Treating Persistent Post-concussion Symptoms With Exercise

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to investigate an aerobic exercise program as a treatment for adults with persistent post-concussive symptoms (PPCS) following mild traumatic brain injury. In this delayed-start trial participants will be initially randomized into either a 6-week low-impact stretching protocol or 12-week aerobic exercise protocol. Following the completion of the stretching protocol participants will continue on to complete the aerobic exercise protocol in full. 56 participants aged 18-65 yrs will be recruited from the Calgary Brain Injury Program (CBIP), including the Early Concussion Education Program at Foothills Medical Centre, Calgary Pain Program, University of Calgary Sports Medicine Centre acute concussion clinic and a physiotherapy clinic (Tower Physio) all of which are located in Calgary, Alberta, Canada. Participants will complete an online follow up (symptom questionnaires and questions regarding exercise behaviour) 3 and 9 weeks post intervention.

Detailed Description
-----------------
Demographic information will be collected prior to study participation and include age, sex, education, family medical history, past medical history, concussion history, litigious status and medication use. The PAR-Q+ questionnaire will be completed to determine readiness for exercise by a physician. Baseline questionnaires will be completed, such as the Fatigue Severity Scale (FSS), Generalized Anxiety Disorder Scale (GAD-7), Headache Intensity Scale-6 (HIT-6), Patient Health Questionnaire(PHQ-9), Epworth Sleepiness Scale(ESS) and Quality of Life After Brain Injury(QOLIBRI), Rivermead Post Concussion Symptoms Questionnaire (RPQ), Modified Godin Leisure-Time Exercise Questionnaire(GLTQ), Rapid Assessment Disuse Index (RADI) and Postconcusion Syndrome Checklist (PCSC). Pre- and post-intervention blood samples will be collected from all participants. Participants will be asked to perform a tactile assessment pre- and post-intervention. Sleep will be monitored using wrist-based actigraphy and a sleep diary for 3-6 days/nights prior to the intervention start and for five days following completion of the exercise protocol. Pre and post magnetic resonance spectroscopy (MRS) will also be completed. Participants will be randomized to a structured aerobic exercise protocol (AEP) or stretching protocol, followed by aerobic exercise protocol(SP+AEP) with a random number generator. Both groups will undergo exercise testing using the Buffalo Concussion Treadmill Test to determine exercise prescription. Upon completion of SP, participants will continue on to the AEP and complete it in full. Following the exercise protocols, all questionnaires will be completed post-intervention. At 3 and 9 weeks following protocol completion, online follow surveys will be completed to assess symptom burden (RPQ, QOLIBRI, HIT-6, ESS, FSS) along with questions regarding current exercise.

Official Title
-----------------
Improving Symptom Burden in Individuals With Persistent Post Concussive Symptoms: A Step-wise Aerobic Exercise Trial

Conditions
-----------------
Brain Injuries, Traumatic, Concussion, Brain, Mild Traumatic Brain Injury, Post-Concussion Syndrome

Intervention / Treatment
-----------------
* Behavioral: Aerobic Exercise Protocol
* Behavioral: Stretching Protocol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of mild traumatic brain injury (mTBI) based on the American Congress of Rehabilitation Medicine (ACRM) criteria. mTBI occurrence from 3 months to 5 years from study start date Diagnosis of persistent post-concussion symptoms based on the ICD-10 criteria. Cleared for physical activity based on The Physical Activity Readiness Questionnaire for Everyone (PAR-Q+) by treating physician exercise intolerance (inability to exercise at pre-injury intensity/duration due to acute presentation of symptoms) Exclusion Criteria: past medical history of neurological disorders (i.e., Parkinson's disease, neuromuscular disorders) contraindications to MRI cardiopulmonary disorder chronic musculoskeletal condition psychiatric disorder other than depression and/or anxiety (i.e., schizophrenia, bipolar disorder) cancer pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerobic Exercise Protocol (AEP)<br>Symptom threshold will be determined at baseline and repeated every 3 weeks using the Buffalo Concussion Treadmill Test. Briefly, there will be an initial 4min warm up at 1.7mph. The protocol will start with treadmill speed se to 3.3 mph and 0.0% incline. Each subsequent minute, the incline will increase by 1.0% to a max of 15%. At 15% grade, if the participant is still able to continue, treadmill speed will increase by 0.4mph each minute. Heart rate (HR) and rating of perceived excretion (RPE Borg scale) will be measured every minute. The test will be terminated upon symptom exacerbation at which time HR and RPE will be recorded. Every 3 weeks the symptom threshold test will be repeated for all participants and exercise prescription will be adjusted accordingly. | Behavioral: Aerobic Exercise Protocol<br>* Participants randomized to AEP will be asked to exercise 30 minutes per day or until symptom exacerbation, 5 days per week either at home, outdoors or at a fitness facility of choice. The assigned exercise prescription target will be 70-80% of the maximum HR achieved during the treadmill test. HR monitors will be provided to monitor exercise intensity.<br>|
| Placebo Comparator: Stretching Protocol (SP)<br>The exercise testing for the stretching protocol to determine exercise prescription will be the same as described above. | Behavioral: Aerobic Exercise Protocol<br>* Participants randomized to AEP will be asked to exercise 30 minutes per day or until symptom exacerbation, 5 days per week either at home, outdoors or at a fitness facility of choice. The assigned exercise prescription target will be 70-80% of the maximum HR achieved during the treadmill test. HR monitors will be provided to monitor exercise intensity.<br>Behavioral: Stretching Protocol<br>* Participants will follow a stretching protocol for 30 minutes a day, 5 days a week. Individuals in the SP group will be given a booklet explaining a low-impact breathing and stretching program developed at the University of Buffalo. All stretches will explained and demonstrated by a member of the study team prior to commencement of the program. Stretches focus on lower extremity muscles. During the protocol HR should be low as to not exceed 50% of age predicted max. A HR monitor will be worn during stretching.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in symptom burden | Rivermead Post-concussion Symptoms Questionnaire (RPQ): an instrument developed to assess the frequency and severity of 16 common post-concussion symptoms. On this paper and pencil tool, patients rate the extent to which their symptoms (compared to their pre-injury levels) have become more problematic over the past 24 hours using a rating scale from 0-4 (0=not experienced, 1=no more of a problem, 2=mild problem, 3=moderate problem, 4=severe problem). A total symptom score is calculated out of 64. | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP, 3-weeks post-AEP, 9-weeks post-AEP | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sleep duration | Wrist actigraphy confirmed by a sleep diary. An actigraph (MotionWatch8 [CamNTech]) watch will be worn on the non-dominant wrist during nighttime hours. Actigraphy results will be confirmed by a sleep diary completed in the morning. | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP | 
| Change in daytime sleepiness | Epworth Sleepiness Scale (ESS): measure of daytime sleepiness. This scale rates the chance of dozing off on a scale of 0-3 (0= would never doze, 1= slight chance of dozing, 2= moderate chance of dozing, 3=high chance of dozing) in 8 different situations. | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP, 3-weeks post-AEP, 9-weeks post-AEP | 
| Change in blood derived neurotrophic factor (BDNF) | BDNF: serum BDNF, a neurotropic factor involved in neuronal repair after injury, will be analyzed for change in serum concentration | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP | 
| Change in cytokine profile | Cytokine profile: serum levels of multiple cytokines will be used to characterise chronic inflammatory changes | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP | 
| Change in telomere length (TL) | Telomeres are non-coding sequences of DNA that are found at the end of linear eukaryotic chromosomes thought to play a role in DNA strand repair. TL length will be analyzed using whole blood collected across time points. | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP | 
| Change in fatigue | Fatigue Severity Scale (FSS): 9 instrument questionnaire. Each item is rated on a 7 point likert scale (1= Strongly disagree, 7=strongly agree). Total score is calculated by adding the score from each item producing a total out of 63. A final item asks to Please mark X on a number line which describes your global fatigue with 0 being worst and 10 being normal. | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP, 3-weeks post-AEP, 9-weeks post-AEP | 
| Change in anxiety | Generalized Anxiety Disorder (GAD-7): a 7-item tool where each item is rated on frequency over a 2 week period based on a 0-3 scale (0=not at all, 1=several days, 2=more than half the days, 3=nearly every day). The total score ranges from 0 to 21, with scores indicating severity of anxiety (ie. 0-5= mild, 6-10= moderate, 11-15= moderately severe, 16-21= very severe). | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP | 
| Change in function related to headaches | Headache Impact Test (HIT-6): a global measure of headache impact. Addresses the 6 categories of headache impact including social, ADL, and cognitive functioning, vitality, psychological distress, and severity of headache pain. Each question is scored on a 5 point scale (never, rarely, sometimes, very often, always). Total score can range from 36-78, with higher total score indicating greater impact. | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP, 3-weeks post-AEP, 9-weeks post-AEP | 
| Change in depression | Patient Health Questionnaire-9 (PHQ-9): 9 item tool to assess the presence and severity of depressive symptoms. Each item is rated based on the frequency of occurrence in the past 2 weeks and is graded ona 0-3 scale (0=not at all, 1=several days, 2= more than half of the days, 3= nearly every day). A stand-alone question asks to rate how difficult problems have made completing tasks at home, doing work, and getting along with people. This is graded on a 4-point scale from not difficult at all to extremely difficult. Total score is calculated out of 27, with the value indicating severity of depression (ie. 0-4= none to mild, 5-9= mild, 10-14= moderate, 15-19= moderately severe, and 20-27= very severe). | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-weeks of AEP | 
| MRS quantification of GABA/Glutathione | Changes in GABA, glutathione and glutamate in the dorsolateral perefrontal cortex between AEP and SP group at 6 months | Repeated measure: Pre-intervention, after 6-weeks of SP/AEP, after 12-week of AEP |