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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
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The Management of Persistent Post-Concussion Symptoms in Youth:
A Randomized Control Trial Protocol
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
Week 2 Standard Care &
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
Week 4 Standard Care &
Active Rehabilitation Groups • Follow-Up on Symptoms
• Modify Active Rehabilitation Program if Necessary
Phone 10 minutes
Week 5 Active Rehabilitation Group Continues Home Program
Week 6 Standard Care &
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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The Management of Persistent Post-Concussion Symptoms in Youth:
A Randomized Control Trial Protocol
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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The Management of Persistent Post-Concussion Symptoms in Youth:
A Randomized Control Trial Protocol
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
Week 1 Standard Care &
Active Rehabilitation Groups • Follow-Up on Symptoms
• Modify Active Rehabilitation Program if Necessary
Phone 10 minutes
Week 2 Standard Care &
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
Week 4 Standard Care &
Active Rehabilitation Groups • Follow-Up on Symptoms
• Modify Active Rehabilitation Program if Necessary
Phone 10 minutes
Week 5 Active Rehabilitation Group Continues Home Program
Week 6 Standard Care &
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
throughout the duration of the study.
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
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 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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REFERENCES
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Concussion in Sport held in Zurich, November 2012. Clin J Sport Med Off J Can Acad Sport Med 2013;23:89–117.
doi:10.1097/JSM.0b013e31828b67cf
2 Zemek R, Duval S, Dematteo C, et al. Guidelines for Diagnosing and Managing Pediatric Concussions. Toronto, Ontario:
Ontario Neurotrauma Foundation 2014.
3 DeMatteo C, Stazyk K, Giglia L, et al. A Balanced Protocol for Return to School for Children and Youth Following
Concussive Injury. Clin Pediatr (Phila) Published Online First: 18 January 2015. doi:10.1177/0009922814567305
34 Halstead ME, McAvoy K, Devore CD, et al. Returning to learning following a concussion. Pediatrics 2013;132:948–57.
doi:10.1542/peds.2013-2867
5 McGrath N. Supporting the student-athlete’s return to the classroom after a sport-related concussion. J Athl Train
2010;45:492–8. doi:10.4085/1062-6050-45.5.492
6 Barlow KM, Crawford S, Stevenson A, et al. Epidemiology of postconcussion syndrome in pediatric mild traumatic brain
injury. Pediatrics 2010;126:e374–81. doi:10.1542/peds.2009-0925
7 Gagnon I, Grilli L, Friedman D, et al. A pilot study of active rehabilitation for adolescents who are slow to recover from
sport-related concussion. Scand J Med Sci Sports Published Online First: 3 March 2015. doi:10.1111/sms.12441
8 Gagnon I, Galli C, Friedman D, et al. Active rehabilitation for children who are slow to recover following sport-related
concussion. Brain Inj 2009;23:956–64. doi:10.3109/02699050903373477
9 Schneider KJ, Iverson GL, Emery CA, et al. The effects of rest and treatment following sport-related concussion: a
systematic review of the literature. Br J Sports Med 2013;47:304–7. doi:10.1136/bjsports-2013-092190
10 Silverberg ND, Iverson GL. Is rest after concussion “the best medicine?”: recommendations for activity resumption
following concussion in athletes, civilians, and military service members. J Head Trauma Rehabil 2013;28:250–9.
doi:10.1097/HTR.0b013e31825ad658
11 Thomas DG, Apps JN, Hoffmann RG, et al. Benefits of Strict Rest After Acute Concussion: A Randomized Controlled
Trial. Pediatrics Published Online First: 5 January 2015. doi:10.1542/peds.2014-0966
12 Cooney GM, Dwan K, Greig CA, et al. Exercise for depression. In: Cochrane Database of Systematic Reviews. John
Wiley & Sons, Ltd 1996. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004366.pub6/abstract (accessed 15
May2014).
13 Mead GE, Morley W, Campbell P, et al. Exercise for depression. In: Cochrane Database of Systematic Reviews. John
Wiley & Sons, Ltd 1996. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004366.pub4/abstract (accessed 15
May2014).
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14 Ekeland E, Heian F, Hagen KB, et al. Exercise to improve self-esteem in children and young people. Cochrane Database
Syst Rev 2004;:CD003683. doi:10.1002/14651858.CD003683.pub2
15 Brand S, Gerber M, Beck J, et al. High exercise levels are related to favorable sleep patterns and psychological functioning
in adolescents: a comparison of athletes and controls. J Adolesc Health Off Publ Soc Adolesc Med 2010;46:133–41.
doi:10.1016/j.jadohealth.2009.06.018
16 Brand S, Beck J, Gerber M, et al. “Football is good for your sleep”: favorable sleep patterns and psychological functioning
of adolescent male intense football players compared to controls. J Health Psychol 2009;14:1144–55.
doi:10.1177/1359105309342602
17 Youngstedt SD. Effects of exercise on sleep. Clin Sports Med 2005;24:355–65, xi. doi:10.1016/j.csm.2004.12.003
18 Chaddock L, Erickson KI, Prakash RS, et al. A neuroimaging investigation of the association between aerobic fitness,
hippocampal volume, and memory performance in preadolescent children. Brain Res 2010;1358:172–83.
doi:10.1016/j.brainres.2010.08.049
19 Chaddock L, Erickson KI, Prakash RS, et al. Basal ganglia volume is associated with aerobic fitness in preadolescent
children. Dev Neurosci 2010;32:249–56. doi:10.1159/000316648
20 Griesbach GS, Hovda DA, Molteni R, et al. Voluntary exercise following traumatic brain injury: brain-derived
neurotrophic factor upregulation and recovery of function. Neuroscience 2004;125:129–39.
doi:10.1016/j.neuroscience.2004.01.030
21 Leddy JJ, Kozlowski K, Donnelly JP, et al. A preliminary study of subsymptom threshold exercise training for refractory
post-concussion syndrome. Clin J Sport Med Off J Can Acad Sport Med 2010;20:21–7.
doi:10.1097/JSM.0b013e3181c6c22c
22 Iverson GL, Gagnon I, Griesbach GS. Active rehabilitation for slow-to-recover children following mild traumatic brain
injury. In: Yeates KO, Kirkwood M, eds. Mild Traumatic Brain Injury in Children and Adolescents: From Basic Science to
Clinical Management New York: Guilford Press 2012: 281-302.
23 Sady MD, Vaughan CG, Gioia GA. Psychometric Characteristics of the Postconcussion Symptom Inventory in Children
and Adolescents. Arch Clin Neuropsychol Off J Natl Acad Neuropsychol Published Online First: 15 April 2014.
doi:10.1093/arclin/acu014
24 Covassin T, Elbin RJ, Harris W, et al. The role of age and sex in symptoms, neurocognitive performance, and postural
stability in athletes after concussion. Am J Sports Med 2012;40:1303–12. doi:10.1177/0363546512444554
25 Lovell MR, Iverson GL, Collins MW, et al. Measurement of symptoms following sports-related concussion: reliability and
normative data for the post-concussion scale. Appl Neuropsychol 2006;13:166–74. doi:10.1207/s15324826an1303_4
26 Beck J, Beck A, Jolly J, et al. Beck Youth Inventories-Second Edition for Children and Adolescents BYIII. San Antonio,
TX: : Harcourt Assessment Inc. 2005.
27 Achenback TM. Manual for Child Behavior Ch ecklist/ 4-18 and 1991 Profile. Burlington, VT: : University of Vermont,
Dept. of Psychiatry. 1991.
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28 Varni JW, Burwinkle TM, Katz ER, et al. The PedsQL in pediatric cancer: reliability and validity of the Pediatric Quality
of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer 2002;94:2090–106.
29 Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0
generic core scales in healthy and patient populations. Med Care 2001;39:800–12.
30 Bruininks RH, Bruininks BD. Bruininks – Oseretsky Test of Motor Proficiency 2nd Edition. Circle Pines, MN: : Pearson
2005.
31 Maroon JC, Lovell MR, Norwig J, et al. Cerebral concussion in athletes: evaluation and neuropsychological testing.
Neurosurgery 2000;47:659–69; discussion 669–72.
32 Spielberger C. Test of Anxiety Inventory: Preliminary Professional Manual. Palo Alto, CA: : Consulting Psychologists
Press 1980.
33 Crocker PR, Bailey DA, Faulkner RA, et al. Measuring general levels of physical activity: preliminary evidence for the
Physical Activity Questionnaire for Older Children. Med Sci Sports Exerc 1997;29:1344–9.
34 Varni JW, Burwinkle TM, Dickinson P, et al. Evaluation of the built environment at a children’s convalescent hospital:
development of the Pediatric Quality of Life Inventory parent and staff satisfaction measures for pediatric health care
facilities. J Dev Behav Pediatr JDBP 2004;25:10–20.
35 Gioia GA, Collins M, Isquith PK. Improving Identification and Diagnosis of Mild Traumatic Brain Injury With Evidence:
Psychometric Support for the Acute Concussion Evaluation. J Head Trauma Rehabil 2008;23:230–42.
doi:10.1097/01.HTR.0000327255.38881.ca
36 Carswell A, McColl MA, Baptiste S, et al. The Canadian Occupational Performance Measure: a research and clinical
literature review. Can J Occup Ther Rev Can Ergothérapie 2004;71:210–22.
37 Roemmich JN, Barkley JE, Epstein LH, et al. Validity of PCERT and OMNI walk/run ratings of perceived exertion. Med
Sci Sports Exerc 2006;38:1014–9. doi:10.1249/01.mss.0000218123.81079.49
38 Gagnon I, Swaine B, Friedman D, et al. Exploring children’s self-efficacy related to physical activity performance after a
mild traumatic brain injury. J Head Trauma Rehabil 2005;20:436–49.
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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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