks (SD= 2.6 weeks) following the

commencement of the active rehabilitation program.

Once allocated to the experimental intervention (active rehabilitation), youth will complete a one-hour in-person

session (week 0) that will consist of an introduction to the active rehabilitation protocol. Youth will begin by participating in

an aerobic exercise of their choosing, either a fast-paced walk or light jog on a treadmill or stationary bicycle. Youth will wear

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a portable heart rate monitor and will be asked to exercise up to a pre-determined sub-maximal heart rate that corresponds to

50-60% of their maximum heart rate (maximum heart rate = 220 beats per minute – participant age) and/or a level 4 on the

Pictorial Children’s Effort Rating Table (PCERT) [37]. Participants will continue the aerobic exercise until post-concussion

symptoms are exacerbated or for a maximum of 15 minutes [8,37]. The time to post-concussion symptom exacerbation (or 15

minutes) becomes the time interval for the aerobic exercise component of the participant’s rehabilitation program (take home

program and in-person visits). This time interval can be adjusted (e.g., made longer up to a maximum of 15 minutes) if the

participant is able to demonstrate the ability to complete the time interval without an exacerbation of symptoms.

Upon completion of the aerobic training, youth will participate in light coordination exercises for up to 10 minutes.

These activities will be tailored to the child’s favorite sport or physical activity. For example, a North American soccer player

may be asked to complete a series of ball and footwork activities that are standard in typical practices. Heart rate will continue

to be monitored to ensure heart rate does not exceed 50-60% of their maximal capacity [8]. Because research has shown that

youth experience decreased self-efficacy in relation to their physical activity performance after mTBI [38], these exercises

combine light aerobic exercise with familiar sport activities in a monitored and supervised environment to target both self-

efficacy and physical function [8]. Participants will be closely monitored for symptom exacerbation during the coordination

exercises. If post-concussion symptoms are exacerbated, the exercises are stopped immediately [8] and procedures for

symptom exacerbation will be followed (see safety reporting and monitoring section below.)

Following the completion of coordination exercise, youth will engage in a sport-specific visualization exercise. The

purpose of this exercise is to re-associate positive experiences in relation to physical activity participation and to target self-

confidence in return to sports and physical activities. Participants will be asked to choose a specific physical activity associated

with their favourite sport for the visualization exercise. Specifically, they will be asked to choose an activity that they typically

perform successfully and that is finite in duration (e.g., footwork or dribbling drills in North American soccer) [8].

Home Program: The final part of the active rehabilitation intervention includes a daily home program. The home

program consists of daily practice of the aerobic training, coordination drills, and visualization exercises at the level pre-

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determined in the initial session in the clinic and without exacerbation of symptoms. Participants will monitor their

participation by recording their completion of each program component using a daily log designed for this purpose [8]. Parents

will be asked to facilitate completion of the daily log. Participants will be contacted by phone at weeks one, two, and four, and

they will have an in-person re-evaluation at week 3. The home program may be modified by the therapist at any of these time

points depending on the participant’s symptoms and progress. A third and final in person session will be held at week 6.

During this session, youth will be verbally instructed in the standard return to activity protocol provided they report remaining

symptom free at rest for at least one week. Youth who continue to experience persistent symptoms beyond the 6-week

intervention may be referred to the Concussion Clinic at Holland Bloorview Kids Rehabilitation Hospital for evaluation by a

physician and/or rehabilitation team.

Compliance

Participants will be aware that they can withdraw from the study at any time without penalty. Participants who choose

to withdraw from the study, regardless of their treatment group assignment (standard care only vs. active rehabilitation), will

be given the opportunity to participate in the protocol’s final data collection point (week 6). This is to ensure that important

data (such as ceased participation due to negative outcomes) is not excluded from analysis. An analysis of participants who

complete at least 80% of the intervention will also be included for exploratory purposes.

Participants will be asked to make up any missed evaluation sessions as soon as possible (preferably within 9 days of

the date the evaluation was initially scheduled). Any missed active rehabilitation and standard education sessions are required

to be made up as soon as possible. The 6-week intervention can extend to a maximum of 9 weeks secondary to missed

sessions. The participant is considered to have dropped out of the study if these criteria are not met.

Co-Intervention and Contamination

Based on our experience, it is expected that some children will be pursuing concurrent physical rehabilitation

interventions (e.g., physiotherapy, massage therapy, chiropractic) for their post-concussion symptoms. Due to the nature of the

randomized control trial design and risk for co-intervention bias, youth will be asked not to participate in any concurrent

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physical rehabilitation for post-concussion symptoms throughout the duration of the study. Participation in a concurrent

physical rehabilitation intervention would impede the study’s ability to determine the effectiveness of the active rehabilitation

intervention as a treatment for post-concussion symptoms, and therefore is considered to be exclusion criteria. A research

coordinator will inquire about co-occurring treatment at weeks 0, 3, and 6 to ensure this exclusion criterion continues to be met


To monitor for contamination (participation in activity outside of the intervention protocol), youth’s activity levels will

be tracked using data collected from the Physical Activity Questionnaire for Children and Adolescents [33] (see Table 2 for

administration schedule).

Safety Reporting and Monitoring

The risk for increased fatigue and exacerbation of post-concussion symptoms will be disclosed to participants.

Although it is possible that participants may experience an exacerbation of symptoms with increased activity, there are also

risks associated with prolonged inactivity, including an increase in post-concussion symptoms [9]. Participants will be

provided with the opportunity to take rest breaks as needed during study intervention and/or data collection sessions.

Participants will be asked to report any new symptoms, or increases in frequency or intensity of post-concussion

symptoms, to the principal investigator throughout the duration of the study. The principal investigator will keep a log of all

adverse events for both treatment groups to enable comparisons upon completion of the study. Youth will be advised to stop

the active rehabilitation intervention and rest at the onset or exacerbation of symptoms. Rest should reverse symptom

exacerbation. Youth will be permitted to continue the protocol once symptoms have resolved and/or returned to baseline for at

least 24 hours. If symptoms persist and/or worsen the principal investigator will assess whether: (i) the child can continue with

the intervention; (ii) the intervention needs to be discontinued or; (iii) the intervention needs to be suspended for a specific

period of time. These youth will be referred back to their community physicians as needed and may require medical clearance

before resuming participation in the study.

Planned Analyses

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Baseline characteristics will be compared using descriptive statistics (mean, SD, 95% CIs). Differences in patient

characteristics (e.g., age, gender, mechanism of injury and presenting post-concussion symptoms) between the experimental

and control groups will be examined using t-tests (Wilcoxon Rank Sum Tests are used if the assumptions of normality and

homogeneity of variance are not met) and Chi-square tests. Any significant difference between groups will be included as

covariates in further analyses. Analyses will be based on intention-to-treat. To address aim 1, comparing changes in post-

concussion symptoms (Post Concussion Symptom Inventory) post-intervention, a two-way ANOVA (group x time [baseline,

2wks, 6 wks) with repeated measures on the time factor will be performed (Friedman two-way analysis of variance by ranks

will be used if the assumptions of normality and homogeneity of variance are not met). The 6-week interval will be of primary

interest. Similar analyses with the secondary outcome measures will be performed for the baseline to 6-week data to address

aim 2.

Dissemination

Knowledge generated from this study will be shared with health care professionals, the general public, sport

associations, and brain injury and relevant organizations, through publication of manuscripts, conference presentations, and

seminars/rounds. Further, this study will engage knowledge translation specialists to create an implementation strategy to reach

as many stakeholders and members of the youth sport community as possible.

CONCLUSION: IMPACT ON CLINICAL PRACTICE

This article describes a protocol for a randomized control trial that tests the efficacy of two interventions for the

rehabilitation of youth with persistent post-concussion symptoms: active rehabilitation plus standard care (comprehensive

education) and standard care only. Results from primary and secondary measures will improve our understanding of the

efficacy of the two interventions in relation to physical, cognitive, social-emotional, and functional recovery. Knowledge from

this study will help clinicians make informed evidence-based decisions regarding return to activity following concussion.

CURRENT STUDY STATUS

This trial is set to begin recruitment in July/August 2015.

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ACKNOWLEDGEMENTS

Funding for the pilot study informing this protocol was provided by Fonds de recherche du Québec-Santé.

COMPETING INTERESTS

Grant Iverson has been reimbursed by the government, professional scientific bodies, and commercial organizations for

discussing or presenting research relating to mild TBI and sport-related concussion at meetings, scientific conferences, and

symposiums. He has a clinical and consulting practice in forensic neuropsychology involving individuals who have sustained

mild TBIs. He has received research funding from several test publishing companies, including ImPACT Applications, Inc.,

CNS Vital Signs, and Psychological Assessment Resources (PAR, Inc.). He is a co-investigator, collaborator, or consultant on

grants relating to mild TBI funded by several organizations, including, but not limited to, the Canadian Institute of Health

Research, Alcohol Beverage Medical Research Council, Rehabilitation Research and Development (RR&D) Service of the US

Department of Veterans Affairs, Vancouver Coastal Health Research Institute, and Roche Diagnostics Canada.

Philippe Fait, is the founder and co-owner of Cortex Medicine and rehabilitation clinic.

FUNDING

Grant Iverson acknowledges sport concussion research funding from the Mooney-Reed Charitable Foundation.

CONTRIBUTIONS

IG designed the experimental intervention. NR, IG, GI, CD, PF refined the study protocol and study implementation. DG

coordinated protocol manuscript development. All authors contributed to the writing and editing of the manuscript.

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CONSORT flow diagram

Telephone screen for eligibility (n= )

Excluded (n= )

♦ Does not meet inclusion criteria (n= )

♦ Declined to participate (n= )

♦ Other reasons (n= )

Intent to treat analysis (n=)

Lost to follow-up (n= )

Discontinued intervention (n= )

Experimental Group (n= )

♦ Received allocated intervention (n=)

♦ Did not receive allocated intervention (n=)

♦ Discontinued intervention (n=)

Lost to follow-up (n= )

Discontinued intervention ( (n= )

Control Group (n= )

♦ Received allocated intervention (n=)

♦ Did not receive allocated intervention (n=)

♦ Discontinued intervention (n=)

Allocation

Analysis

Follow-Up

Randomized (n= )

Enrollment

Informed consent obtained and baseline assessment Excluded (n= )

♦ Does not meet inclusion criteria (n= )

♦ Declined to participate (n= )

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym _____1________

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry _____ 3_____

2b All items from the World Health Organization Trial Registration Data Set ____NA________

Protocol version 3 Date and version identifier _______2______

Funding 4 Sources and types of financial, material, and other support ___16__________

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors ____1,2_______

5b Name and contact information for the trial sponsor _____1________

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

_____16________

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

____NA_______

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Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

_ 4-6__________

6b Explanation for choice of comparators __4-6_______

Objectives 7 Specific objectives or hypotheses ___6__________

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

_____6________

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will

be collected. Reference to where list of study sites can be obtained

________6_____

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

_____7________

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

__10-13_______

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose

change in response to harms, participant request, or improving/worsening disease)

____14_________

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence

(eg, drug tablet return, laboratory tests)

____13_________

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ____13_________

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood

pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,

median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen

efficacy and harm outcomes is strongly recommended

_9-10________

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for

participants. A schematic diagram is highly recommended (see Figure)

__6________

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

_____8_______

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______7_______

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any

factors for stratification. To reduce predictability of a random sequence, details of any planned restriction

(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants

or assign interventions

______9_______

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,

opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

______9_______

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

______9_______

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

_____6________

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

_____NA______

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related

processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.

Reference to where data collection forms can be found, if not in the protocol

____9-10______

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be

collected for participants who discontinue or deviate from intervention protocols

___13_______

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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality

(eg, double data entry; range checks for data values). Reference to where details of data management

procedures can be found, if not in the protocol

_NA_(in REB

application)______

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the

statistical analysis plan can be found, if not in the protocol

_____15________

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _____15________

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any

statistical methods to handle missing data (eg, multiple imputation)

_____15_______

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of

whether it is independent from the sponsor and competing interests; and reference to where further details

about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not

needed

_____NA_______

_

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim

results and make the final decision to terminate the trial

____NA_______

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse

events and other unintended effects of trial interventions or trial conduct

_____14_____

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

__NA (part of REB

process)_______

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ______8_______

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

_____NA (Part of

REB

application)______

__

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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

___8__________

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

____NA_______

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained

in order to protect confidentiality before, during, and after the trial

_____NA- Already

in REB

application____

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site ______16_______

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

_____NA- part of

REB

application_____

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

_____NA______

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

____15_________

31b Authorship eligibility guidelines and any intended use of professional writers _____NA______

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ________NA- no

plans_____

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates ___NA- in REB

application_____

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

_____NA______

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*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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