Exercise as Concussion Therapy Trial
Phase: PHASE2
Conditions: Mild Traumatic Brain Injury, Concussion, Mild
Sponsor: ANSwers Neuroscience, Inc.

 
60472 
 
Page 1 of 2 
 
 
Ethics Committee 
 
Certificate of Approval of Amendments 
 
This is to certify that amendments to 
 
Project: 60472 (Local reference: 10/20) A Therapeutic Intervention, Open Label 
Study to Compare the Efficacy and Safety of Graded Exercise Compared to 
Passive Stretching in Subjects Who Have Sustained a Mild Traumatic Brain 
Injury 
 
Coordinating Principal Investigator:  
Dr Sandy Schultz 
 
Amendment:  
Amendments to Protocol – change in email address for submission of SAEs, 
baseline period during testing increased to 5 minutes; changes to PICFs; and 
addition of new supporting documents 
 
Attachments: 
Protocol – Summary of Changes dated July 2020 
Protocol version 4 dated 30-Jul-2020 
MASTER Participant Information Sheet & Consent Form version 7 dated 19-Aug-2020 
(Alfred Health Local Governance version dated 19-Aug-2020) 
MASTER Participant Information Sheet & Consent Form (Parent/Guardian) version 6 
dated 19-Aug-2020 
(Alfred Health Local Governance version dated 19-Aug-2020) 
Certificate of Insurance dated 29-Jul-2020 
Caretaker4 User Manual version 8 dated 19-Apr-2018 
Study Device Cleaning Requirements version 1 dated 26-Feb-2020 
 
have been approved under the National Mutual Acceptance (NMA) scheme in 
accordance with your amendment application dated 7-Aug-2020 on the understanding 
that you observe the National Statement on Ethical Conduct in Human Research. 
 
SPECIAL CONDITION: All research projects approved by the Alfred Hospital Ethics 
Committee are subject to, and must be carried out in compliance with, the most recent 
applicable COVID-19 government and relevant institution’s restrictions. 
 
It is now your responsibility to ensure that all people associated with this particular 
research project are made aware of what has actually been approved and any caveats 
specified in correspondence with the Ethics Committee.  Any further change to the 
application which is likely to have a significant impact on the ethical considerations of 
this project will require approval from the Ethics Committee. 
 

 
60472 
 
Page 2 of 2 
 
Professor John J. McNeil 
 
Date: 1-Sep-2020  
Chair, Ethics Committee 
 
All research subject to Alfred Hospital Ethics Committee review must be conducted in accordance with the 
National Statement on Ethical Conduct in Human Research (2007). 
 
The Alfred Ethics Committee is a properly constituted Human Research Ethics Committee operating in 
accordance with the National Statement on Ethical Conduct in Human Research (2007).
 

 
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Participant Information Sheet/Consent Form 
Interventional Study - Adult providing own consent 
 
Alfred Health 
 
Title 
Exercise As Concussion Therapy Trial  
Protocol Number 
ExACTT-2 
Australian Project Sponsor 
ANSwers Neuroscience, Pty Ltd 
Principal Investigator 
Prof Terence O’Brien 
Location  
 
The Alfred Hospital 
99 Commercial Rd 
Melbourne, VIC 3004 
 
 
 
 
Part 1 
What does my participation involve? 
 
1 
Introduction 
You are invited to take part in this research project. This is because you have mild traumatic 
brain injury, which is also known as concussion.  The research project is testing new ways to 
assess and treat initially diagnosed concussion. The new treatment is called graded exercise, 
which is exercise that is gradually increased in intensity. The devices being researched are: 
• 
The i-Touch application called ClearPlay©, the i-Touch application is used with a wrist-
worn fitness device called Waveband®.  Waveband® assesses heart rate and how 
much it varies over time.  
• 
a hand-cooling device called ClearHeart© which, when used in conjunction with the 
Caretaker4® monitor, measures changes in blood pressure and heart rate when the 
hand is cooled. 
• 
a device worn on the head that assesses how the body perceives position and 
movement of the head called ClearNeck©. 
 
This Participant Information Sheet/Consent Form tells you about the research project. It 
explains the tests and treatments involved. Knowing what is involved will help you decide if you 
want to take part in the research. 
 
Please read this information carefully. Ask questions about anything that you don’t understand 
or want to know more about. Before deciding whether or not to take part, you might want to talk 
about it with a relative, friend or your local doctor. 
 
Participation in this research is voluntary. If you don’t wish to take part, you don’t have to. You 
will receive the best possible care whether or not you take part. 
 
If you decide you want to take part in the research project, you will be asked to sign the consent 
section. By signing it you are telling us that you: 
• Understand what you have read 
• Consent to take part in the research project 
• Consent to have the tests and treatments that are described 
 
• Consent to the use of your personal and health information as described. 
 

 
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You will be given a copy of this Participant Information and Consent Form to keep. 
 
2  
What is the purpose of this research? 
As an initial treatment for concussion, exercise has been shown to improve the rate of recovery 
when compared to physical and mental rest. Non-contact forms of aerobic exercise that use 
oxygen to create energy and that do not worsen concussion symptoms are recommended as a 
treatment for concussion.  
 
The purpose of this study is to use the ClearPlay© i-Touch  application (App) in participants with 
recently diagnosed concussion to compare the effects and recovery rate of exercise that is 
gradually increased in intensity against the effects of passive stretching.  
 
The ClearPlay© App collects information regarding heart rate, to recommend the rate at which 
you should escalate your exercise that should be completed on a daily basis. The information is 
collected by the Waveband®.  
 
The study also will assess the usefulness of two devices: ClearHeart© and ClearNeck©. 
ClearHeart© is a hand cooling device, which, when used in conjunction with the Caretaker4® 
monitor, measures changes in blood pressure and heart rate when the hand is cooled. 
ClearNeck©, is a device worn on the head that assesses how the body perceives neck position 
and movement. 
 
Medications, drugs and devices have to be approved for use by the Australian Federal 
Government. Exercise that is gradually increased in intensity is not an approved treatment for 
initially diagnosed concussion. The ClearPlay© App including Waveband®, the ClearHeart© 
and the ClearNeck© are experimental devices. This means that they are not approved ways to 
assess or treat concussion in Australia.  
 
This research is being conducted by ANSwers Neuroscience, Pty Ltd and sponsored in 
Australia by ANSwers Neuroscience, Pty Ltd.  
 
3 
What does participation in this research involve? 
Study Design 
This is an open-label study which means both the researchers and study participants know 
which treatment is being given.  
 
You will be participating in a randomised controlled research project. Sometimes we do not 
know which treatment is best for treating a condition. To find out we need to compare different 
treatments. We put people into groups and give each group a different treatment. The results 
are compared to see if one is better.  
 
In this study there will be two groups; 
1. graded exercise – this is investigational treatment. 
2. passive stretching - this is called a control group because the treatment received is 
considered the current standard of care. 
 
You will have a 50% chance (1-in-2, like flipping a coin) of receiving the graded exercise 
investigational treatment. 
 
This research project has been designed to make sure the researchers interpret the results in a 
fair and appropriate way and avoids study doctors or participants jumping to conclusions.   
 
Study Activities 
You will complete the following assessments in this study. Two study visits are required to the 
centre. Some activities are completed when you are at home during the 8-week period between 
the two study visits. Each study visit will take approximately 2 hours. 
 
The following activities will be performed when you attend Alfred Health for study visits: 

 
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• 
Informed consent (Baseline visit only): Before you begin the study, you will be given 
detailed information about the study treatment, devices and any other relevant information 
by research staff. If you decide to participate, you will be asked to sign this information 
sheet and consent form before any procedures are completed. 
• 
Eligibility Criteria Review (Baseline visit only): The study doctor will ask you questions and 
complete tests to assess if you are eligible for the study. 
• 
Demographic information and medical history (Baseline visit only): The study doctor will 
ask you about your concussion, other medical conditions that you have, your medical 
history and demographics. 
• 
Review of previous scans (Baseline visit only): If you have had scans performed 
previously of your head to help diagnose and treat your concussion, these will be 
collected and reviewed by the study staff. 
• 
Vital Signs (baseline and 8-week visit): Your vital signs such as heart rate and blood 
pressure will be measured with a device on your right hand for 6 minutes on two 
occasions at each study visit. This device is called Caretaker4® and is approved in 
Australia. 
• 
Medications and treatments (during entire study): You will be asked about the medications 
and treatments that you have taken in the 7 days prior to the baseline study visit, and 
between the start of the study until your 8-week study visit. This includes medications 
such as over-the-counter medicines, vitamins, herbal remedies or other alternative 
treatments and treatments such as acupuncture, occupational therapy, physical therapy, 
vestibular therapy, visual therapy, cognitive behavioural therapy, chiropractic therapy, and 
other therapies. 
• 
Adverse Events (during entire study): You will be asked how you are feeling, if they had to 
visit a hospital or have been seriously ill.  
• 
Post study survey (8-week visit): you will be asked to complete a survey about your 
experience on this research study and any leave you have had to take from work or 
normal duties during your time on the study. 
• 
Sample collection for biomarkers (baseline and 8-week visit): A biomarker is a naturally 
occurring molecule or substance in your body that allows a specific disease or medical 
condition to be identified and measured. You can either have a blood test to collect 
biomarkers, or if you do not want to have a blood test, a sample of your saliva and a 
cotton tip will be rubbed on the inside of your cheek (a mouth swab) can be collected 
instead. 
• 
Optional additional blood or saliva samples for genetic testing and biobanking (baseline 
and 8-week visit): This testing is optional and involves testing your genes, which are the 
DNA instructions you inherit from your mother and your father. You can nominate your 
choice to participate in this optional testing at the end of this Participant Information and 
Consent Form. The results of this optional genetic testing will not be available to you, 
should you choose to participate in this optional testing because information obtained from 
these studies will not provide significant information relating to the health of participants, 
relatives or other family members. 
• 
Questionnaires: You will be asked to complete questionnaires at the Baseline and Follow-
up visits, The questionnaires ask about your health, thoughts, feelings, behaviour, 
exercise habits, and experiences, and take 45- 60 minutes to complete. The 
questionnaires include; 
 
o Post-Concussion Symptom Scale (PCSS) 
o Godin Leisure Time Exercise Questionnaire 
o The Beck Anxiety Inventory (BAI)  
o Brief Symptom Inventory 
o Reiss-Epstein-Gursky Anxiety Sensitivity Index 
o Conners' Adult Attention Deficit Hyperactivity Disorder Rating Scale (CAARS) 
o Center for Epidemiologic Studies - Depression Scale (CES-D) 
 

 
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You will also be required to complete the Post-Concussion Symptom Scale daily and the Godin 
Leisure Time Exercise Questionnaire weekly during the study Therapy period. They are 
available on the ClearPlay© App. It will take approximately 5 minutes each day. 
 
• 
Assessments that will be administered to you by the study staff (baseline and 8-week 
visit): 
• Cold Pressor Test: This tests how your heart and blood vessels respond to the 
cooling of your left hand while placed in ice water for 2 minutes (the ice bucket test) 
and also when placed in the ClearHeart© hand-cooling device for 2 minutes. You will 
be asked to remain seated for 5 minutes before and after both of these tests. During 
this test you will be fitted with the Caretaker4® device on your right hand and finger.  
• Neck range of motion and ClearNeck© testing: The Joint Position Error Test will be 
performed which assesses your neck’s strength, how much it moves, if it is painful or 
sore and if whiplash is present. Whiplash is when your head extends outside of its 
normal range of motion. You will also be asked to wear the ClearNeck©, which is a 
cap that contains a laser. You will be asked to direct the laser onto a target while 
opening and closing your eyes and moving your head and neck. 
• Buffalo Concussion Bike Test: This test measures the symptoms of concussion during 
up to 15 minutes of exercise. You will have vital signs collected and will be asked to 
report your concussion symptom severity and your level of physical exertion for 5 
minutes before, during and after riding a stationary bicycle. The intensity of exercise 
will increase each minute and will be stopped when you are exhausted or want to 
stop, if you feel unwell, or when you have experienced a significant change in 
physical exertion compared to before the test.  
 
After the baseline visit, if your study doctor considers you eligible to participate, you will be 
provided a Waveband® to wear and its charger. This is a wristband that will assess your heart 
rate and how much it varies over time. You will be asked to return the Waveband® and the 
charger at your 8-week visit. At your first visit you will also be provided with an Apple i-Touch. 
You are not required to return the i-Touch at the completion of the study. The ClearPlay© App 
will be preloaded on your i-Touch. .  
 
You need to complete the exercises the ClearPlay App©  recommends for 20 minutes once every 
day for 8 weeks.  
 
You will be shown how to use the ClearPlay© App. The exercises it recommends will be based 
on the treatment group you will be randomized to participate in, and the information obtained from 
your Waveband® and questionnaires. 
 
During the study, you will be contacted by phone each fortnight to check on your progress and 
how you are feeling. 
 
You will cease your exercise or stretching study intervention once you achieved three daily 
consecutive PCSS scores that is equalled to or lower than your injury PCSS score. A member of 
the study team will notify you once you have reached this milestone, advising you to stop your 
study intervention. You will still be required to complete your 8-week visit, regardless of the date 
you reach this milestone.  
 
Once you complete the 8-week visit, your involvement in the study will be completed.  
 
The table below outlines the activities performed during the study.  
 
Study Activities 
Baseline Visit Therapy Period 
(8 weeks)  
8-week Visit  
Informed consent 
X 
 
 
Eligibility Criteria Review 
X 
 
 

 
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Study Activities 
Baseline Visit Therapy Period 
(8 weeks)  
8-week Visit  
Demographic and medical history 
X 
 
 
Review of medical and medication history  
X 
 
 
Review of medications and treatments 
X 
X 
X 
Review of previous scans (if applicable) 
X 
 
 
Height  
X 
 
 
Weight 
X 
 
X 
Vital signs  
X 
 
X 
Adverse Events 
X 
X 
X 
Biomarker sample collection 
X 
 
X 
Optional blood sample for genetic testing 
and biobanking 
X 
 
X 
Neuropsychologic Questionnaires 
X 
 
X 
Ice Bucket and ClearHeartÓ Tests 
X 
 
X 
ClearNeckÓ Testing 
X 
 
X 
Buffalo Concussion Bike Test 
X 
 
X 
Neurologic Testing (Eyes, Neck, 
Balance) 
X 
 
X 
Download ClearPlay© App 
X 
 
 
Receive the Waveband® and charger 
X 
 
 
Use the Waveband® and ClearPlay© 
App  
 
X 
(daily) 
 
Complete activities as instructed by the 
ClearPlay© App 
 
X 
(daily) 
 
Return of Waveband® and charger 
 
 
X 
Post-study survey 
 
 
X 
 
4 
What do I have to do? 
If you decide to take part, it is your responsibility to keep your study appointments and complete 
all study assessments. If you cannot attend an appointment, please tell the study staff (such as 
the study doctor or research staff) as soon as possible to set a new appointment. Tell the 
clinical contact person (listed in section 20) about any unusual symptoms you have immediately; 
do not wait until your next scheduled visit. Also tell them about changes in medications, doctor 
or nurse appointments, or any hospital admissions. 
 
During the study, you must be willing to exercise or stretch for 20 minutes each day following 
the directions provided by the ClearPlay© App. Outside of this, you should not engage in any 
exercise that will cause you to become short of breath during the 8-week study period. You will 
wear the Waveband® during exercising or stretching for 20 minutes each day.  When you 
achieve three daily consecutive PCSS scores that is equalled to or lower than your injury PCSS 
score, you may stop your study intervention. If this occurs before the 8-week study visit, then 
please refer to your doctor to confirm if you can resume exercise or sporting activities at a 
higher intensity.  
 
During the study, you must upload data from your i-Touch via the ClearPlay© App every day. If 
you have concerns when using the ClearPlay© App or the Waveband®, please tell the study 
staff as soon as possible so that they can assist you. You may receive a phone call from the 
study staff if data is not uploaded. 
 
Once per day, you must complete the Post-Concussion Symptom Scale on the ClearPlay© App. 
Once per week, you must complete the Godin Leisure Time Exercise questionnaire on the 
ClearPlay© App. 
You also must not smoke, drink alcohol or consume caffeinated or sugary beverages for 1 hour 
prior to each daily exercise or stretching session.  
 

 
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It is important to tell your study doctor and the study staff about any treatments or medications 
you may be taking. You should also tell your study doctor about any changes to these during 
your participation in the research project.  
 
Some medications that affect chemical levels in the brain or impact your mood or behaviour are 
prohibited during the study. If you do take these medications, please tell your study doctor.  
 
Some medications, current and previous medical conditions and family medical history may 
prohibit you from participating in the research study. Notify your study doctor if you have any of 
the following: 
• 
History of prior head injuries in the last 12 months from which you have any associated 
residual symptoms 
• 
History of prior head injuries in the last 3 months diagnosed as a concussion, or that 
included amnesia, loss of consciousness, feeling dazed, or “having your bell rung”, 
• 
Evidence of small amounts of bleeding found on previously performed scans of your brain,  
• 
Past or present neurological, mental, emotional, or behavioural conditions,  
• 
History of drug or alcohol dependency within the last 2 years,  
• 
Risk factors for cardiac disease, including high blood pressure, high cholesterol in your 
blood, or a prior diagnosis or indications requiring you to take medication for a cardiac, 
lung or diabetes related reason. 
• 
Familial history of cardiac disease, heart attacks or sudden death, 
• 
Circulation problems in your arms or legs, 
• 
Swelling from or pooling of lymph fluid in your left arm, 
• 
If you are unable or do not want to exercise,  
• 
Injuries that could make exercise difficult or painful. 
• 
Currently taking beta-blockers, which is a class of high blood pressure medication.  
 
5 
Other relevant information about the research project 
At least 400 participants aged between 14 and 45 years with concussion will be enrolled in this 
study at up to 5 study centres in Australia. Up to 104 participants will be involved in the study at 
this treating centre.  
 
The maximum duration for each participant in this study is 8 weeks.  
 
There are no additional costs associated with participating in this research project, nor will you be 
paid. All medication, tests and medical care required as part of the research project will be 
provided to you free of charge. 
 
You may be reimbursed a maximum of $50AUD per visit for any reasonable travel, parking, 
meals and other expenses associated with the research project upon presentation of a valid 
receipt.  
 
If you decide to participate in this research project, the study doctor will inform your local doctor. 
 
6 
Do I have to take part in this research project? 
Participation in any research project is voluntary. If you do not wish to take part, you do not have 
to. If you decide to take part and later change your mind, you are free to withdraw from the 
project at any stage. 
 
If you do decide to take part, you will be given this Participant Information and Consent Form to 
sign and you will be given a copy to keep. 
 
Your decision whether to take part or not to take part, or to take part and then withdraw, will not 
affect your routine treatment, your relationship with those treating you or your relationship with 
Alfred Health. 
 
 
7 
What are the alternatives to participation?  

 
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You do not have to take part in this research project to receive treatment at this centre.  Other 
options are available; these include physical and mental rest. Your study doctor will discuss 
these options with you before you decide whether or not to take part in this research project.  
You can also discuss the options with your local doctor. 
 
8 
What are the possible benefits of taking part? 
We cannot guarantee or promise that you will receive any benefits from this research. However, 
your participation in this study may help develop important scientific knowledge that could 
contribute to the treatment of patients with concussion in the future.   
 
 
9 
What are the possible risks and disadvantages of taking part? 
Medical treatments often cause side effects. You may have none, some or all of the effects 
listed below, and they may be mild, moderate or severe. If you have any of these side effects, or 
are worried about them, talk with your study doctor. Your study doctor will also be looking out for 
side effects. 
 
There may be side effects that the researchers do not expect or do not know about and that 
may be serious. Tell your study doctor immediately about any new or unusual symptoms that 
you get. 
 
Many side effects go away shortly after treatment ends. However, sometimes side effects can 
be serious, long lasting or permanent. If a severe side effect or reaction occurs, your study 
doctor may need to stop your treatment. If you experience a side effect, contact your study 
doctor who will discuss the best way to manage the side-effect. 
 
If you become upset or distressed as a result of your participation in the research, the study 
doctor will be able to arrange for counselling or other appropriate support. Any counselling or 
support will be provided by qualified staff who are not members of the research project team. 
This counselling will be provided free of charge.  
 
Exercise: The risk caused by undertaking daily exercise that is gradually increased in intensity 
or passive stretching is minimal.  
- 
When you perform the Buffalo Concussion Treadmill Test, you may experience 
tiredness, faintness, unsteady on your feet or find it difficult to continue the test, at which 
point the test will be terminated. You will be assessed and monitored by appropriately 
trained staff during the test who will ensure that any risks associated with the study 
including exercise are minimised. Your care will be adjusted if any risks become 
apparent.  
 
- 
During your daily home 20 minute exercise sessions you can take breaks while 
exercising and can stop exercising at any time 
 
- 
You may experience strained ligaments or joints or other musculoskeletal injuries as a 
result of exercising. As this is a risk inherent to exercising, by agreeing to participate in 
this study you agree to assume all the risks of exercising. 
 
- 
You may experience an adverse cardiac event while exercising. However, such events 
are extremely rare. 
 
Blood Tests: Blood sampling and needle punctures carry some risk. Possible side effects 
include, but are not limited to: fainting, bleeding, bruising, discomfort, dizziness, infection and/or 
pain at the puncture site. 
 
Mouth swab: You may experience discomfort when the cotton tip is rubbed on the inside of 
your cheek.  
 

 
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Wearing a Waveband® or Caretaker4®: You may experience discomfort when wearing a 
Waveband® or Caretaker4®.  
 
Questionnaire Completion: You may experience discomfort while completing the 
questionnaire, because some of the questions are personal questions. You do not have to 
answer any question that makes you uncomfortable or anxious. 
 
Ice Bucket and ClearHeart© autonomic testing: You will experience cold hands, that will 
resolve in minutes following the test. Very infrequently this testing may cause Peripheral 
Circulatory Disturbances and/or Lymphedema. 
 
ClearNeck© whiplash testing: Infrequently, you may experience mild to moderate neck 
discomfort during testing for whiplash. 
  
There are no other known risks associated with device deficiencies or serious adverse device 
effects.  
 
10 
What will happen to my test samples? 
Your samples will be stored in a secure location and will be labelled with your unique study 
participant number and will not contain any information that can identify you personally.  
 
Your blood or saliva and a mouth swab will be collected to test for biomarkers. This is 
mandatory testing if you participate in the study. This testing is for research purposes and you 
will not be notified of the results. The total volume of blood collected is approximately 10 mL 
(equivalent to 2 teaspoons). Alternatively, if you provide a saliva sample, approximately 1 mL 
(equivalent to 1/5th teaspoons) of saliva will be collected. 
 
Samples of your blood, saliva and mouth swab obtained for the purpose of this research project 
will be transferred to Monogram Biosciences, Inc., a division of Labcorp, Inc. The biomarker test 
will be performed by Monogram Biosciences, Inc. a division of Labcorp, Inc. Your samples will 
not be sold by Alfred Health, however Alfred Health, may charge study doctors a fee to recover 
some of the costs of storing and administering these samples. 
 
Once your blood, saliva and mouth swab samples are transferred to Monogram Biosciences, 
Inc. a division of Labcorp, Inc, Alfred Health, will not be able to control whether Monogram 
Biosciences, Inc. a division of Labcorp, Inc transfers or sells your samples at some future date, 
however Alfred Health, will not knowingly transfer your samples to anyone who has expressed 
intent to sell the samples. 
 
The samples will be retained for future research about concussion for up to 5 years. Samples 
will then be destroyed by Monogram Biosciences, Inc. a division of Labcorp, Inc. The results 
maymay be published.  
You have the right to request that the sponsor destroy your samples at any time. If you choose to 
have your samples destroyed, please contact your study doctor. If you decide to have your 
samples destroyed, any information generated prior to your request will not be destroyed. 
 
Optional additional blood samples for genetic testing and biobanking  
You may also participate in optional additional blood sample collections. This research will help 
determine if there are differences in your genetic material that determine your response to 
exercise, or the severity and recovery from the concussion. The total volume of blood collected 
for optional biobanking is approximately 10 mL (equivalent to 2 teaspoons). Alternatively, if you 
provide a saliva sample, approximately 1 mL (equivalent to 1/5th teaspoons) of saliva will be 
collected. This testing will be performed for research purposes only and the results will not be 
shared because information obtained from these studies will not provide significant information 
relating to the health of participants, relatives or other family members. It is hoped that this 
research may identify differences in genetic material and help determine the best treatment 
approach following concussion. 

 
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Your choice to participate or not in this optional testing will be collected at the end of this 
Participant Information and Consent Form. 
 
11 
What if new information arises during this research project? 
Sometimes during the course of a research project, new information becomes available about 
the treatment that is being studied. If this happens, your study doctor will tell you about it and 
discuss with you whether you want to continue in the research project. If you decide to 
withdraw, your study doctor will make arrangements for your regular health care to continue. If 
you decide to continue in the research project you will be asked to sign an updated consent 
form. 
 
Also, on receiving new information, your study doctor might consider it to be in your best 
interests to withdraw you from the research project. If this happens, he/ she will explain the 
reasons and arrange for your regular health care to continue. 
 
12 
Can I have other treatments during this research project? 
Whilst you are participating in this research project, you may not be able to take some or all of 
the medications or treatments you have been taking for your condition or for other reasons. It is 
important to tell your study doctor and the study staff about any treatments or medications you 
may be taking. This includes medications such as over-the-counter medicines, vitamins, herbal 
remedies or other alternative treatments and treatments such as acupuncture, occupational 
therapy, physical therapy, vestibular therapy, visual therapy, cognitive behavioural therapy, 
chiropractic therapy, and other therapies. You should also tell your study doctor about any 
changes to these during your participation in the research project. Your study doctor should also 
explain to you which treatments or medications need to be stopped for the time you are involved 
in the research project. 
 
13 
What if I withdraw from this research project? 
If you decide to withdraw from the project, please notify a member of the research team when 
you withdraw from the research project. This notice will allow that person or the research 
supervisor to discuss any health risks or special requirements linked to withdrawing. There are 
no health risks if you decide to withdraw from this project. 
 
If you do withdraw your consent during the research project, the study doctor and relevant study 
staff will not collect additional personal information from you, although personal information 
already collected will be retained to ensure that the results of the research project can be 
measured properly and to comply with law. You should be aware that data collected by the 
sponsor up to the time you withdraw will form part of the research project results.  If you do not 
want them to do this, you must tell them before you join the research project. 
 
14 
Could this research project be stopped unexpectedly? 
This research project may be stopped unexpectedly for a variety of reasons. These may include 
reasons such as: 
• Unacceptable side effects 
• The treatment/device being shown not to be effective 
• The treatment/device being shown to work and not need further testing 
• Decisions made in the commercial interests of the sponsor or by local regulatory/health 
authorities.  
 
You may be withdrawn from the study if data is not uploaded via the ClearPlay© App. 
 
15 
What happens when the research project ends? 
At the end of your involvement in the study, you will be required to return your Waveband® ,and 
charger to the study staff. You should discuss your options for treatment with your doctor. 
 
The results of the study may be published or a summary provided to the study doctor. It is usual 
for a number of years to elapse before definitive results of this type of study are available. 
These may be published in medical journals that are available to the public. You will not be 

 
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personally identified in any of these publications. Study results can be obtained from your study 
doctor.  
 
Part 2 
How is the research project being conducted? 
 
16 
What will happen to information about me? 
By signing the consent form you consent to the study doctor and relevant research staff 
collecting and using personal information about you for the research project. Any information 
obtained in connection with this research project that can identify you will remain confidential. 
Your information will only be used for the purpose of this research project and it will only be 
disclosed with your permission or in compliance with the law. 
 
Data from your study medical record will be identifiable and stored in secured offices at Alfred 
Health. After the study is completed, your study medical record will be archived at Alfred Health, 
for up to 15 years after the completion of the study. 
 
Information about you may be obtained from your health records held at this and other health 
services for the purpose of this research. By signing the consent form you agree to the study 
team accessing health records if they are relevant to your participation in this research project. 
 
Your health records and any information obtained during the research project are subject to 
inspection (for the purpose of verifying the procedures and the data) by the relevant authorities 
and authorised representatives of the Sponsor, ANSwers Neuroscience, Inc. and ANSwers 
Neuroscience, Pty Ltd and is being funded by ANSwers Neuroscience, Pty Ltd., the institution 
relevant to this Participant Information Sheet, Alfred Health, or in compliance with the law. By 
signing the Consent Form, you authorise release of, or access to, this confidential information to 
the relevant study personnel and regulatory authorities as noted above.  
 
It is anticipated that the results of this research project will be published and/or presented in a 
variety of forums. In any publication and/or presentation, information will be provided in such a 
way that you cannot be identified, except with your permission.   
 
Your re-identified data may be transferred within Australia or to countries outside Australia such 
as the USA, where data protection requirements may be different or that are not covered by 
data protection legislation. Re-identifiable data is information collected about you that is 
associated with the you by using a code, rather than using identifying information such as your 
name. It remains possible to re-identify you by using the code. Your name or any other personal 
identifiers will not appear on any documentation forwarded to the sponsor, nor on any data 
gathered or published from this study. Although absolute confidentiality cannot be guaranteed, 
the sponsor will take reasonable measures to keep your personal health information confidential 
by using a unique study code to label data and not your name or hospital number. By signing 
this document, you agree to the transfer of your personal health information to such countries. 
 
Data will be stored for 1510 years by ANSwers Neuroscience, Inc. and will be located at Weill 
Cornell Medicine, 1300 York Ave, New York, NY 10065, United States. 
 
Information about your participation in this research project may be recorded in your health 
records. 
 
In accordance with relevant Australian and/or Victorian privacy and other relevant laws, you 
have the right to request access to your information collected and stored by the research team. 
You also have the right to request that any information with which you disagree be corrected. 
Please contact the study team member named at the end of this document if you would like to 
access your information. 
 
Any information obtained for the purpose of this research project and for the future research 
described in Section 10 that can identify you will be treated as confidential and securely stored.  
It will be disclosed only with your permission, or in compliance with the law. 
 

 
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17 
What if I get injured in the research? 
If you suffer any injuries or complications as a result of this research project, you should contact 
the study team as soon as possible and you will be assisted with arranging appropriate medical 
treatment. Under Medicare, you can receive any medical treatment required to treat the injury or 
complication, free of charge, as a public patient in any Australian public hospital.  
 
 Medication required to treat injuries or complications as a result of this research project will be 
paid by the sponsor. 
 
There are two avenues that may be available to you for seeking compensation if you suffer an 
injury as a result of your participation in this research project: 
 
• The pharmaceutical industry has set up a compensation process, with which the Sponsor 
ANSwers Neuroscience, Pty Ltd of this research project has agreed to comply.  Details of the 
process and conditions are set out in the Medicines Australia Guidelines for Compensation for 
Injury Resulting from Participation in a Company-Sponsored Clinical Trial.  In accordance with 
these Guidelines, the sponsor will determine whether to pay compensation to you, and, if so, 
how much.  The research staff will give you a copy of the Guidelines together with this 
Participant Information and Consent Form.  If you have any questions about the Guidelines, 
please ask to speak to Brendan Major. 
 
• You may be able to seek compensation through the courts. 
 
18 
Who is organising and funding the research? 
This research project is being conducted by ANSwers Neuroscience, Inc. and sponsored in 
Australia by ANSwers Neuroscience, Pty Ltd and is being funded by ANSwers Neuroscience, 
Pty Ltd. 
 
ANSwers Neuroscience, Pty Ltd may benefit financially from this research project if, for 
example, the project assists ANSwers Neuroscience, Pty Ltd to obtain approval for a new 
device.   
 
By taking part in this research project you agree that samples of your blood, saliva or mouth 
swabs (or data generated from analysis of these materials) may be provided to ANSwers 
Neuroscience, Pty Ltd.   
 
ANSwers Neuroscience, Pty Ltd may directly or indirectly benefit financially from your samples 
or from knowledge acquired through analysis of your samples. 
 
You will not benefit financially from your involvement in this research project even if, for 
example, your samples (or knowledge acquired from analysis of your samples) prove to be of 
commercial value to ANSwers Neuroscience, Pty Ltd. 
 
In addition, if knowledge acquired through this research leads to discoveries that are of 
commercial value to ANSwers Neuroscience, Pty Ltd, the study doctors or their institutions, 
there will be no financial benefit to you or your family from these discoveries. 
 
Alfred Health will receive a payment from ANSwers Neuroscience, Pty Ltd for undertaking this 
research project.  
 
No member of the research team will receive a personal financial benefit from your involvement 
in this research project (other than their ordinary wages). 
 
19 
Who has reviewed the research project? 
All research in Australia involving humans is reviewed by an independent group of people called 
a Human Research Ethics Committee (HREC).  The ethical aspects of this research project 
have been approved by the Alfred Hospital Ethics Committee.  
 

 
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This project will be carried out according to the National Statement on Ethical Conduct in 
Human Research (2007). This statement has been developed to protect the interests of people 
who agree to participate in human research studies. 
 
20 
Further information and who to contact 
The person you may need to contact will depend on the nature of your query.  
 
If you want any further information concerning this project or if you have any medical problems 
which may be related to your involvement in the project (for example, any side effects), you can 
contact the principal study doctor on 03 9903 0304 or any of the following people: 
 
 Clinical contact person 
 
 
 
 
HREC Office/Complaints contact person 
 
Please quote the following Project ID number: 60472 
 
 
Name 
Prof Terence O’Brien 
Position 
Department of Neurology 
Telephone 
03 9903 0304   
Email 
te.obrien@alfred.org.au 
Name 
Brendan Major 
Position 
Research Assistant 
Telephone 
03 9246 8383 
Email 
brendan.major@monash.edu 
Reviewing HREC name 
Alfred Hospital Ethics Committee 
Position 
Complaints Officer, Office of Ethics & Research Governance, 
Alfred Health 
Telephone 
(03) 9076 3619 
Email 
research@alfred.org.au 

 
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Consent Form - Adult providing own consent 
 
Title 
Exercise As Concussion Therapy Trial  
Protocol Number 
ExACTT-2 
Australian Project Sponsor 
ANSwers Neuroscience, Pty Ltd 
Principal Investigator 
Prof Terence O’Brien 
Location  
The Alfred Hospital,  
99 Commercial Rd 
Melbourne, VIC 3004 
Declaration by Participant 
 
I have read the Participant Information Sheet. 
 
I understand the purposes, procedures and risks of the research described in the project. 
 
I give permission for my doctors, other health professionals, hospitals or laboratories outside this hospital 
to release information to Alfred Health concerning my disease and treatment for the purposes of this 
project. I understand that such information will remain confidential.  
 
I have had an opportunity to ask questions and I am satisfied with the answers I have received. 
 
I freely agree to participate in this research project as described and understand that I am free to 
withdraw at any time during the study without affecting my future health care.  
 
I understand that I will be given a signed copy of this document to keep.  
 
I consent to the storage and use of blood or saliva and mouth swab samples taken from me for biomarker 
research, as described in the relevant section of the Participant Information Sheet, for: 
• This specific research project 
• Other research that is closely related to this research project 
 
Optional additional blood or saliva sample for genetic testing and biobanking: By signing this 
consent section, I agree to the use of my blood or salvia samples for genetic testing, as outlined in the 
relevant Section of the Participant Information Sheet.  
□ Yes, I agree to the optional testing 
□ No, I do not agree to the optional testing 
 
Name of Participant (please print) 
Signature 
Date 
 
Declaration by Study Doctor/Senior Researcher† 
I have given a verbal explanation of the research project, its procedures and risks and I believe 
that the participant has understood that explanation. 
Name of Study Doctor/ 
Senior Researcher† (please print) 
Signature 
Date 
† A senior member of the research team must provide the explanation of, and information concerning, the research 
project.  
Note: All parties signing the consent section must date their own signature.

 
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Form for Withdrawal of Participation - Adult providing own consent 
 
Title 
Exercise As Concussion Therapy Trial  
Protocol Number 
ExACTT-2 
Australian Project Sponsor 
ANSwers Neuroscience, Pty Ltd 
Principal Investigator 
Prof Terence O’Brien 
Location  
The Alfred Hospital,  
99 Commercial Rd 
Melbourne, VIC 3004 
 
 
Declaration by Participant 
I wish to withdraw from participation in the above research project and understand that such 
withdrawal will not affect my routine treatment, my relationship with those treating me or my 
relationship with Alfred Health. 
 
Name of Participant (please print) 
Signature 
Date 
 
In the event that the participant’s decision to withdraw is communicated verbally, the Study Doctor/Senior 
Researcher will need to provide a description of the circumstances below. 
 
 
 
 
 
 
Declaration by Study Doctor/Senior Researcher† 
I have given a verbal explanation of the implications of withdrawal from the research project and 
I believe that the participant has understood that explanation. 
 
Name of Study Doctor/ 
Senior Researcher† (please print) 
Signature 
Date 
† A senior member of the research team must provide the explanation of and information concerning withdrawal from 
the research project.  
 
Note: All parties signing the consent section must date their own signature. 

Master Parent/Guardian Information Sheet/Consent Form version 6.0 , 19 August 2020  
 
Alfred Health Local governance version V4, 19 August 2020 
Page 1 of 15 
 
 
 
 
Participant Information Sheet/Consent Form – Parent/Guardian 
Interventional Study - Parent/Guardian consenting on behalf of participant 
 
Alfred Health 
 
Title 
Exercise As Concussion Therapy Trial  
Protocol Number 
ExACTT-2 
Australian Project Sponsor 
ANSwers Neuroscience, Pty Ltd 
Principal Investigator 
Prof Terence O’Brien 
Location  
The Alfred Hospital 
99 Commercial Rd 
Melbourne, VIC 3004 
 
 
Part 1 
What does my child’s participation involve? 
 
1 
Introduction 
This is an invitation for the child in your care to take part in this research project because they 
have mild traumatic brain injury, which is also known as concussion.  The research project is 
testing new ways to assess and treat initially diagnosed concussion. The new treatment is 
called graded exercise, which is exercise that is gradually increased in intensity. The devices 
being researched are:  
• 
the i-Touch application called ClearPlay©, the i-Touch application is used with a 
wristband called the Waveband®. The Waveband® assesses heart rate and how much it 
varies over time.  
• 
a hand-cooling device called the ClearHeart©, which, when used in conjunction with the 
Caretaker4® monitor, measures changes in blood pressure and heart rate when the 
hand is cooled. 
• 
a device worn on the head that assesses how the body perceives position and 
movement of the head called the ClearNeck©. 
 
This Participant Information Sheet/Consent Form tells you about the research project. It 
explains the tests and treatments involved. Knowing what is involved will help you decide if you 
want the child to take part in the research. 
 
Please read this information carefully. Ask questions about anything that you don’t understand 
or want to know more about. Before deciding whether or not your child can take part, you might 
want to talk about it with a relative, friend or your child’s local doctor. 
 
Participation in this research is voluntary. If you do not wish your child to take part, they do not 
have to. Your child will receive the best possible care whether or not they take part. 
 
If you decide you want your child to take part in the research project, you will be asked to sign 
the consent section. By signing it you are telling us that you: 
• Understand what you have read 
• Consent to your child taking part in the research project 
• Consent for your child to have the tests and treatments that are described 
 
• Consent to the use of your child’s personal and health information as described. 
 

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You will be given a copy of this Participant Information and Consent Form to keep. 
 
2  
What is the purpose of this research? 
As an initial treatment for concussion, exercise has been shown to improve the rate of recovery 
when compared to physical and mental rest. Non-contact forms of aerobic exercise that use 
oxygen to create energy and that do not worsen concussion symptoms are recommended as a 
treatment for concussion.  
 
The purpose of this study is to use the ClearPlay© i-Touch application (App) in participants with 
recently diagnosed concussion to compare the effects and recovery rate of exercise that is 
gradually increased in intensity against the effects of passive stretching.  
 
The ClearPlay© App collects information, regarding your child’s heart rate to recommend the 
rate at which your child should escalate on a daily basis. The information is collected by the 
Waveband®.  
 
The study also will assess the usefulness of two devices: ClearHeart© and ClearNeck©. 
ClearHeart© is a hand cooling device, which, when used in conjunction with the Caretaker4® 
monitor, measures changes in blood pressure and heart rate when the hand is cooled. 
ClearNeck©, is a device worn on the head that assesses how the body perceives neck position 
and movement. 
ClearHeart© and ClearNeck© devices are considered safe for use in children. 
 
Medications, drugs and devices have to be approved for use by the Australian Federal 
Government. Exercise that is gradually increased in intensity is not an approved treatment for 
initially diagnosed concussion. The ClearPlay© App including Waveband®, the ClearHeart© 
and the ClearNeck© are experimental devices. This means that they are not approved ways to 
assess or treat concussion in Australia. 
 
This research is being conducted by ANSwers Neuroscience, Pty Ltd and sponsored in 
Australia by ANSwers Neuroscience, Pty Ltd.  
 
3 
What does participation in this research involve? 
Study Design 
This is an open-label study which means both the researchers and study participants know 
which treatment is being given.  
 
Your child will be participating in a randomised controlled research project. Sometimes we do 
not know which treatment is best for treating a condition. To find out we need to compare 
different treatments. We put people into groups and give each group a different treatment. The 
results are compared to see if one is better.  
In this study there will be two groups; 
1. graded exercise – this is investigational treatment. 
2. passive stretching - this is called a control group because the treatment received is 
considered the current standard of care. 
 
Your child will have a 50% chance (1-in-2, like flipping a coin) of receiving the graded exercise 
investigational treatment. 
 
This research project has been designed to make sure the researchers interpret the results in a 
fair and appropriate way and avoids study doctors or participants jumping to conclusions.   
 
Study Activities 
Your child will complete the following assessments in this study. Two study visits are required to 
the centre. Some activities are completed when your child is at home during the 8-week period 
between the two study visits. Each study visit will take approximately 2 hours. 
 

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The following activities will be performed when your child attends Alfred Health for study visits: 
• 
Informed consent (Baseline visit only): Before your child begins the study, you will be 
given detailed information about the study treatment and devices, and any other relevant 
information by research staff. If you decide that they can participate, you will be asked to 
sign this information sheet and consent form before any procedures are completed. 
• 
Eligibility Criteria Review (Baseline visit only): The study doctor will ask your child 
questions and complete tests to assess if they are eligible for the study. 
• 
Demographic information and medical history (Baseline visit only): The study doctor will 
ask you and your child about their concussion, other medical conditions that they have, 
their medical history and demographics. 
• 
Review of previous scans (Baseline visit only): If your child has had scans performed 
previously of their head to help diagnose and treat their concussion, these will be 
collected and reviewed by the study staff. 
• 
Vital Signs (baseline and 8-week visit): Your child’s vital signs such as heart rate and 
blood pressure will be measured with a device on your right hand for 6 minutes on two 
occasions at each study visit.  
• 
Medications and treatments (during entire study): You and your child will be asked about 
the medications and treatments that they have taken in the 7 days prior to the baseline 
study visit, and between the start of the study, until their 8-week study visit. This includes 
medications such as over-the-counter medicines, vitamins, herbal remedies or other 
alternative treatments and treatments such as acupuncture, occupational therapy, 
physical therapy, vestibular therapy, visual therapy, cognitive behavioural therapy, 
chiropractic therapy, and other therapies. 
• 
Adverse Events (during entire study): You and your child will be asked how they are 
feeling, if they had to visit a hospital or have been seriously ill.  
• 
Post study survey (8-week visit): Your child will be asked to complete a survey about their 
experience on this research study and any leave they have had to take from school, work 
or normal duties during their time on the study. 
• 
Sample collection for biomarkers (baseline and 8-week visit): A biomarker is a naturally 
occurring molecule or substance in the body that allows a specific disease or medical 
condition to be identified and measured. Your child can either have a blood test to collect 
biomarkers, or if they do not want to have a blood test, a sample of their saliva and a 
cotton tip will be rubbed on the inside of their cheek (a mouth swab) can be collected 
instead. 
• 
Optional additional blood samples or saliva for genetic testing and biobanking (baseline 
and 8-week visit): This testing is optional and involves testing genes, which are the DNA 
instructions that are inherited from your child’s parents. The results of this optional genetic 
testing will not be available to you, should you choose to participate in this optional testing 
because information obtained from these studies will not provide significant information 
relating to the health of participants, relatives or other family members. You can nominate 
your choice for your child to participate in this optional testing at the end of this Participant 
Information and Consent Form.  
• 
Questionnaires (during entire study): Your child will be asked to complete questionnaires 
at the Baseline and Follow-up visits, The questionnaires ask about their health, thoughts, 
feelings, behaviour, exercise habits, and experiences, and will take 45- 60 minutes to 
complete. The questionnaires include; 
o Post Concussion Symptom Scale (PCSS) 
o Godin Leisure Time Exercise Questionnaire 
o The Beck Anxiety Inventory (BAI)  
o Brief Symptom Inventory 
o Reiss-Epstein-Gursky Anxiety Sensitivity Index 
o Adult Attention Deficit Hyperactivity Disorder Rating Scale (CAARS) 
o Center for Epidemiologic Studies - Depression Scale (CES-D) 
 

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Your child will also be required to complete the Post-Concussion Symptom Scale daily 
during the study Therapy period and the Godin Leisure Time Exercise Questionnaire 
weekly during the study Therapy period. They are available on the ClearPlay© App. It will 
take up to 15 minutes each day. 
 
• 
Assessments that will be administered to the child by the study staff (baseline and 8-week 
visit): 
• Cold Pressor Test: This tests how your child’s heart and blood vessels respond to the 
cooling of their left hand while placed in ice water for 2 minutes (the ice bucket test) 
and also when placed in the ClearHeart© hand-cooling device for 2 minutes. They will 
be asked to remain seated for 5 minutes before and after both of these tests. During 
this test your child will be fitted with the Caretaker4® device on their right arm and 
finger. 
• Neck range of motion and ClearNeckÓ Testing: The Joint Position Error Test will be 
performed, which assesses your child’s neck strength, how much it moves, if it is 
painful or sore and if whiplash is present. Whiplash is when the head extends outside 
of its normal range of motion. Your child will also be asked to wear the ClearNeck©, 
which is a cap that contains a laser. They will be asked to direct the laser onto a 
target while opening and closing their eyes and moving their head and neck. 
• Buffalo Concussion Bike Test: This test measures the symptoms of concussion during 
up to 15 minutes of exercise. Your child will have vital signs collected and will be 
asked to report their concussion symptom severity and their level of physical exertion 
for 5 minutes before, during and after riding a stationary bicycle. The intensity of 
exercise will increase each minute and will be stopped when they are exhausted or 
want to stop, if they feel unwell, or when they have experienced a significant change 
in physical exertion compared to before the test.  
 
After the baseline visit, if the study doctor considers that your child is eligible to participate, they 
will be provided  a Waveband® to wear and its charger. This is a wristband that will assess their 
heart rate and how much it varies over time. They will be asked to return the Waveband® and 
the charger at the 8-week visit. At your first visit your child will also be provided with an Apple i-
Touch. You are not required to return the i-Touch at the completion of the study. The 
ClearPlay© App will be preloaded on your child’s i-Touch.   
 
 Your child will need tocomplete the exercises the ClearPlay© App recommends for 20 minutes 
once every day for 8 weeks. They will be shown how to use the ClearPlay© App. The exercises 
it recommends will be based on the treatment group your child will be randomized to participate 
in, and the on the information obtained from the child’s Waveband® and questionnaires. 
 
During the study, your child will be contacted by phone each fortnight to check on their progress 
and how they are feeling. 
 
Your child will cease their exercise or stretching study intervention once they have achieved three 
daily consecutive PCSS scores that is equalled to or lower than your injury PCSS score. A 
member of the study team will notify you once your child has reached this milestone, advising 
your child to stop their study intervention. They will still be required to complete your 8-week visit, 
regardless of the date they reach this milestone.  
 
Once your child completes the 8-week visit, their involvement in the study will be completed.  
 
The table below outlines the activities performed during the study.  
 
Study Activities 
Baseline Visit Therapy Period 
(8 weeks)  
8-week Visit  
Informed consent 
X 
 
 
Eligibility Criteria Review 
X 
 
 
Demographic and medical history 
X 
 
 

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Study Activities 
Baseline Visit Therapy Period 
(8 weeks)  
8-week Visit  
Review of medical and medication history  
X 
 
 
Review of medications and treatments 
X 
X 
X 
Review of previous scans (if applicable) 
X 
 
 
Height  
X 
 
 
Weight 
X 
 
X 
Vital signs  
X 
 
X 
Adverse Events 
X 
X 
X 
Biomarker sample collection 
X 
 
X 
Optional blood sample for genetic testing 
and biobanking 
X 
 
X 
Neuropsychologic Questionnaires 
X 
 
X 
Ice Bucket and ClearHeartÓ Tests 
X 
 
X 
Neck range of motion and ClearNeckÓ 
Testing 
X 
 
X 
Buffalo Concussion Bike Test 
X 
 
X 
Download ClearPlay© App 
X 
 
 
Receive the Waveband® and charger 
X 
 
 
Use the Waveband® and ClearPlay© 
App  
 
X 
(daily) 
 
Complete activities as instructed by the 
ClearPlay© App 
 
X 
(daily) 
 
Return of Waveband® and charger 
 
 
X 
Post-study survey 
 
 
X 
 
4 
What does my child have to do? 
If you decide that your child can take part, it is your and their responsibility to keep study 
appointments and complete all study assessments. If you and your child cannot attend an 
appointment, please tell the study staff (such as the study doctor or research staff) as soon as 
possible to set a new appointment. Tell the clinical contact person (listed in section 20) about 
any unusual symptoms your child has immediately; do not wait until your child’s next scheduled 
visit. Also tell them about changes in medications, doctor or nurse appointments, or any hospital 
admissions. 
 
During the study, your child must be willing to exercise or stretch for 20 minutes each day 
following the directions provided by the ClearPlay© App. Outside of this, your child should not 
engage in any exercise that will cause them to become short of breath during the during the 8-
week study period. Your child will wear the Waveband® during exercising or stretching for 20 
minutes each day. When your child has achieved three daily consecutive PCSS scores that is 
equalled to or lower than their injury PCSS score, they may stop their study intervention. If this 
occurs before the 8-week study visit, then please refer to your child’s doctor to confirm if they 
can resume exercise or sporting activities at a higher intensity.   
 
 
During the study, you and your child must upload data from their i-Touch via the ClearPlay© 
App every day. If you or your child have concerns when using the ClearPlay© App or the 
Waveband®, please tell the study staff as soon as possible so that they can assist you and your 
child. You or your child may receive a phone call from the study staff if data is not uploaded.  
 
Once per day your child must complete the Post-Concussion Symptom Scale on the ClearPlay© 
App. Once per week, your child must complete the Godin Leisure Time Exercise questionnaire 
on the ClearPlay© App. 
 
Your child also must not smoke, drink alcohol or consume caffeinated or sugary beverages for 1 
hour prior to each daily exercise or stretching session.  
 

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It is important to tell your child’s study doctor and the study staff about any treatments or 
medications that your child may be taking. You should also tell your study doctor about any 
changes to these during your child’s participation in the research project.  
 
Some medications that affect chemical levels in the brain or impact your child’s mood or 
behaviour are prohibited during the study. If your child does take these medications, please tell 
your child’s study doctor.  
 
Some medications, current and previous medical conditions and family medical history may 
prohibit your child from participating in the research study. Notify your child’s study doctor if your 
child has any of the following: 
• 
History of prior head injuries in the last 12 months from with associated residual symptoms 
• 
History of prior head injuries in the last 3 months diagnosed as a concussion, or that 
included amnesia, loss of consciousness, feeling dazed, or “having your bell rung”, 
• 
Evidence of small amounts of bleeding found on previously performed scans of your childs 
brain.  
• 
Past or present neurological, mental, emotional, or behavioural conditions,  
• 
History of drug or alcohol dependency within the last 2 years,  
• 
Risk factors for cardiac disease, including high blood pressure, high cholesterol in your 
blood, or a prior diagnosis or indications requiring you to take medication for a cardiac, 
lung or diabetes related reason, 
• 
Familial history of cardiac disease, heart attacks or sudden death, 
• 
Circulation problems in your child’s arms or legs, 
• 
Swelling from or pooling of lymph fluid in the child’s left arm, 
• 
If your child is unable or does not want to exercise, Injuries that could make exercise 
difficult or painful. 
•       Currently taking beta-blockers, which is a class of high blood pressure medication. 
 
5 
Other relevant information about the research project 
At least 400 participants aged between 14 and 45 years with concussion will be enrolled in this 
study at up to 5 study centres in Australia. Up to 104 participants will be involved in the study at 
this treating centre.  
 
The maximum duration for each participant in this study is 8 weeks.  
 
There are no additional costs associated with participating in this research project, nor will you or 
your child be paid. All medication, tests and medical care required as part of the research project 
will be provided to your child free of charge. 
 
You may be reimbursed up to $50AUD per clinic visit for any reasonable travel, parking, meals 
and other expenses associated with the research project upon presentation of a valid receipt.  
 
If you decide that your child can participate in this research project, the study doctor will inform 
your child’s local doctor. 
 
6 
Does my child have to take part in this research project? 
Participation in any research project is voluntary. If you do not wish for your child to take part, 
they do not have to. If you decide that they can take part and later change your mind, you are 
free to withdraw your child from the project at any stage. 
 
If you do decide that your child can take part, you will be given this Participant Information and 
Consent Form to sign and you will be given a copy to keep. 
 
Your decision that your child can or cannot take part, or that they can take part and then be 
withdrawn, will not affect their routine treatment, relationship with those treating them, or their 
relationship with Alfred Health. 
 

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7 
What are the alternatives to participation?  
Your child does not have to take part in this research project to receive treatment at this centre.  
Other options are available; these include physical and mental rest. The study doctor will 
discuss these options with you before you decide whether or not your child can take part in this 
research project.  You can also discuss the options with your child’s local doctor. 
 
 
 
8 
What are the possible benefits of taking part? 
We cannot guarantee or promise that your child will receive any benefits from this research. 
However, your child’s participation in this study may help develop important scientific knowledge 
that could contribute to the treatment of patients with concussion in the future.   
 
9 
What are the possible risks and disadvantages of taking part? 
Medical treatments often cause side effects. The participant may have none, some or all of the 
effects listed below, and they may be mild, moderate or severe. If the participant has any of 
these side effects, or you worried about them, talk with the study doctor. The study doctor will 
also be looking out for side effects. 
 
There may be side effects that the researchers do not expect or do not know about and that 
may be serious. Tell the study doctor immediately about any new or unusual symptoms that the 
participant gets. 
 
Many side effects go away shortly after treatment ends. However, sometimes side effects can 
be serious, long lasting or permanent. If a severe side effect or reaction occurs, the study doctor 
may need to stop your child’s treatment. Your child’s study doctor will discuss the best way of 
managing any side effects with you. 
 
If your child becomes upset or distressed as a result of participation in the research, the study 
doctor will be able to arrange for counselling or other appropriate support. Any counselling or 
support will be provided by qualified staff who are not members of the research project team. 
This counselling will be provided free of charge 
 
Exercise: The risk caused by undertaking daily exercise that is gradually increased in intensity 
or passive stretching is minimal.  
- 
When your child performs the Buffalo Concussion Treadmill Test, they may experience 
tiredness, faintness, unsteady on their feet or find it difficult to continue the test, at which 
point the test will be terminated.  Your child will be assessed and monitored by 
appropriately trained staff during the test who will ensure that any risks associated with 
the study including exercise are minimised. Your child’s care will be adjusted if any risks 
become apparent.  
 
- 
During your daily home 20 minute exercise sessions you can take breaks while 
exercising and can stop exercising at any time. 
 
- 
Your child may experience strained ligaments or joints or other musculoskeletal injuries 
as a result of exercising. As this is a risk inherent to exercising, by agreeing that your 
child can participate in this study you agree to assume all the risks of exercising. 
 
- 
Your child may experience an adverse cardiac event while exercising. However, such 
events are extremely rare. 
 
Blood Tests: Blood sampling and needle punctures carry some risk. Possible side effects 
include, but are not limited to: fainting, bleeding, bruising, discomfort, dizziness, infection and/or 
pain at the puncture site. 
 
Mouth swab: Your child may experience discomfort when the cotton tip is rubbed on the inside 
of their cheek.  

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Wearing a Waveband® or Caretaker4®: Your child may experience discomfort when wearing 
a Waveband®, the Caretaker4® device. 
 
Questionnaire Completion: Your child may experience discomfort while completing the 
questionnaire, because some of the questions are personal questions. They do not have to 
answer any question that makes them uncomfortable or anxious. 
 
Ice Bucket and ClearHeart© autonomic testing: Your child will experience cold hands, that 
will resolve in minutes following the test. Very infrequently this testing may cause Peripheral 
Circulatory Disturbances  and/or Lymphedema. 
 
ClearNeck©  whiplash testing: Infrequently, your child may experience mild to moderate neck 
discomfort during testing for whiplash. 
 
There are no other known risks associated with device deficiencies or serious adverse device 
effects. 
 
10 
What will happen to my child’s test samples? 
Your child’s samples will be stored in a secure location and will be labelled with a unique study 
participant number and will not contain any information that can identify them personally.  
 
Their blood or saliva and a mouth swab will be collected to test for biomarkers. This is 
mandatory testing if they participate in the study. This testing is for research purposes and they 
will not be notified of the results. The total volume of blood collected is approximately 10 mL 
(equivalent to 2 teaspoons). Alternatively, if they provide a saliva sample, approximately 1 mL 
(equivalent to 1/5th  teaspoons) of saliva will be collected. 
Samples of blood, saliva and mouth swab obtained for the purpose of this research project will 
be transferred to Monogram Biosciences, Inc. a division of Labcorp, Inc. The biomarker test will 
be performed by Monogram Biosciences, Inc. a division of Labcorp, Inc. Your child’s samples 
will not be sold by Alfred Health however Alfred Health may charge study doctors a fee to 
recover some of the costs of storing and administering these samples. 
 
Once your child’s blood, saliva and mouth swab samples are transferred to Monogram 
Biosciences, Inc. a division of Labcorp, Inc, Alfred Health will not be able to control whether 
Monogram Biosciences, Inc. a division of Labcorp, Inc transfers or sells the samples at some 
future date, however Alfred Health will not knowingly transfer samples to anyone who has 
expressed intent to sell the samples. 
 
The samples will be retained for future research about concussion for up to 5 years. Samples 
will then be destroyed by Monogram Biosciences, Inc. a division of Labcorp, Inc. The results 
may be published.  
You have the right to request that the sponsor destroy your child’s samples at any time. If you 
choose to have your child’s samples destroyed, please contact the study doctor. If you decide to 
have your child’s samples destroyed, any information generated prior to your request will not be 
destroyed. 
 
Optional additional blood samples for genetic testing and biobanking  
You may also agree for your child to participate in optional additional blood sample collections. 
This research will help determine if there are differences in genetic material that determine a 
person’s response to exercise, or the severity and recovery from concussion. The total volume 
of blood collected for optional biobanking is approximately 10 mL (equivalent to 2 teaspoons). 
Alternatively, your child may provide a saliva sample, approximately 1 mL (equivalent to 1/5th 
teaspoons) of saliva will be collected. 
 
This testing will be performed for research purposes only and the results will not be shared 
because information obtained from these studies will not provide significant information relating 

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to the health of participants, relatives or other family members. It is hoped that this research 
may identify differences in genetic material and help determine the best treatment approach 
following concussion. 
Your choice for the child to participate or not in this optional testing will be collected at the end 
of this Parent/Guardian Information and Consent Form. 
 
11 
What if new information arises during this research project? 
Sometimes during the course of a research project, new information becomes available about 
the treatment that is being studied. If this happens, the study doctor will tell you and your child 
about it and discuss with you whether you want the child to continue in the research project. If 
you decide to withdraw your child, the study doctor will make arrangements for the child’s 
regular health care to continue. If you decide that your child can continue in the research project 
you and your child will be asked to sign an updated consent form. 
 
Also, on receiving new information, the study doctor might consider it to be in the child’s best 
interests to withdraw them from the research project. If this happens, he/ she will explain the 
reasons and arrange for your child’s regular health care to continue. 
 
12 
Can my child have other treatments during this research project? 
Whilst the child is participating in this research project, they may not be able to take some or all 
of the medications or treatments that they have been taking for their condition or for other 
reasons. It is important to tell the study doctor and the study staff about any treatments or 
medications that they may be taking. This includes medications such as over-the-counter 
medicines, vitamins, herbal remedies or other alternative treatments and treatments such as 
acupuncture, occupational therapy, physical therapy, vestibular therapy, visual therapy, 
cognitive behavioural therapy, chiropractic therapy, and other therapies. You should also tell the 
study doctor about any changes to these during participation in the research project. The study 
doctor should also explain to you which treatments or medications need to be stopped for the 
time that the child is involved in the research project. 
 
13 
What if I withdraw my child from this research project? 
If you decide to withdraw your child from the project, please notify a member of the research 
when you withdraw from the research project.. This notice will allow that person or the research 
supervisor to discuss any health risks or special requirements linked to withdrawing. There are 
no health risks if your child withdraws from this project. 
 
If you do withdraw your consent during the research project, the study doctor and relevant study 
staff will not collect additional personal information from your child, although personal 
information already collected will be retained to ensure that the results of the research project 
can be measured properly and to comply with law. You should be aware that data collected by 
the sponsor up to the time you withdraw your child will form part of the research project results.  
If you do not want them to do this, you must tell them before you join the research project. 
 
14 
Could this research project be stopped unexpectedly? 
This research project may be stopped unexpectedly for a variety of reasons. These may include 
reasons such as: 
• Unacceptable side effects 
• The treatment/device being shown not to be effective 
• The treatment/device being shown to work and not need further testing 
• Decisions made in the commercial interests of the sponsor or by local regulatory/health 
authorities.  
 
Your child may be withdrawn from the study if data is not uploaded via the ClearPlay© App. 
 
15 
What happens when the research project ends? 
At the end of your  child’s involvement in the study, they will be required to return the 
Waveband® and the chargers to the study staff. You should discuss treatment options for your  
child with their doctor. 

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The results of the study may be published or a summary provided to the study doctor. It is usual 
for a number of years to elapse before definitive results of this type of study are available. 
These may be published in medical journals that are available to the public. Your child will not 
be personally identified in any of these publications. Study results can be obtained from the 
study doctor.  
  
Part 2  
How is the research project being conducted? 
 
16 
What will happen to information about my child? 
By signing the consent form you consent to the study doctor and relevant research staff 
collecting and using personal information about your child for the research project. Any 
information obtained in connection with this research project that can identify your child will 
remain confidential. Their information will only be used for the purpose of this research project 
and it will only be disclosed with your permission or in compliance with the law. 
 
Data from your child’s study medical record will be identifiable and stored in secured offices at 
Alfred Health. After the study is completed, their study medical record will be archived at Alfred 
Health for up to 15 years from when the child turns 18 years old. 
 
Information about your child may be obtained from their health records held at this and other 
health services for the purpose of this research. By signing the consent form you agree to the 
study team accessing your child’s health records if they are relevant to their participation in this 
research project. 
 
Your child’s health records and any information obtained during the research project are subject 
to inspection (for the purpose of verifying the procedures and the data) by the relevant 
authorities and authorised representatives of the Sponsor, ANSwers Neuroscience, Inc. and 
ANSwers Neuroscience, Pty Ltd and is being funded by ANSwers Neuroscience, Pty Ltd., the 
institution relevant to this Participant Information Sheet, Alfred Health or in compliance with the 
law. By signing the Consent Form, you authorise release of, or access to, your  child’s 
confidential information to the relevant study personnel and regulatory authorities as noted 
above.  
 
It is anticipated that the results of this research project will be published and/or presented in a 
variety of forums. In any publication and/or presentation, information will be provided in such a 
way that your child cannot be identified, except with your permission.   
 
Your child’s re-identified data may be transferred within Australia or to countries outside 
Australia such as the USA, where data protection requirements may be different or that are not 
covered by data protection legislation. Re-identifiable data is information collected about the 
child that is associated with the child by using a code, rather than using identifying information 
such as their name. It remains possible to re-identify your child by using the code. Your child’s 
name or any other personal identifiers will not appear on any documentation forwarded to the 
sponsor, nor on any data gathered or published from this study. Although absolute 
confidentiality cannot be guaranteed, the sponsor will take reasonable measures to keep 
personal health information confidential by using a unique study code to label data and not your 
child’s name or hospital number. By signing this document, you agree to the transfer of your 
child’s personal health information to such countries. 
 
Data will be stored for 15 years from when the child turns 18 years old. by ANSwers 
Neuroscience, Inc and will be located at Weill Cornell Medicine, 1300 York Ave, New York, NY 
10065, United States. 
 
Information about your child’s participation in this research project may be recorded in their 
health records. 
 

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In accordance with relevant Australian and/or Victorian privacy and other relevant laws, you 
have the right to request access to your child’s information collected and stored by the research 
team. You also have the right to request that any information with which you disagree be 
corrected. Please contact the study team member named at the end of this document if you 
would like to access your child’s information. 
 
Any information obtained for the purpose of this research project and for the future research 
described in Section 10 that can identify you or your child will be treated as confidential and 
securely stored.  It will be disclosed only with your permission, or in compliance with the law. 
 
17 
What if I get injured in the research? 
If your child suffers any injuries or complications as a result of this research project, you should 
contact the study team as soon as possible and you will be assisted with arranging appropriate 
medical treatment for your child. Under Medicare, your child can receive any medical treatment 
required to treat the injury or complication, free of charge, as a public patient in any Australian 
public hospital. Medication required to treat injuries or complications as a result of this research 
project will be paid by the sponsor.  
 
There are two avenues that may be available to you for seeking compensation if your child 
suffers an injury as a result of their participation in this research project: 
 
• The pharmaceutical industry has set up a compensation process, with which the Sponsor 
ANSwers Neuroscience, Pty Ltd of this research project has agreed to comply.  Details of the 
process and conditions are set out in the Medicines Australia Guidelines for Compensation for 
Injury Resulting from Participation in a Company-Sponsored Clinical Trial.  In accordance with 
these Guidelines, the sponsor will determine whether to pay compensation to you, and, if so, 
how much.  The research staff will give you a copy of the Guidelines together with this 
Participant Information and Consent Form.  If you have any questions about the Guidelines, 
please ask to speak to Brendan Major.  
 
• You may be able to seek compensation through the courts. 
 
18 
Who is organising and funding the research? 
This research project is being conducted by ANSwers Neuroscience, Inc. and sponsored in 
Australia by ANSwers Neuroscience, Pty Ltd and is being funded by ANSwers Neuroscience, 
Pty Ltd. 
 
ANSwers Neuroscience, Pty Ltd may benefit financially from this research project if, for 
example, the project assists ANSwers Neuroscience, Pty Ltd to obtain approval for a new 
device.   
 
By taking part in this research project you agree that samples of the child’s blood, saliva or 
mouth swabs (or data generated from analysis of these materials) may be provided to ANSwers 
Neuroscience, Pty Ltd.   
 
ANSwers Neuroscience, Pty Ltd may directly or indirectly benefit financially from the child’s 
samples or from knowledge acquired through analysis of the child’s samples. 
 
You will not benefit financially from the child’s involvement in this research project even if, for 
example, the child’s samples (or knowledge acquired from analysis of the child’s samples) 
prove to be of commercial value to ANSwers Neuroscience, Pty Ltd. 
 
In addition, if knowledge acquired through this research leads to discoveries that are of 
commercial value to ANSwers Neuroscience, Pty Ltd, the study doctors or their institutions, 
there will be no financial benefit to you, the child, or family from these discoveries. 
 

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Alfred Health will receive a payment from ANSwers Neuroscience, Pty Ltd for undertaking this 
research project.  
 
No member of the research team will receive a personal financial benefit from the child’s 
involvement in this research project (other than their ordinary wages). 
 
19 
Who has reviewed the research project? 
All research in Australia involving humans is reviewed by an independent group of people called 
a Human Research Ethics Committee (HREC).  The ethical aspects of this research project 
have been approved by the Alfred Hospital Ethics Committee.  
This project will be carried out according to the National Statement on Ethical Conduct in 
Human Research (2007). This statement has been developed to protect the interests of people 
who agree to participate in human research studies. 
 
20 
Further information and who to contact 
The person you may need to contact will depend on the nature of your query.  
 
If you want any further information concerning this project or if your child has any medical 
problems which may be related to their involvement in the project (for example, any side 
effects), you can contact the principal study doctor on 03 9903 0304 or any of the following 
people: 
 
Clinical contact person 
 
 
Reviewing HREC approving this research and HREC Executive Officer details 
 
 
 
 
Name 
Prof Terence O’Brien 
Position 
Department of Neurology 
Telephone 
03 9903 0304   
Email 
te.obrien@alfred.org.au 
Name 
Brendan Major 
Position 
Research Assistant 
Telephone 
03 9246 8383 
Email 
brendan.major@monash.edu 
Reviewing HREC name 
Alfred Hospital Ethics Committee 
Position 
Governance Officer, Ethics and Research Governance, Alfred 
Health 
Telephone 
03 9076 3619  
Email 
research@alfred.org.au 

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Consent Form – Parent/Guardian 
 
 
Title 
Exercise As Concussion Therapy Trial  
Protocol Number 
ExACTT-2 
Australian Project Sponsor 
ANSwers Neuroscience, Pty Ltd 
Principal Investigator 
Prof Terence O’Brien 
Location  
The Alfred Hospital,  
99 Commercial Rd 
Melbourne, VIC 3004 
 
Declaration by Parent/Guardian 
I have read the Participant Information Sheet.  
 
I understand the purposes, procedures and risks of the research described in the project. 
 
I give permission for my child’s doctors, other health professionals, hospitals or laboratories 
outside this hospital to release information to Alfred Health concerning my child’s disease and 
treatment for the purposes of this project. I understand that such information will remain 
confidential.  
 
I have had an opportunity to ask questions and I am satisfied with the answers I have received. 
 
I freely agree to my child participating in this research project as described and understand that 
I am free to withdraw them at any time during the research project without affecting their future 
health care.  
 
I understand that I will be given a signed copy of this document to keep.  
 
I understand that, if I decide to discontinue my child’s study treatment, a request may be made 
for them to attend follow-up visits to allow collection of information regarding their health status.  
Alternatively, a member of the research team may request my permission to obtain access to 
my child’s medical records for collection of follow-up information for the purposes of research 
and analysis. 
 
I consent to the storage and use of blood and tissue samples taken from my child for use, as 
described in the relevant section of the Participant Information Sheet, for: 
• This specific research project 
• Other research that is closely related to this research project 
 
Optional additional blood/saliva sample for genetic testing and biobanking: By signing this 
consent section, I agree to the use of my child’s blood samples for genetic testing, as outlined in 
the relevant Section of the Participant Information Sheet.  
□ Yes, I agree to the optional testing 
□ No, I do not agree to the optional testing 
 
 

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Name of Child (please print) 
Name of Parent/Guardian (please print) 
Signature of Parent/Guardian 
Date
 
Under certain circumstances (see Note for Guidance on Good Clinical Practice CPMP/ICH/135/95 at 
4.8.9) a witness* to informed consent is required  
Name of Witness* to 
Parent/Guardian’s Signature (please print) 
Signature 
Date 
* Witness is not to be the investigator, a member of the study team or their delegate.  In the event that an interpreter 
is used, the interpreter may not act as a witness to the consent process.  Witness must be 18 years or older. 
 
Declaration by Study Doctor/Senior Researcher† 
I have given a verbal explanation of the research project, its procedures and risks and I believe 
that the parent/guardian has understood that explanation. 
Name of Study Doctor/ 
Senior Researcher† (please print) 
Signature 
Date 
† A senior member of the research team must provide the explanation of, and information concerning, the research 
project.  
 
 
Note: All parties signing the consent section must date their own signature. 
 
 

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Form for Withdrawal of Participation – Parent/Guardian 
 
 
Title 
Exercise As Concussion Therapy Trial  
Protocol Number 
ExACTT-2 
Australian Project Sponsor 
ANSwers Neuroscience, Pty Ltd 
Principal Investigator 
Prof Terence O’Brien 
Location  
The Alfred Hospital,  
99 Commercial Rd 
Melbourne, VIC 3004 
 
Declaration by Parent/Guardian 
I wish to withdraw my child from participation in the above research project and understand that 
such withdrawal will not affect their routine treatment, relationships with those treating them or  
the relationship with Alfred Health. 
 
Name of Child (please print) 
Name of Parent/Guardian (please print) 
Signature of Parent/Guardian 
Date
 
In the event that the parent/guardian’s decision to withdraw is communicated verbally, the Study 
Doctor/Senior Researcher will need to provide a description of the circumstances below. 
 
 
 
 
 
 
Declaration by Study Doctor/Senior Researcher† 
I have given a verbal explanation of the implications of withdrawal from the research project and 
I believe that the parent/guardian has understood that explanation. 
Name of Study Doctor/ 
Senior Researcher† (please print) 
Signature 
  Date 
† A senior member of the research team must provide the explanation of, and information concerning, withdrawal 
from the research project.  
 
Note: All parties signing the consent section must date their own signature. 

CONFIDENTIAL 
ANSwers Neuroscience, Pty Ltd 
Page 1 of 54 
 
 
CLINICAL STUDY PROTOCOL 
Protocol Title: A Therapeutic Intervention, Open Label Study to 
Compare the Efficacy and Safety of Graded Exercise Compared to 
Passive Stretching in Subjects Who Have Sustained a Mild Traumatic 
Brain Injury 
 
Protocol Short Title: Exercise As Concussion Therapy Trial 
(ExACTT) 
 
Protocol Number: ExACTT-2 
 
Sponsor: ANSwers Neuroscience, Pty Ltd 
c/o Prime Accounting & Business Advisory, Pty, Ltd 
Level 19, HWT Tower, 40 City Road, Southbank, VIC 3006, Australia 
 
Version: Final V 4 
Date: 30 July2020 
 
CONFIDENTIAL 
This protocol may not be reproduced or communicated to a third party without the 
written permission of ANSwers Neuroscience, Pty Ltd. 
 

 
 
Final Version 4 
ExACTT-2 
 
30 July 2020 
 
CONFIDENTIAL 
ANSwers Neuroscience, Pty Ltd 
Page 2 of 54 
PROTOCOL APPROVAL SIGNATURE 
Protocol Title:  
A Therapeutic Intervention, Open Label Study to Compare the 
Efficacy and Safety of Graded Exercise Compared to Passive 
Stretching in Subjects Who Have Sustained a Mild Traumatic Brain 
Injury 
Protocol Number: 
ExACTT-2 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use, Good Clinical Practice and applicable regulatory 
requirements. 
Sponsor Signatory 
 
 
 
Signature:  
Barry Kosofsky 
President 
ANSwers Neuroscience, Pty Ltd 
 
Date:          July 30, 2020 
 
 

 
 
Final Version 4 
ExACTT-2 
 
30 July 2020 
 
CONFIDENTIAL 
ANSwers Neuroscience, Pty Ltd 
Page 3 of 54 
STATEMENT OF COMPLIANCE 
The investigator will conduct this study as detailed herein, in compliance with current 
standards for the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use, Good Clinical Practice and the applicable regulatory 
requirements and will make every reasonable effort to complete the study within the time 
designated. 
The investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Human 
Research Ethics Committee, except where necessary to eliminate an immediate hazard(s) to 
the study subjects. 
This document contains information that is privileged or confidential. As such, it may not be 
disclosed unless specific prior permission is granted in writing by the sponsor or such 
disclosure is required by federal or other laws or regulations. Persons to whom any of this 
information is to be disclosed must first be informed that the information is confidential. 
These restrictions on disclosure will apply equally to all future information supplied, which is 
indicated as privileged or confidential. 
The investigator agrees that all staff members involved in the conduct of this study are 
informed about their obligations in meeting the above commitments.  
Investigator:  
Print/Type Name:  
________________________________  
Signed: 
 
________________________________ 
Date:   
 
________________________________ 
 
 

 
 
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ExACTT-2 
 
30 July 2020 
 
CONFIDENTIAL 
ANSwers Neuroscience, Pty Ltd 
Page 4 of 54 
TABLE OF CONTENTS 
 
PROTOCOL APPROVAL SIGNATURE ............................................................................ 2 
STATEMENT OF COMPLIANCE ....................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................ 4 
List of Figures within the Protocol .................................................................................... 7 
List of Tables within the Protocol ..................................................................................... 7 
LIST OF ABBREVIATIONS ................................................................................................. 8 
SYNOPSIS .............................................................................................................................. 10 
1 
INVESTIGATIONAL TEAM ................................................................................ 15 
2 
INTRODUCTION: BACKGROUND AND SCIENTIFIC 
RATIONALE ........................................................................................................... 15 
2.1 
Mild Traumatic Brain Injury ................................................................................. 15 
2.2 
Therapeutic Intervention ........................................................................................ 16 
2.3 
Clinical Studies ........................................................................................................ 17 
2.4 
Known and Potential Risks .................................................................................... 17 
2.5 
Study Rationale ........................................................................................................ 18 
2.6 
Risk Assessment ....................................................................................................... 18 
3 
STUDY OBJECTIVES ........................................................................................... 19 
3.1 
Primary Objective ................................................................................................... 19 
3.2 
Secondary Objectives .............................................................................................. 19 
3.3 
Exploratory Objectives ........................................................................................... 19 
4 
STUDY DESIGN AND ENDPOINTS ................................................................... 19 
4.1 
Description of the Study Design ............................................................................. 19 
4.2 
Study Objectives and Endpoints ............................................................................ 21 
4.3 
Appropriateness of Measures ................................................................................. 22 
5 
STUDY ENROLMENT AND WITHDRAWAL .................................................. 23 
5.1 
Inclusion Criteria .................................................................................................... 23 
5.2 
Exclusion Criteria .................................................................................................... 24 
5.3 
Withdrawal and Replacement of Subjects ............................................................ 25 
5.3.1 
Reasons for Withdrawal of Subjects ........................................................ 25 

 
 
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5.3.2 
Handling of Withdrawals or Early Termination of Subjects .................... 26 
5.4 
Premature Termination or Suspension of Study .................................................. 26 
6 
THERAPEUTIC INTERVENTION ..................................................................... 26 
6.1 
Therapeutic Interventions Administered .............................................................. 26 
6.2 
Therapeutic Intervention Components ................................................................. 27 
6.3 
Blinding and Randomization .................................................................................. 27 
6.3.1 
Blinding .................................................................................................... 27 
6.3.2 
Randomization .......................................................................................... 27 
6.4 
Accountability Procedures ...................................................................................... 28 
6.4.1 
Storage of Supplies ................................................................................... 28 
6.4.2 
Control of Supplies ................................................................................... 28 
6.4.3 
Return of Supplies .................................................................................... 28 
6.4.4 
Compliance to Therapeutic Intervention .................................................. 28 
6.5 
Concomitant Medications ....................................................................................... 28 
6.5.1 
Prohibited Medications ............................................................................. 29 
6.5.2 
Allowed Medications ............................................................................... 29 
6.6 
Concomitant Therapies ........................................................................................... 29 
6.7 
Lifestyle and Dietary Study Restrictions ............................................................... 29 
7 
STUDY ASSESSMENTS AND SCHEDULES ..................................................... 30 
7.1 
Safety Assessments .................................................................................................. 30 
7.1.1 
Baseline Demographics ............................................................................ 30 
7.1.2 
Medical and Medication History .............................................................. 30 
7.1.3 
Body Weight and Height .......................................................................... 30 
7.1.4 
Vital Signs including Beat to Beat Blood Pressure .................................. 30 
7.1.5 
Adverse Events ......................................................................................... 30 
7.2 
Biomarkers ............................................................................................................... 36 
7.3 
BioBank .................................................................................................................... 37 
7.4 
Neuropsychology Testing ........................................................................................ 37 
7.4.1 
Post-Concussion Symptom Scale ............................................................. 37 
7.4.2 
Godin Leisure Time Exercise Questionnaire ........................................... 38 
7.4.3 
Beck Anxiety Inventory ........................................................................... 38 
7.4.4 
Brief Symptom Inventory-18 ................................................................... 38 
7.4.5 
Reiss-Epstein-Gursky Anxiety Sensitivity Index ..................................... 38 
7.4.6 
Conners' Adult Attention Deficit Hyperactivity Disorder Rating 
Scale ......................................................................................................... 38 
7.4.7 
Center for Epidemiologic Studies - Depression Scale ............................. 38 
7.5 
Autonomic Tests ...................................................................................................... 39 
7.5.1 
Cold Pressor Test (Ice Bucket and ClearHeart© Testing) ....................... 39 
7.5.2 
Buffalo Concussion Bicycle Test ............................................................. 39 

 
 
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7.6 
Evaluation of Neck Range and Motion .................................................................. 40 
7.6.1 
Whiplash Test (Whiplash Testing (ClearNeck©) .................................... 40 
7.6.2 
Neurologic Examination ........................................................................... 40 
7.7 
Post Study Survey .................................................................................................... 40 
8 
STUDY SCHEDULE OF EVENTS ....................................................................... 41 
8.1 
Order of Assessments .............................................................................................. 41 
9 
STATISTICAL METHODS ................................................................................... 45 
9.1 
Determination of Sample Size ................................................................................ 45 
9.2 
Statistical and Analytical Plans .............................................................................. 45 
9.3 
Analysis Populations ............................................................................................... 45 
9.3.1 
All Subjects Population ............................................................................ 45 
9.3.2 
Safety Population ..................................................................................... 45 
9.3.3 
Efficacy Population .................................................................................. 45 
9.4 
Demographic and Other Baseline Characteristics ............................................... 46 
9.5 
Safety Analysis ......................................................................................................... 46 
9.5.1 
Adverse Event Analysis ........................................................................... 46 
9.5.2 
Vital Signs Analysis ................................................................................. 46 
9.5.3 
Prior and Concomitant Medication Analysis ........................................... 46 
9.6 
Efficacy Analysis ...................................................................................................... 47 
9.6.1 
Biomarker Data Analysis ......................................................................... 47 
9.6.2 
Neuropsychology Testing Analysis .......................................................... 47 
9.7 
Interim Analyses ...................................................................................................... 47 
9.8 
Handling of Missing Data ....................................................................................... 48 
10 
STUDY DOCUMENTATION ................................................................................ 48 
10.1 Data Management ................................................................................................... 48 
10.2 Access to Source Documents .................................................................................. 48 
10.3 Protocol Amendments ............................................................................................. 48 
10.4 Protocol Deviations .................................................................................................. 48 
11 
QUALITY ASSURANCE AND QUALITY CONTROL .................................... 49 
11.1 Audit and Inspection ............................................................................................... 49 
11.2 Monitoring ............................................................................................................... 49 
12 
ETHICS .................................................................................................................... 49 
12.1 Human Research Ethics Committee Approval ..................................................... 49 
12.2 Regulatory Approval ............................................................................................... 49 

 
 
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12.3 Ethical Conduct of the Study ................................................................................. 50 
12.4 Subject Information and Consent .......................................................................... 50 
13 
REPORTING AND PUBLICATION, INCLUDING ARCHIVING .................. 50 
14 
FINANCING AND INSURANCE ......................................................................... 51 
15 
REFERENCES ........................................................................................................ 52 
16 
APPENDICES ......................................................................................................... 54 
16.1 Post-Concussion Symptom Scale ........................................................................... 54 
16.2 Godin Leisure Time Exercise Questionnaire ........................................................ 54 
16.3 Beck Anxiety Inventory .......................................................................................... 54 
16.4 Brief Symptom Inventory ....................................................................................... 54 
16.5 Reiss-Epstein-Gursky Anxiety Sensitivity Index .................................................. 54 
16.6 CAARS (Attention) ................................................................................................. 54 
16.7 CES-D (Depression) ................................................................................................ 54 
16.8 Post-study survey ..................................................................................................... 54 
 
 
List of Figures within the Protocol 
Figure 1: Sample of ClearPlay© Interface .............................................................................. 17 
Figure 2: Study Design ............................................................................................................ 20 
 
List of Tables within the Protocol 
Table 1: Study Objectives and Endpoints ............................................................................... 21 
Table 2: Therapeutic Interventions .......................................................................................... 27 
Table 3: Categories of Adverse Events ................................................................................... 31 
Table 4: Order of Assessments Post Randomization .............................................................. 41 
Table 5: Schedule of Events .................................................................................................... 42 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADHD 
attention deficit hyperactivity disorder  
AE 
adverse event 
ASI 
Anxiety Sensitivity Index 
BAI 
Beck Anxiety Inventory 
BCBT 
Buffalo Concussion Bicycle Test 
BCTT 
Buffalo Concussion Treadmill Test 
BESS 
Balance Error Scoring System 
BP 
blood pressure 
BSI 
Brief Symptom Inventory 
CAARS 
Conners’ Adult Attention Deficit Hyperactivity Disorder Rating Scale 
CES-D 
Center for Epidemiologic Studies - Depression Scale 
CT 
computed tomography 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
HR 
heart rate 
HREC 
Human Research Ethics Committee 
HRV 
heart rate variability 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
mTBI 
mild traumatic brain injury 
PCSS 
Post-Concussion Symptom Scale 
PICF 
patient information and consent form 
PPCS 
persistent post-concussive symptoms 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SNP 
single nucleotide polymorphisms 
SSRI 
selective serotonin reuptake inhibitors 
SUSAR 
suspected unexpected serious adverse reactions 
TBI 
traumatic brain injury 
TCA 
tricyclic antidepressants 

 
 
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Abbreviation 
Definition 
VOMS 
Vestibular-Oculomotor Screening 
 
 

 
 
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SYNOPSIS 
Protocol Number: 
ExACTT-2 
Title: 
A Therapeutic Intervention, Open Label Study to Compare the Efficacy and Safety 
of Graded Exercise Compared to Passive Stretching in Subjects Who Have 
Sustained a Mild Traumatic Brain Injury 
Therapeutic 
Intervention: 
The therapeutic intervention (graded exercise) to be used in this study is delivered 
through the ClearPlay© mobile application. ClearPlay© provides the subject with a 
graded exercise program or passive stretching program, which is used in 
conjunction with a wrist-worn heart rate monitoring device (Waveband®). 
Study Centre: 
Multiple sites in Australia 
Development Phase: 
Phase 2 
Objectives and 
Endpoints: 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
To compare the effects of 
graded exercise to passive 
stretching using 
ClearPlay© on 
symptomatic recovery 
rate following mTBI. 
• Within-subject analysis of change in 
symptoms over time using the PCSS, 
comparing short-term ‘survival rates’ 
between graded exercise and stretching using 
Kaplan-Meier analyses for days since 
concussion.  
Secondary Objectives 
Secondary Endpoints 
To compare the safety 
and tolerability of graded 
exercise to passive 
stretching in patients 
following mTBI.   
• Adverse events reported from Day 1 through 
Day 56, including those identified during 
exercise or passive stretching during the 20 
minutes of daily therapy. 
To compare symptom 
resolution following 
graded exercise compared 
to passive stretching 
using ClearPlay© 
following mTBI. 
• Within subject analysis of change in the 
number of subjects who are symptom free at 
8 weeks between the 2 groups. Symptom free 
is defined by subjects having 3 consecutive 
days of PCSS scores lower than pre-
concussion. 
Note: This objective is similar to the primary one, 
with the primary endpoint being recovery (binary 
outcome) vs. symptom resolution (continuous 
variable). 
• Determine differences in symptomatic 
recovery based on gender, baseline scores on 
the PCSS, baseline athletic fitness (Godin 
leisure-time exercise questionnaire), the 
history of injury, a history of migraine, as 
well as the presence of pre-morbid anxiety. 
To compare the effects of 
graded exercise to passive 
stretching using 
ClearPlay© on 
physiologic recovery rate 
following mTBI. 
• Within subject analysis of normalization of 
physiologic measurements obtained during 
the BCBT comparing data collected on entry 
to the study on Day 0 vs. follow up on Day 56 
including: 
- 
Beat to beat BP; 
• Determine differences in physiologic 
recovery based on gender, baseline scores on 
the PCSS, baseline athletic fitness (Godin 

 
 
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leisure-time exercise questionnaire), the 
history of injury, a history of migraine, as 
well as the presence of pre-morbid anxiety 
(BAI; BSI-18; ASI). 
To compare the effects of 
graded exercise to passive 
stretching using 
ClearPlay© on 
accelerating symptomatic 
vs. physiologic recovery 
rate following mTBI. 
• Combined analysis of data from the two 
secondary analyses outlined above to confirm 
or refute a significant correlation between 
symptom resolution (defined by subjects 
having 3 consecutive days of PCSS scores 
lower than pre-concussion) and physiologic 
measurements obtained during the BCBT 
comparing data obtained on entry to the study 
on Day 0 vs. follow up on Day 56 including: 
- 
Beat to beat BP; 
 
To develop a composite 
physiologic metric to 
predict the magnitude and 
duration of ongoing post-
concussive symptoms. 
• 
Develop predictive modeling algorithms 
to establish a composite physiologic 
metric predictive of subjects becoming 
symptom free (as defined by subjects 
having 3 consecutive days of PCSS scores 
lower than pre-concussion) using data 
derived from baseline physiologic testing 
with: 
- 
BCBT 
- 
Ice bucket testing 
- 
ClearPlay© testing 
To develop a composite 
neuropsychologic metric 
to predict the magnitude 
and duration of ongoing 
post-concussive 
symptoms. 
• Develop predictive modeling algorithms to 
establish a composite neuropsychologic 
metric predictive of subjects becoming 
symptom free (as defined by subjects having 
3 consecutive days of PCSS scores lower than 
pre-concussion) using data derived from 
baseline neuropsychologic testing with the 
following instruments: 
- 
Attention (CAARS) 
- 
Depression (CES-D) 
- 
Anxiety (BAI; BSI-18; ASI). 
To develop a composite 
blood-based OR saliva 
biomarker metric to 
predict the magnitude and 
duration of ongoing post-
concussive symptoms. 
• Analysis of biomarkers at baseline testing 
including: 
- 
Structural proteins [t-tau, NF-L, GFAP 
and UCH-L1] 
- 
Inflammatory cytokines [IL-6, IL-10 and 
TNFα] 
- 
SNPs [APO-E4, BDNF, and NFkB] 
To validate the 
performance of 
ClearHeart© against ice 
bucket testing. 
• Bland-Altman plots will be used to evaluate 
the agreement between HR measured by 
ClearHeartÓ and ice bucket testing.  
• Bland-Altman plots will be used to evaluate 
the agreement between BP measured by 
ClearHeartÓ and ice bucket testing. 
To validate the 
performance of 
• Correlations will be used to assess the 
association between results obtained through 
ClearNeck© testing and those obtained 

 
 
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ClearNeck© against 
examination of the neck 
during the neurologic examination for neck 
range of motion and tenderness.  
Abbreviations: ASI = Anxiety Sensitivity Index, BAI = Beck Anxiety Inventory, 
BCBT = Buffalo Concussion Bicycle Test, BESS = Balance Error Scoring 
System,; BP=blood pressure, BSI = Brief Symptom Inventory, CAARS = Conners’ 
Adult Attention Deficit Hyperactivity Disorder Rating Scale, CES-D = Center for 
Epidemiologic Studies - Depression Scale,HRV = Heart Rate Variability, TBI = 
mild traumatic brain injury; PCSS = Post-Concussive Symptom Scale, SNP = 
single nucleotide polymorphisms. 
Study Design: 
This study is a Phase 2, open label study of a therapeutic intervention (graded 
exercise) compared to a reference therapy (passive stretching) in patients who have 
sustained mTBI. Subjects will be randomly assigned with a ratio of 1:1 to complete 
either graded exercise or passive stretching using a parallel group design.  
Recruitment 
The study sites will have well-established concussion research programs and 
referral populations. 
Administration of 
Therapeutic 
Intervention: 
The therapeutic intervention is either 20 minutes daily of graded exercise or 20 
minutes daily of passive stretching, according to the randomization schedule, from 
Day 1 to Day 56. 
Inclusion Criteria: 
To be eligible for study entry, subjects must satisfy all of the following criteria: 
1. Male or female subjects aged ≥14 to ≤45, able and willing to provide 
informed consent (≥18 years), or informed consent is obtained by the 
parent or legal guardian for minor subjects, with the minor providing age 
appropriate assent, according to local law and regulations; 
2. Subject is fluent in English, able to understand and agree to comply with 
protocol requirements, able to complete all assessments, and able to be;  
3. Subject has a history of recent concussion as diagnosed by a health care 
professional within 3 to 14 days of enrolment; 
Note: Concussion is defined as a head injury/blow to the head resulting in 
any of the following 3 signs and/or new symptoms: (1) Amnesia for less 
than 24 hours; (2) Loss of consciousness for less than 30 minutes; (3) 
Glasgow Coma Scale score > = 13;  (4) Dazed and Confused/bell rung; 
with at least 1 new symptom or augmentation of a previous symptom on 
the Post-Concussion Symptom Scale (PCSS) as compared  with baseline 
at the time of enrolment, including: headaches, dizziness, fatigue, 
irritability, insomnia, difficulty concentrating, and/or memory difficulties; 
(5) The composite symptom score on the PCSS must be at least 3 points 
higher post-concussion than pre-concussion. 
4. Subject has daily access to the internet. 
Exclusion Criteria: 
Subjects will be excluded from the study if any of the following criteria are 
applicable: 
1. History of prior head injury as defined by: 
• An injury/blow to the head within 12 months prior to screening with 
any associated residual symptoms; 
• An injury/blow to the head within 3 months prior to screening 
diagnosed as a concussion; 
• An injury/blow to the head within 3 months prior to screening with 
any of the following symptoms: amnesia, loss of consciousness, dazed 
and confused/bell rung; 
2. Evidence of blood or micro-hemorrhages on prior or current computed 
tomography scan or magnetic resonance imaging scan if obtained; 
3. Diagnosis of a neurological condition including the following: stroke, 
multiple sclerosis, epilepsy, brain tumor/cancer, encephalitis, dementia, 
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4. Psychiatric history with any of the following:  
• History of psychiatric hospitalization, history of legal trouble for 
violence; 
• Requires psychotropic medication other than (1) stable dose of a 
selective serotonin reuptake inhibitors (SSRI) medication, or (2) stable 
dose of a tricyclic antidepressants (TCA) medication; 
• Prior diagnosis of psychotic disorder, bipolar disorder, eating disorder, 
substance (incl. alcohol) abuse disorder; 
5. Current use of beta blockers (an anti-hypertensive medication); 
6. History of drug or alcohol dependency or abuse within a year before 
Screening, by self-report; 
7. Two or more of the following cardiovascular risk factors:  
• 
Prior diagnosis of, or currently taking medication for 
cardiovascular, metabolic or pulmonary conditions; 
• 
Family history of myocardial infarction, coronary 
revascularization or sudden death before 55 years; 
• 
Diagnosis of hypertension; 
• 
Diagnosis of hyperlipidemia;  
• 
Subjects with peripheral circulatory disorders; 
8. Subjects who are unable or unwilling to exercise for health or personal 
reasons; 
9. Subjects who have musculoskeletal injuries which could make exercise 
difficult or painful. 
Sample Size: 
At least 400 subjects aged 14 to 45 will be enrolled in this study at up to 5 study 
sites. 
Analysis: 
No interim analysis is planned for this study.  
In general, data will be summarized using descriptive statistics (number of non-
missing observations, mean, median, standard deviation, minimum and maximum) 
or frequency counts and percentages, as appropriate to the type of data.  
Adverse events and medical history will be coded with Medical Dictionary for 
Regulatory Activities (MedDRA, the latest version) and concomitant medications 
are coded with World Health Organization Drug coding Dictionary (latest version).  
For all subjects, daily reported PCSS scores collected from ClearPlay© mobile 
application will be utilized to determine the resolution of symptoms. The resolution 
of symptoms is defined as a symptom-severity score of less than each subject’s pre-
injury PCSS score for 3 consecutive days. To assess differences in the probability 
of symptom resolution between graded exercise and passive stretching during the 8 
weeks of therapy, both unadjusted and adjusted logistic regression models will be 
used. The primary outcome of the study will be to confirm or refute the superiority 
of sub-threshold aerobic exercise versus passive stretching to result in resolution of 
symptoms following mTBI. Confounders for the adjusted models will include age, 
gender, anxiety at baseline, history of migraine, cardiovascular fitness, the presence 
or absence of neurologic findings, and site of enrolment.  
The survival probability will be compared using Kaplan-Meier (log rank test) 
analyses between the 2 treatment arms. Cox proportional hazards regression 
models will be used to evaluate the differences in time to symptom resolution. 
Adjusted treatment effects will be estimated in Cox proportional hazards regression 
models, controlling for the variables listed above. To identify that our 
randomization strategy was effective, analysis of variance will be used to assess for 
group-wise differences in age, days since injury to initial visit, initial PCSS score, 
resting heart rate (HR), and ΔHR during the BCBT and resting BP and ΔBP during 
the ice bucket test on Day 1. Non-parametric tests of medians will be used to 
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squared tests will be used to assess group-wise differences in gender, history of 
concussions, and incidence of persistent post-concussive symptoms. 
Safety Analysis 
Incidence, severity, relationship of treatment emergent adverse events will be 
presented by treatment group. All vital signs measurements will be summarized at 
each protocol scheduled time point by treatment group, using either summary 
statistics or frequency tabulations, as applicable to the type of data. Given the 
cardiovascular exclusion criteria, ECG data is redundant, and will not be collected.  
Efficacy Analysis 
Biomarkers will be summarized at each protocol scheduled time point by treatment 
group, using either summary statistics or frequency tabulations, as applicable to the 
type of data. Changes from baseline will also be presented where applicable. 
Neuropsychology testing will be assessed using the patient reported outcomes and 
will be summarized at each protocol scheduled time point by treatment group, 
using either summary statistics or frequency tabulations, as applicable to the type 
of data. Changes from baseline will also be presented where applicable. 
Results of the cold pressor test, whiplash test and BCBT will be summarized at 
each protocol scheduled time point by treatment group, using either summary 
statistics or frequency tabulations, as applicable to the type of data. Changes from 
baseline will also be presented where applicable. 
 
 
 

 
 
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1 
INVESTIGATIONAL TEAM 
Refer to the trial specific contact list for details of investigators, sponsor personnel, clinical 
research organization personnel and facilities used in the study. 
2 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE 
2.1 
Mild Traumatic Brain Injury 
Concussion or mild traumatic brain injury (mTBI) is defined as a blow or jolt to the head 
(i.e., a non- penetrating head injury) that disrupts the normal function of the brain. 
Concussion can be described as a brain injury defined by a complex pathophysiological 
process that is induced by biomechanical forces. Mild traumatic brain injury is described as a 
continuum of brain injury and associated pathophysiology of mild vs. more severe trauma-
induced brain injury.1 Recent years has seen greater emphasis placed on the importance of 
brainstem systems impaired as a result of diffuse axonal injury resulting from inertial forces 
imparted by mTBI damaging axonal pathways traversing the interface of the cerebral 
hemispheres and the brainstem.2-4 Autonomic function which controls eye movement, 
balance and neck control appears to be vulnerable to concussive injury. Injury to this pathway 
may result in impairments in a number of daily functions such as reading or driving 5 which 
may predispose concussed individuals for more prolonged deficits, and the need for earlier, 
symptom-targeted therapies. 
Traumatic brain injury (TBI) is a major cause of death and disability in all age groups and is 
responsible for significant healthcare costs. Concussion management consensus statements 
consistently call for the need for additional research to improve outcomes for this patient 
population.6,7  
Accurately identifying the true incidence and duration of ongoing symptoms following 
concussion has remained elusive, with no reliable way to confirm that symptomatic recovery 
coincides with brain physiologic recovery.9 The diagnosis of concussion relies on self-
reported symptoms, which are prone to both over-reporting (e.g., in anxious individuals and 
malingerers5); and under-reporting (e.g., in both athletes and members of the military8). An 
estimated 20% of individuals have persistent post-concussive symptoms (PPCS), as defined 
by symptoms lasting 2 or more weeks in adults, and 4 or more weeks in adolescents.10 The 
2 best validated instruments for assessing symptom persistence are the Post-Concussion 
Symptom Inventory (validated in youth from age 5 to 18 years of age11) and the Post-
Concussion Symptom Scale (PCSS) (validated in adults12 and in 13 to 22 year olds13). Four 
distinct symptom clusters: cognitive-fatigue-migraine, affective, somatic, and sleep have been 
identified as being affected following a concussion.13 The presence of pre-existing 
neuropsychological conditions, especially anxiety, as well as a lack of resilience, have been 
implicated as contributing to PPCS. Other factors contributing to the severity and duration of 
post-concussive symptoms have been identified including sex, age, extent of athleticism, 
history of prior concussions, as well as a history of migraine headaches. Consistent with the 
objectives of this clinical trial, symptoms of autonomic dysfunction, including exercise-
induced headaches, are amongst most prevalent during the first week post-injury, and have 
also been reported to be the most persistent following mTBI.5 
Autonomic dysfunction in the form of impaired cerebral autoregulation is commonly seen 
following mTBI.15 Standard clinical evaluations are able to assess the integrity of eye 
movement, balance, and neck function14, however, there is no easy way to assess autonomic 

 
 
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function in clinical settings. Options for diagnosing autonomic dysfunction following 
concussion include the Buffalo Concussion Treadmill Test (BCTT);16 a test performed within 
a week of injury that has the ability to predict prolonged recovery in concussed adolescents 
with a sensitivity of 73% and a specificity of 78%.17 and the “ice bucket test” (also known as 
the cold pressor test);18 a simpler and faster way to diagnose autonomic dysfunction 
following mTBI19.  
The current standard of care for patients with mTBI is cognitive and physical rest. However, 
a recently conducted randomized control trial suggests that the implementation of exercise 
activity as opposed to physical and cognitive rest during the initial period of injury 
accelerates recovery.20 Sub-symptom threshold aerobic exercise, has been shown to improve 
autonomic function as reflected by non-invasive measures such as heart rate variability 
(HRV),21 and to accelerate recovery following concussion.  
It is anticipated that results from our study, in combination with those evolving from similar 
research studies now underway in Australia as well as the US, will provide support for 
decision making by physicians, trainers, and other clinicians during the days/weeks following 
concussion, including what activities should be avoided, what therapies can accelerate 
recovery, and when the brain has recovered so that it is safe to resume sport or work.  
2.2 
Therapeutic Intervention 
A number of governing bodies now endorse an active rehabilitation program of progressive 
reintroduction of noncontact aerobic activity that does not exacerbate symptoms along with 
close monitoring of symptom expression.22  
In order to promote this, ANSwers Neuroscience Pty Ltd has developed a novel therapeutic 
intervention, downloadable to an Apple i-touch or i-phone device, that provides a telemetry-
based graded exercise program which enables remote monitoring of symptoms. The sponsor 
will provide an i-touch or i-phone to each eligible subject during the Baseline Visit, which 
they will use daily during the 8 weeks of clinical study. Subjects keep the i-touch or i-phone 
on completion of study participation. The digital therapeutic application permits the ‘dosing 
of heart rate (HR)’ approach23 while monitoring symptomatic and physiologic recovery on a 
daily basis. It is hypothesized that the mobile application, ClearPlay©, will accelerate 
recovery time following concussion by improving activity-induced blood flow to the brain 
and aid in the rehabilitation process. ClearPlay© is intended to be used in a professional 
setting following point of injury or onset of the condition and can also be used by patients at 
home. Refer to Figure 1 for an image of the ClearPlay© interface. 

 
 
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Figure 1: Sample of ClearPlay© Interface 
 
To support the use of ClearPlay©, ANSwers Neuroscience Pty Ltd has developed 2 devices: 
• ClearHeart©, a Cooling Glove System as an alternative to ice bucket testing, to 
enable providers to perform a quick, real-time diagnosis of autonomic nervous system 
disorders, including mTBI. The results are available immediately through a computer 
interface, permitting healthcare providers to make immediate diagnostic assessments 
and therapeutic recommendations. 
• ClearNeck© a prototype device for cervico-genic proprioception measurement. This 
test is based on the joint position error test to assess “whiplash”. 
2.3 
Clinical Studies 
Historically, concussion has been described as a cognitive injury and patients have been 
advised not to engage in any cognitive or physical exertion while symptomatic. More 
recently, however, concussion has been described as a physiological injury affecting both the 
heart and autonomic nervous system, and patients suffering from prolonged concussion-
related symptoms and deficits have been encouraged to begin aerobic exercise as part of their 
concussion care. While intensive exercise too soon after concussion has been associated with 
delayed recovery and used to justify prolonged periods of rest, recent studies have shown that 
controlled, sub-symptom threshold aerobic exercise may aid recovery by improving 
autonomic balance and cerebral blood flow auto-regulation after concussion.  
2.4 
Known and Potential Risks 
Potential risks exist to the following groups of patients: 

 
 
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• Subjects with musculoskeletal or cardiac or pulmonary conditions that preclude 
participation in exercise; 
• Subjects using anti-hypertensive medications; 
• Subjects with peripheral circulatory disorders due to conditions such as, but not 
limited to, Raynaud’s syndrome, scleroderma, or diabetes. These subjects may 
experience hand discomfort when exposed to the ClearHeart© cooling; 
• Subjects with lymphedema in the left arm, as they may experience arm discomfort 
when using the ClearHeart© device. 
2.5 
Study Rationale 
This study has been designed as a multicenter, open-label clinical intervention trial to 
compare 8 weeks of graded exercise to passive stretching to accelerate recovery following 
mTBI. The study aims to demonstrate the superiority of graded exercise to passive stretching 
to accelerate subjective symptoms following mTBI. The primary endpoint is resolution of 
self-reported symptoms (therapeutic). Symptom resolution will be defined as a symptom-
severity score less than pre-mTBI values on the PCSS for 3 consecutive days. The secondary 
endpoint is physiologic normalization of autonomic function (diagnostic/prognostic). Change 
in physiologic measures (e.g. HRV) over time will be disturbed using the Buffalo Concussion 
Bike Test (BCBT) and ice bucket test. 
Mild TBI is one of the most common neurological conditions that occurs during childhood 
and, depending on the age of the individual, typical causes of mTBI vary greatly. Children 
aged 5 to 14 years are most likely to be seen in the emergency department with TBI resulting 
from falls (approximately 35%) and from being struck by or against an object (35%) 
occurring during athletic and recreational activities. Motor vehicle accidents, assaults, falls, 
and being struck by or against an object, each account for approximately 20% of emergency 
department visits for TBI in adolescents and young adults (15-24 years), with an increased 
incidence of sport-related injuries in that age range.4 Females tend to report a greater number, 
more severe, and a longer duration of symptoms compared to men, both before as well as 
after puberty.24 Most publications in middle aged adults have studied sport-induced 
concussion in athletes, a population who may recover more quickly as a result of 
cardiovascular conditioning.25 By broadening the enrolment criteria in this study to include 
athletic and non-athletic men and women aged 14-45, and by including individuals with 
known co-morbidities (such as migraine,26 anxiety,27 and other psychologic factors28) this 
study aims to yield results that are relevant to the general population who may experience 
mTBI.  
2.6 
Risk Assessment 
As this is a therapeutic intervention study, there are minimal risks associated with taking part 
in this investigational study. The current standard of care for subjects with mTBI is cognitive 
and physical rest. However, a number of governing bodies now endorse an active 
rehabilitation program following concussion and clinical trials have also been completed to 
assess the safety of graded exercise following mTBI.  
During the study, appropriately trained staff will ensure that any risks associated with the 
study, including exercise testing, are closely monitored. Real time review of safety data will 

 
 
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be performed, with safety monitoring to be adjusted as required if any risks become apparent. 
Enrolment of subjects will only occur at study sites that have appropriately trained staff to 
ensure subjects receive the best standard of care. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to compare the effects of graded exercise and passive 
stretching using ClearPlay© (ANSwers Neuroscience Pty Ltd commercial mobile 
application) on recovery following mTBI in the Australian setting.  
3.2 
Secondary Objectives 
The secondary objectives of the study are to: 
• Compare the safety and tolerability of graded exercise compared to passive stretching 
following mTBI; 
• Develop a composite physiologic scale to predict the magnitude and duration of 
ongoing post-concussive symptoms; 
• Validate the performance of ClearHeart©, ANSwers Neuroscience Pty Ltd 
commercial prototype for cold pressure testing, compared to ice bucket testing. 
3.3 
Exploratory Objectives 
The exploratory objectives of the study are to: 
• Validate the performance of ClearNeck©, ANSwers Neuroscience Pty Ltd 
commercial prototype based on the joint position error test to assess “whiplash”. 
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
Description of the Study Design 
This study is designed as an open label study of a therapeutic intervention in subjects who 
have sustained mTBI. At least 400 subjects aged 14 to 45 inclusive will be enrolled in this 
study at up to 5 study sites. Subjects will be randomly assigned with a ratio of 1:1 to 
complete either graded exercise or passive stretching. The study sites will have well-
established concussion research programs and referral populations.  
The therapeutic intervention is either 20 minutes daily of graded exercise or 20 minutes daily 
of passive stretching delivered through the ClearPlay© mobile application, downloaded  to an 
Apple i-touch or i-phone device, used in conjunction with a wrist-worn heart rate monitoring 
device (Waveband®). The sponsor will provide one i-touch or i-phone to each subject to 
provide them with access to ClearPlay App. This device will also allow subjects to access 
music for use during exercise or stretching.  
 
 

 
 
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Randomization of each subject will occur when the subject has completed all of their 
Baseline physiologic testing (Ice Bucket Test, ClearHeart© and BCBT) on Day 0.  
Both the site staff treating subjects and the subjects themselves will be aware of the assigned 
exercise regimen. Subjects will be stratified based on baseline scores on the PCSS (threshold 
≥30).  
The study consists of 2 study visits and 3 remote telephone visits between the 2 study visits: 
• Study Visit 1 (Day 0) – Screening/Baseline visit: within 3 to 14 days of concussion. 
This visit will serve as a screening visit, to determine eligibility to participate in the 
study. Eligible subjects will be enrolled, and baseline assessments performed; 
• Remote telephone safety assessments – Day 14, Day 28 and Day 42 for safety follow 
up; 
• Study Visit 2 – Follow-up visit: 8 weeks following enrolment (Day 56). 
A schematic diagram of the study design is presented in Figure 2. 
Figure 2: Study Design 
 
Visit 1 = Day 0 
(within 3 to 14 days of concussion) 
- Consent 
- Screening assessments 
 
 
 
 
 
Visit 1: Eligible Subjects 
- Enrollment 
- Baseline Assessments 
 
Visit 1: Screen Failures 
- Reason for screen fail 
 
 
 
 
 
Remote Telephone Assessment 
- Day 14 
- Day 28 
- Day 42 
 
 
 
 
 
Visit 2: Follow-Up Visit 
- Week 8 Study Visit (Day 56) 
 
 
 
 
 

 
 
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4.2 
Study Objectives and Endpoints 
The study objectives and endpoints to be evaluated in this study are presented in Table 1. 
Table 1: Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
To compare the effects of 
graded exercise to passive 
stretching using ClearPlay© 
on symptomatic recovery rate 
following mTBI. 
• Within-subject analysis of change in symptoms over time 
using the PCSS, comparing short-term ‘survival rates’ 
between graded exercise and stretching using Kaplan-Meier 
analyses for days since concussion.  
Secondary Objectives 
Secondary Endpoints 
To compare the safety and 
tolerability of graded exercise 
to passive stretching in 
patients following mTBI.   
• Adverse events reported from Day 1 through Day 56, 
including those identified during exercise or passive 
stretching during the 20 minutes of daily therapy. 
To compare symptom 
resolution following graded 
exercise compared to passive 
stretching using ClearPlay© 
following mTBI. 
• Within subject analysis of change in the number of subjects 
who are symptom free at 8 weeks between the 2 groups. 
Symptom free is defined by subjects having 3 consecutive 
days of PCSS scores lower than pre-concussion. 
Note: This objective is similar to the primary one, with the 
primary endpoint being recovery (binary outcome) vs. symptom 
resolution (continuous variable). 
• Determine differences in symptomatic recovery based on 
gender, baseline scores on the PCSS, baseline athletic fitness 
(Godin leisure-time exercise questionnaire), the history of 
injury, a history of migraine, as well as the presence of pre-
morbid anxiety. 
To compare the effects of 
graded exercise to passive 
stretching using ClearPlay© 
on physiologic recovery rate 
following mTBI. 
• Within subject analysis of normalization of physiologic 
measurements obtained during the BCBT comparing data 
collected on entry to the study on Day 0 vs. follow up on Day 
56 including: 
- 
Beat to beat BP; 
• Determine differences in physiologic recovery based on 
gender, baseline scores on the PCSS, baseline athletic fitness 
(Godin leisure-time exercise questionnaire), the history of 
injury, a history of migraine, as well as the presence of pre-
morbid anxiety (BAI; BSI-18; ASI). 
To compare the effects of 
graded exercise to passive 
stretching using ClearPlay© 
on accelerating symptomatic 
vs. physiologic recovery rate 
following mTBI. 
• Combined analysis of data from the two secondary analyses 
outlined above to confirm or refute a significant correlation 
between symptom resolution (defined by subjects having 3 
consecutive days of PCSS scores lower than pre-concussion) 
and physiologic measurements obtained during the BCBT 
comparing data obtained on entry to the study on Day 0 vs. 
follow up on Day 56 including: 
- 
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Objectives 
Endpoints 
To develop a composite 
physiologic metric to predict 
the magnitude and duration of 
ongoing post-concussive 
symptoms. 
• 
Develop predictive modeling algorithms to establish a 
composite physiologic metric predictive of subjects 
becoming symptom free (as defined by subjects having 3 
consecutive days of PCSS scores lower than pre-
concussion) using data derived from baseline physiologic 
testing with: 
- 
BCBT 
- 
Ice bucket testing 
- 
ClearPlay© testing 
To develop a composite 
neuropsychologic metric to 
predict the magnitude and 
duration of ongoing post-
concussive symptoms. 
• Develop predictive modeling algorithms to establish a 
composite neuropsychologic metric predictive of subjects 
becoming symptom free (as defined by subjects having 3 
consecutive days of PCSS scores lower than pre-concussion) 
using data derived from baseline neuropsychologic testing 
with the following instruments: 
Attention (CAARS) 
- 
Depression (CES-D) 
- 
Anxiety (BAI; BSI-18; ASI). 
To develop a composite 
blood-based or saliva 
biomarker metric to predict 
the magnitude and duration of 
ongoing post-concussive 
symptoms. 
• Analysis of biomarkers at baseline testing including: 
- 
Structural proteins [t-tau, NF-L, GFAP and UCH-L1] 
- 
Inflammatory cytokines [IL-6, IL-10 and TNFα] 
- 
SNPs [APO-E4, BDNF, and NFkB] 
To validate the performance 
of ClearHeart© against ice 
bucket testing. 
• Bland-Altman plots will be used to evaluate the agreement 
between HR measured by ClearHeartÓ and ice bucket 
testing.  
• Bland-Altman plots will be used to evaluate the agreement 
between BP measured by ClearHeartÓ and ice bucket testing. 
To validate the performance 
of ClearNeck© against 
examination of the neck 
• Correlations will be used to assess the association between 
results obtained through ClearNeck© testing and those 
obtained during the neurologic examination for neck range of 
motion and tenderness.  
Abbreviations: ASI = Anxiety Sensitivity Index, BAI = Beck Anxiety Inventory, BCBT = Buffalo Concussion Bicycle Test, 
BESS = Balance Error Scoring System,; BP=blood pressure, BSI = Brief Symptom Inventory, CAARS = Conners’ Adult 
Attention Deficit Hyperactivity Disorder Rating Scale, CES-D = Center for Epidemiologic Studies - Depression Scale,; HRV 
= heart rate variability; mTBI = mild traumatic brain injury; PCSS = Post-Concussive Symptom Scale, SNP = single 
nucleotide polymorphisms 
4.3 
Appropriateness of Measures 
Multiple study sites are required to ensure efficient recruitment of subjects. Medical centers 
with well-established concussion research programs and referral populations have been 
selected to ensure subjects have access to appropriately trained and qualified healthcare 
providers.  
The study is randomized to avoid the bias of subject selection for factors known and 
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Randomization will be stratified by site and baseline symptom severity score on the PCSS 
(threshold < or ≥30).  
All assessments proposed in this study are considered by ANSwers Neuroscience Pty Ltd and 
the Investigators to be appropriate and necessary to compare graded exercise to passive 
stretching in post-mTBI recovery.  
The PCSS is a well validated 21-item self-report measure that records symptom severity 
using a 7-point Likert scale of severity. This widely used symptom checklist ranks 
concussion symptoms by their severity and persistence. 
Assessments used in this study to assess autonomic function include the BCBT, which 
measures the exacerbation of post-concussive symptoms during 15 minutes of step-wise 
escalation of cardio-vascular function and the cold pressor test (known as the “ice bucket 
test”), which has been shown to be diagnostic of mTBI. The BCBT has been validated 
against the BCTT, which has been shown to be diagnostic of mTBI, and to be predictive of 
PPCS. 
The safety assessments used in this study such as adverse events (AEs) identified during 
graded exercise or passive stretching during the 20 minutes of daily therapy from Day 1 
through Day 56, remote monitoring of vital signs including beat to beat blood pressure (BP), 
and daily self-reporting of symptoms on the PCSS are considered appropriate for monitoring 
subject health and well-being in this type of study. 
In collaboration with a private diagnostic laboratory (Monogram Biosciences, a Division of 
Labcorp) who have validated a set of biomarkers reflective of the  severity of mTBI assay 
structural proteins [t-tau, NF-L, GFAP and UCH-L1] and inflammatory cytokines [IL-6, IL-
10 and TNFα]) will be analyzed. Blood and saliva samples will be collected at the time of 
enrollment and at the end of the study.  
In addition, a set of single nucleotide polymorphisms (SNP) and micro ribonucleic acids 
(RNA) that have been implicated in contributing to the biologic vulnerability to PPCS will be 
analyzed. Deoxyribonucleic acid (DNA) and RNA will be isolated for bio-banking and 
subsequent analysis. Sample collection will be either blood collection or buccal swab and 
collection of saliva. 
New tests, ClearHeart© and ClearNeck© will be validated as part of the study objectives by 
comparing against the equivalent validated methods, Ice Bucket Testing and neurological 
examination respectively, which will be also be performed as part of the study.  
5 
STUDY ENROLMENT AND WITHDRAWAL 
5.1 
Inclusion Criteria 
To be eligible for study entry subjects must satisfy all of the following criteria: 
1. Male or female subjects aged ≥14 to ≤45, able and willing to provide informed 
consent (≥18 years), or informed consent is obtained by the parent or legal guardian 
for minor subjects, with the minor providing age appropriate assent, according to local 
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2. Subject is fluent in English, able to understand and agree to comply with protocol 
requirements, and complete all assessments;  
3. Subject has a history of recent concussion as diagnosed by a health care professional 
within 3 to 14 days of enrolment; 
Note: Concussion is defined as a head injury/blow to the head resulting in any of the 
following 3 signs and/or new symptoms: (1) amnesia for less than 24 hours; (2) Loss 
of consciousness for less than 30 minutes; (3) Glasgow Coma Scale score > = 13; (4) 
Dazed and Confused/bell rung; with at least 1 new symptom or augmentation of a 
previous symptom on the PCSS as compared  with baseline at the time of enrolment, 
including: headaches, dizziness, fatigue, irritability, insomnia, difficulty 
concentrating, and/or memory difficulties; (5) The composite symptom score on the 
PCSS must be at least 3 points higher post-concussion than pre-concussion. 
4. Subject has daily access to the internet. 
5.2 
Exclusion Criteria 
Subjects will be excluded from the study if one or more of the following criteria are 
applicable: 
1. History of prior head injury as defined by: 
• An injury/blow to the head within 12 months prior to screening with any 
associated residual symptoms; 
• An injury/blow to the head within 3 months prior to screening diagnosed as a 
concussion; 
• An injury/blow to the head within 3 months prior to screening with any of the 
following symptoms: amnesia, loss of consciousness, dazed and confused/bell 
rung; 
2. Evidence of blood or micro-hemorrhages on prior or current computed tomography 
scan or magnetic resonance imaging scan if obtained; 
3. Diagnosis of a neurological condition including the following: stroke, multiple 
sclerosis, epilepsy, brain tumor/cancer, encephalitis, dementia, movement disorder, or 
spontaneous nystagmus; 
4. Psychiatric history with any of the following:  
• 
History of psychiatric hospitalization, history of legal trouble for violence; 
• 
Requires psychotropic medication other than (1) stable dose of a selective 
serotonin reuptake inhibitors (SSRI) medication, or (2) stable dose of a tricyclic 
antidepressants (TCA) medication; 
• 
Prior diagnosis of psychotic disorder, bipolar disorder, eating disorder, substance 
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5. Current use of a beta blocker; 
6. History of drug or alcohol dependency or abuse within a year before Screening, by 
self-report; 
7. Two or more of the following cardiovascular risk factors: 
• 
Prior diagnosis of, or currently taking medication for cardiovascular, metabolic or 
pulmonary conditions; 
• 
Family history of myocardial infarction, coronary revascularization or sudden 
death before 55 years; 
• 
Diagnosis of hypertension; 
• 
Diagnosis of hyperlipidemia;  
• 
Subjects with peripheral circulatory disorders; 
8. Subjects who are unable or unwilling to exercise for health or personal reasons; 
9. Subjects who have musculoskeletal injuries which could make exercise difficult or painful. 
5.3 
Withdrawal and Replacement of Subjects 
5.3.1 Reasons for Withdrawal of Subjects 
Subjects will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care. The investigator also has the right to 
withdraw subjects from the study for any of the following reasons: 
• Subject non-adherence to therapeutic intervention or protocol requirements. Please 
refer to Section 6.5 for lifestyle and dietary study restrictions. Subjects must also be 
able to upload data via the ClearPlay© mobile application daily. Failure to do so for 
3 consecutive days will trigger a call from the site. Subjects who do not upload data 
for 5 consecutive days are to be contacted by the site again. Subjects who do not 
upload for 7 consecutive days are to be withdrawn from the study for poor 
compliance; 
• Subjects from either group who exercise at a rate that exceeds that which is 
prescribed, as identified by either self-report (the Godin Leisure Time Exercise 
questionnaire) or by autonomic monitoring (using ClearPlay©) will be withdrawn 
from the study and coded as “lost to follow up”. 
• Subject unwillingness to continue in the study; 
• Any other reason based upon the medical judgment of the investigator.  
The reason for study withdrawal is to be documented in the subject’s source documents and 
electronic case report form (eCRF).  

 
 
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At the time of discontinuation from the study, subjects are to have all the assessments 
planned for the follow-up visits performed after the last study drug dose, if feasible. 
5.3.2 Handling of Withdrawals or Early Termination of Subjects 
Withdrawals or early termination: If a subject is withdrawn from the study for any reason, 
whether related to the study drug or not, or if a subject voluntarily withdraws, such subject 
will be considered an early termination subject. The investigator will make every effort to 
ensure that early-termination subjects complete an Early Termination visit. 
Lost to follow-up: Reasonable efforts will be made to contact subjects who are lost to follow-
up. These efforts must be documented in the subject’s file.  
5.4 
Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the investigator, and 
regulatory authorities.  
If the study is prematurely terminated or suspended, the investigator will promptly inform the 
Human Research Ethics Committee (HREC) and will provide the reason(s) for the 
termination or suspension.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
• Determination of unexpected, significant, or unacceptable risk to subjects; 
• Insufficient compliance to protocol requirements; 
• Data that are not sufficiently complete and/or evaluable; 
• Sponsor terminates the study for administrative, financial or other reasons. 
6 
THERAPEUTIC INTERVENTION 
6.1 
Therapeutic Interventions Administered 
The therapeutic intervention (graded exercise) to be used in this study is delivered through 
the ClearPlay© application. This application will be preloaded on the i-touch or i-phone 
device, which will be supplied to each eligible subject during the Baseline Visit.   ClearPlay© 
provides the subject with a graded exercise program or passive stretching, which is used in 
conjunction with a wrist-worn HR monitoring device (Waveband®).29  
Each subject will cease their assigned Therapeutic Intervention when they have reach three 
consecutive days of PCSS score that is less than or equalled to the subject’s pre-mTBI PCSS 
score. All subjects will be required to complete the Follow Up, Day 56 Visit, regardless of 
the date they cease Therapeutic Intervention. 
 
 

 
 
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Table 2: Therapeutic Interventions 
Therapeutic Intervention 
Description 
Duration 
Frequency 
Telemetry-based graded 
exercise 
Sub-symptom threshold 
aerobic exercise 
20 minutes  
Daily for 8 
weeks 
Passive stretching 
Passive stretching 
20 minutes  
Daily for 8 
weeks 
6.2 
Therapeutic Intervention Components 
ClearPlay© Application: The downloadable app will be available from the app store. The app 
has 4 components: connectivity with the Waveband® to transmit physiologic (HRV) data 
remotely; a fillable version of the PCSS; and a fillable version of the Godin leisure-time 
exercise questionnaire; an instrument for communication of AEs.  
Waveband®: Each subject will be fitted with a Waveband® (fit-bit like device to remotely detect 
HR and HRV). This is to be worn while the subject completes the graded exercise program or 
passive stretching program.  
6.3 
Blinding and Randomization 
6.3.1 Blinding 
This study is an open-label study and thus the investigator, site staff, sponsor, sponsors 
delegates (if applicable) and subjects will not be blinded to treatment allocation.  
6.3.2 Randomization 
A computer-generated randomization schedule will be prepared by a statistician prior to the 
start of the study. Treatment allocation will be made per the randomization list.  
After signing the informed consent form/providing assent, subjects will be administered the 
screening instruments via REDCap Cloud, along with generation of unique subject ID.  
Once eligibility has been established, subjects must proceed to complete all Baseline 
assessments. The Order of Assessment is listed in Section 8.1, Table 4. Randomization of 
each subject will occur when the subject has completed all of their Baseline physiologic 
testing on Day 0.  
The subject will be assigned a unique randomization number, which will be allocated 
sequentially based on the pre-determined randomization schedule, and according to their 
chronological order of inclusion in the study.  
Both the unique subject ID and randomization numbers will be used to identify the subject 
throughout the study period and on all study-related documentation. 
Stratification: randomization will be stratified at each enrolment site by the baseline symptom 
severity score on the PCSS (threshold < or ≥30). The baseline PCSS score is reflective of 
multiple pre-morbid, neurologic, psychologic, and other factors that collectively are likely to 
significantly impact the presence of PCSS. Rather that stratify the population based on 

 
 
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individual factors, the single composite measure should provide the most efficient and 
effective starting point for this clinical trial. 
6.4 
Accountability Procedures 
The investigator is responsible for the accountability of study materials. The investigator or 
designated site staff must maintain product accountability records throughout the course of 
the study. The amount of product received from the sponsor, the amount supplied and/or 
administered to and returned by subjects, if applicable, will be documented. 
6.4.1 Storage of Supplies 
Study materials will be stored by the study personnel according to the documentation 
provided with the study materials. The sponsor reserves the right to inspect the storage area 
before and during the study. A written record will be made of the storage condition of the 
study materials and retained for the Investigator File. 
6.4.2 Control of Supplies 
Dispensing of the study materials will be carefully recorded on appropriate forms. 
The accountability logs should include dates, quantities, material identification number 
assigned to the study materials and/or subject. The accountability logs will also include 
general details related to the study including the protocol/amendment number, sponsor name, 
indication and the investigator. 
6.4.3 Return of Supplies 
The study monitor will review the study materials accountability logs and check all product 
returns prior to authorizing the return of the product to the sponsor. 
6.4.4 Compliance to Therapeutic Intervention 
The study site will be able to monitor subject use of the ClearPlay mobile application in 
conjunction with the Waveband® for compliance and to monitor AEs and symptom 
escalation. Subjects who do not upload data for 3 consecutive days are to be contacted and 
reminded of the study requirements. Subjects who do not upload data for 5 consecutive days 
are to be contacted again. Subjects who do not upload for 7 consecutive days are to be 
withdrawn from the study for poor compliance. 
6.5 
Concomitant Medications  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrolment (within 
14 days before the time of randomization) or receives during the study must be recorded on 
the eCRF along with: 
• Reason for use; 
• Dates of administration including start and end dates; 
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If the use of any concomitant treatment becomes necessary (eg, for treatment of an AE), the 
treatment and administration details must be recorded in the source documents and the eCRF. 
The medical monitor must be notified of all prohibited medications administered to any 
subject, in order to assess the subject’s eligibility to continue in the study. 
6.5.1 Prohibited Medications 
The following medications are prohibited during the study: 
• Psychotropic medications other than stable dose of an SSRI medication, or stable dose 
of a TCA medication; 
• Subjects using beta-blockers. 
Use of prohibited medications during the study will be captured as protocol deviations and 
discussed with the sponsor. 
6.5.2 Allowed Medications 
All medications are permitted, with the exception of those listed in Section 6.5.1. 
6.6 
Concomitant Therapies  
Any concomitant therapy (occupational therapy, physical therapy, vestibular therapy, visual 
therapy, cognitive behavioral therapy, acupuncture, chiropractor, and/or other therapies) that 
the subject is receiving or receives during the study must be recorded on the eCRF along 
with: 
• Reason for use; 
• Dates of therapy including start and end dates. 
6.7 
Lifestyle and Dietary Study Restrictions 
The following lifestyle and dietary restrictions should be followed during the study: 
• Physical Exercise: Subjects must be willing to exercise or stretch for 20 minutes each 
day, while wearing the wrist-worn HR monitoring device (Waveband®), by following 
the directions provided by the ClearPlay© mobile application. Outside of this, 
subjects should not engage in any exercise during the 8-week study period that will 
make them short of breath. 
• Smoking: Subjects must be willing to refrain from smoking for 1 hour prior to their 
daily exercise or stretching sessions.  
• Alcohol: Subjects must be willing to refrain from drinking alcohol for 1 hour prior to 
their daily exercise or stretching sessions.  
• Dietary: Subjects must be willing to refrain from consuming caffeinated or sugary 
beverages that may impact HR for 1 hour prior to their daily exercise or stretching 
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7 
STUDY ASSESSMENTS AND SCHEDULES 
7.1 
Safety Assessments 
Refer to the Schedule of Events (Table 5) for the timing of all safety assessments. 
7.1.1 
Baseline Demographics 
Subject demographics will be recorded, including date of birth, gender, race, ethnicity, 
alcohol history, drug/tobacco history.  
7.1.2 Medical and Medication History 
A detailed history of the head injury will be taken.  
A complete medical history will be collected, not limited to but including evaluation for past 
or present neurological, cardiovascular, metabolic or pulmonary conditions, history of 
migraines, psychiatric history.  
A detailed record of the head injury will be collected. Review of computed tomography (CT) 
scans or magnetic resonance imaging (MRI)s to be performed if applicable. 
A review of prior medications will be completed. Prior medications are those used within 
7 days of Screening. 
7.1.3 Body Weight and Height 
Body weight (in kg) (wearing light clothes, no shoes) and height (in cm) will be measured to 
allow the calculation of body mass index (rounded to 1 decimal place). Note: Height will only 
be captured at the screening visit. 
7.1.4 Vital Signs including Beat to Beat Blood Pressure 
Vital signs will be collected via a third-party FDA approved device (Caretaker4®).30 The 
subject will be fitted with the Caretaker4® device which attaches to right arm and right finger 
and measures continuous beat to beat HR and BP. Once connected, 2 minutes of baseline data 
collection will occur, followed by 2 minutes of ice bucket (or ClearHeart©) data collection, 
and a further 2 minutes post-ice bucket data collection.  
The investigator (or a qualified observer at the investigational site) will interpret the vital 
signs using one of the following categories: within normal limits, abnormal but not clinically 
significant, or abnormal and clinically significant (reported with corresponding AE). 
7.1.5 Adverse Events 
The categorization of AEs by seriousness, relationship and expectedness is summarized in 
Table 3, and forms the basis for understanding the reporting requirements of events.  

 
 
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Table 3: Categories of Adverse Events 
Event 
Seriousness 
Event Relationship and Expectedness 
Not Related 
Related 
Non-serious 
Adverse event  
Adverse event 
Serious 
Serious adverse event 
Serious Adverse Event 
 
Expected 
Serious Adverse Event 
Unexpected 
Suspected Unexpected 
Serious Adverse Reaction) 
Unanticipated problems relating to the therapeutic intervention, involving risks to subjects 
and others will be monitored throughout the study. 
7.1.5.1 Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical study subject. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease. This includes an exacerbation of pre-existing conditions or events, 
intercurrent illnesses or the significant worsening of the indication under investigation that is 
not recorded elsewhere in the eCRF under specific efficacy assessments. Anticipated 
fluctuations of pre-existing conditions, including the disease under study that do not represent 
a clinically significant exacerbation or worsening need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study. 
AEs should be reported on the appropriate page of the eCRF. 
7.1.5.2 Adverse Device Effect 
An ADE is an AE related to the use of an investigational medical device.  
This definition includes: 
• Adverse events with a relationship to the use of the investigational medical device; 
 
• Adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation or operation, or any malfunction of the 
investigational medical device; 
 
• Any event resulting from use error or from intentional misuse of the investigational 
medical device. 
 
7.1.5.3 Definition of Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening (ie, the subject is at immediate risk of death at the time the event 
occurred; it does not refer to an event which might hypothetically have caused death 
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• Requires in-patient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; 
• Is a medically important event or reaction. 
Medical and scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These should also usually be considered serious. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in hospitalizations, or the 
development of drug dependency or drug abuse. 
The following hospitalizations/admissions do not need to be reported as SAEs: 
• Hospitalization for social reason (e.g. caregiver relief); 
• Hospitalization for surgery/procedure planned prior to study entry; 
• Hospital visit less than 24 hours e.g. held for observation or treatment, but duration of 
stay less than 24 hours; 
• Treatment at hospital or center for minor procedures (e.g. laser eye surgery).  
7.1.5.4 Definition of a Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a related SAE that is both 
serious and unexpected as assessed using the current Investigator’s Brochure or Product 
Information. 
7.1.5.5 Anticipated Serious Adverse Device Effect 
An anticipated SADE is a SADE which by its nature, incidence, severity or outcome has been 
identified in the current version of the Investigator’s Brochure or Product Information.  
 
7.1.5.6 Unanticipated Serious Adverse Device Effect 
An unanticipated SADE is a SADE which by its nature, incidence, severity or outcome has 
not been identified in the current version of the Investigator’s Brochure or Product 
Information.  
 
7.1.5.7 Device Deficiency 
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. Device deficiencies include malfunctions, use 
errors and inadequate labelling.  
 

 
 
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7.1.5.8 Severity of Adverse Events 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study. The assessment will be based on the investigator’s clinical judgment. The severity 
of each AE and SAE recorded in the eCRF should be assigned to one of the following 
categories: 
Mild: 
An AE that is easily tolerated by the subject, causes minimal discomfort 
and does not interfere with everyday activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed. 
Severe: 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed 
7.1.5.9 Relationship of Adverse Events 
The investigator is obligated to assess the relationship between graded exercise and passive 
stretching and the occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. Alternative causes, such as natural history of the underlying 
diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to 
the therapeutic intervention will be considered and investigated. 
The causal relationship of the AE to the therapeutic intervention or study procedures should 
be assessed by the investigator (or medically qualified delegate) using the following 
classifications: 
Not Related: 
In the investigator’s opinion, there is not a causal relationship 
between the therapeutic intervention and the AE. 
Unlikely: 
The temporal association between the AE and therapeutic 
intervention is such that the study product is not likely to have any 
reasonable association with the AE. 
Possible: 
The AE follows a reasonable temporal sequence from the time of 
therapeutic intervention but could have been caused by the study 
subject’s clinical state or other modes of therapy administered to 
the subject. 
Probable: 
The AE follows a reasonable temporal sequence from the time of 
therapeutic intervention, abates upon discontinuation of the 
therapeutic intervention and cannot be reasonably explained by 
the known characteristics of the study subject’s clinical state. 
Highly Probable: 
The AE follows a reasonable temporal sequence from the time of 
therapeutic intervention, abates upon discontinuation of the 
therapeutic intervention and reappears when the therapeutic 
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7.1.5.10 Relationship of Adverse Events to Investigational Device 
The investigator is obligated to assess the relationship between the investigational device and 
the occurrence of each AE/SAE. The investigator will use clinical judgment to determine the 
relationship. Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
device use will be considered and investigated. 
The causal relationship of the AE to the investigational device or study procedures should be 
assessed by the investigator (or medically qualified delegate) using the following 
classifications: 
 
Not Related: 
In the investigator’s opinion, there is not a causal relationship between the 
investigational device and the AE. 
Unlikely: 
The temporal association between the AE and investigational device is 
such that the investigational device is not likely to have any reasonable 
association with the AE. 
Possible: 
The AE follows a reasonable temporal sequence from the time of use of 
the investigational device but could have been caused by the study 
subject’s clinical state or other modes of therapy administered to the 
subject. 
Probable: 
The AE follows a reasonable temporal sequence from the time of use of 
the investigational device, and cannot be reasonably explained by the 
known characteristics of the study subject’s clinical state. 
 
Adverse events that have a relationship (possible or probable) to the investigational device, 
are termed ADEs.  
 
7.1.5.11 Recording of Adverse Events 
Adverse events will be recorded and reported from Day 1 to Day 56. Adverse events will be 
captured at clinic visits on Day 1 and Day 56, and at telephone safety visits on Day 14, 
Day 28 and Day 42.  
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostic reports) relative to the 
event. The investigator will then record all relevant information regarding an AE/SAE in to 
the eCRF. All details of any treatments initiated due to the AE should also be recorded in the 
subjects’ notes and the eCRF. 
Each AE will be documented in the subject’s eCRF. If an AE changes in frequency or 
intensity during a study, a new entry of the event must be made in the eCRF. 
In the event where the principal investigator is not a clinician, then the principal investigator 
must delegate the safety review duty to a clinician.  
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In the absence of a diagnosis, the individual 
signs/symptoms should be documented. 
All AEs occurring during the study must be documented on the relevant eCRF pages. The 
following data should be documented for each AE: 

 
 
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• Description of the symptom event; 
• Classification of ‘serious’ or ‘not serious’; 
• Severity; 
• Date of first occurrence and date of resolution (if applicable); 
• Action taken; 
• Causal relationship; 
• Outcome of event (unknown, recovered, not yet recovered, recovered with sequelae, 
death [with date and cause reported]. 
After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the sponsor on the subjects’ condition. 
All AEs are required to be assessed by a medical practitioner. All AEs or SAEs documented 
at a previous visit/contact that are designated as ongoing, will be reviewed at subsequent 
visits/contacts. All AEs or SAEs will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up. The 
investigator will ensure that follow-up includes any supplemental investigations as may be 
indicated to elucidate the nature and/or causality of the AE or SAE.   
7.1.5.12 Reporting of Device Deficiencies 
All device deficiencies related to the identity, quality, durability, reliability, safety or 
performance of an investigational medical device shall be documented throughout the study.  
Device deficiencies will be further classified as those that potentially could lead to SADE 
(device deficiency with SADE potential), and those that could not (device deficiency without 
SADE potential).  
 
To determine SADE potential, the investigator may consider whether the device deficiency 
might have led to an important medical occurrence in any of the following situations: 
a) if either suitable action had not been taken; 
b) if intervention had not been made, or; 
c) if circumstances had been less fortunate. 
 
7.1.5.13 Reporting of Serious Adverse Events 
As the sponsor has a legal responsibility to notify the appropriate regulatory authorities about 
the safety of a new therapeutic intervention, prompt notification by the investigator, or 
nominee, of any SAEs, SADEs or device deficiencies with SADE potential, to the sponsor is 
required. 
All SAEs, SADEs or device deficiencies with SADE potential, whether related or unrelated, 
and regardless of expectedness, should be recorded on the SAE Form and submitted to the 
study sponsor within 24 hours of site awareness via email as follows:  

 
 
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• Email to:  pharmacovigilance@answersneuro.com 
If the investigator learns of any SAE/SADEs/device deficiency with SADE potential, 
including death, at any other time after a subject completes the study, and he/she considers 
the event reasonably related to the therapeutic intervention, the investigator will promptly 
notify the sponsor. 
In addition to reporting the SAE/SADEs/device deficiency with SADE potential to sponsor, 
the investigator must also notify the HREC which approved the study according to their 
requirements. 
Copies of all correspondence relating to reporting of any SAEs/SADEs/device deficiency 
with SADE potential should be maintained in the site’s study files and will be checked 
routinely by the Study Monitor. 
If the sponsor and the investigator consider that the SAE/SADEs/device deficiency with 
SADE potential is related to the therapeutic intervention (ie, an adverse reaction) and 
unexpected it will be reported to the appropriate regulatory authorities by the sponsor (or 
designee) within the pre-defined timelines.   
In the event where the principal investigator is not a clinician, then the principal investigator 
must delegate the safety review duty to a clinician.  
Non-serious or expected adverse reactions, or events (without causal relationship to the 
therapeutic intervention), should be recorded in the eCRF by the investigator as part of 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Good Clinical Practice (GCP), and will be reported to the appropriate 
regulatory authorities by the sponsor (or designee) as required.  
7.2 
Biomarkers 
Samples will be collected at Baseline and Week 8.  The following biomarkers will be 
assessed: 
• Structural proteins [t-tau, NF-L, GFAP and UCH-L1] 
• Inflammatory cytokines [IL-6, IL-10 and TNFα] 
• Single nucleotide polymorphisms [APO-E4, BDNF, and NFkB] 
Analyses will be performed by Monogram Biosciences/ LabCorp for structural proteins (t-
tau, NF-L, GFAP, and UCH-L1) and inflammatory cytokines (IL-6, IL-10, and TNF-alpha). 
Samples may be collected as follows:  
• Blood collection by direct venipuncture is the preferred option; 
• Buccal swab and collection of saliva if subject is needle phobic. 
A detailed description of sample handling and processing of samples will be provided in the 
Study Procedures Manual.   

 
 
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7.3 
BioBank 
Genetics will be evaluated at a future date as a supplemental component of this study.  
A blood or saliva sample for DNA and RNA isolation will be collected at baseline and a 
blood or saliva sample for RNA isolation will be collected at Week 8 from subjects who have 
consented to participate in the BioBank project. Participation is optional. Subjects who do not 
wish to participate in the genetic research may still participate in the study. Separate consent 
will be obtained for this sample collection. 
Genetic variation may impact a subject’s response to study intervention, susceptibility to, and 
severity and recovery from mTBI. Research will be limited to genetic, epigenetic and 
transcriptomic factors that will inform prognosis and aid in evaluation of clinical outcomes in 
mTBI. Therefore, where local regulations and IRB/IEC allow, a blood OR saliva sample will 
be collected for DNA and RNA analysis from consenting subjects. A blood sample is the 
preferred option, if agreeable to the subject.  
Genetic research may consist of the analysis of 1 or more candidate genes or the analysis of 
genetic markers throughout the genome [or analysis of the entire genome] (as appropriate). 
DNA samples will be analyzed for single nucleotide polymorphisms and RNA for RNAseq 
analyses. Additional analyses may be conducted if it is hypothesized that this may help 
further understand the clinical data. 
The samples will be analyzed as part of a multi-study assessment of genetic factors involved 
in the clinical outcomes of mTBI. 
The results of genetic analyses will not be reported in the clinical study report or provided to 
subjects. 
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
The samples will be retained while research on mTBI continues but no longer than 5 years or 
other period as per local requirements.  
Details on processes for collection and shipment and destruction of these samples can be 
found in the Study Manual. 
7.4 
Neuropsychology Testing 
7.4.1 Post-Concussion Symptom Scale 
The PCSS is a well validated 21-item self-report measure that records symptom severity 
using a 7-point Likert scale of severity. It ranks possible concussion symptoms by their 
severity to determine if a concussion has occurred, and whether further evaluation is required. 
For all subjects, daily reported PCSS scores collected from ClearPlay© mobile application 
will be utilized to determine the resolution of symptoms. 
This scale will be used to identify post-concussion symptom burden of each subject daily. 

 
 
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7.4.2 Godin Leisure Time Exercise Questionnaire 
The Godin leisure-time exercise questionnaire is a well validated activity scale. It asks 
subjects to rate their exercise as either mild, moderate or strenuous, and will provide an 
indication for how each subject perceived the exercise allocated to them.  
This scale will be used to identify the degree of self-reported athletic exertion of each subject 
weekly. 
7.4.3 Beck Anxiety Inventory 
The Beck Anxiety Inventory (BAI) enables clinicians to measure the severity of anxiety in 
adolescents and adults. The BAI has been found to discriminate well between anxious and 
non-anxious diagnostic groups in a variety of clinical populations. 
Subjects respond to 21 items rated on a scale from 0 to 3, each item is descriptive of 
subjective, somatic, or panic-related symptoms of anxiety.  
This scale will be used as a predictor of anxiety-induced prolongation of PPCS.  
7.4.4 Brief Symptom Inventory-18 
The Brief Symptom Inventory (BSI)-18 is an instrument that evaluates psychological distress 
and psychiatric disorders in people. The test can be used for areas such as subject progress, 
treatment measurements, and psychological assessment. 
The BSI-18 is a 53-item self-report scale that uses the 5 point Likert scale. 
This scale will be used as a predictor of anxiety-induced prolongation of PPCS.  
7.4.5 Reiss-Epstein-Gursky Anxiety Sensitivity Index  
The Reiss-Epstein-Gursky Anxiety Sensitivity Index (ASI) is a 16-item scale that focuses on 
apprehension about the symptoms of anxiety itself.  
The ASI is a good predictor of anticipatory and situational anxiety-induced prolongation of 
PPCS.  
7.4.6 Conners' Adult Attention Deficit Hyperactivity Disorder Rating Scale  
The Conners’ adult attention deficit hyperactivity disorder (ADHD) Rating Scale (CAARS) 
provides a multimodal assessment of symptoms and behaviors associated with ADHD in 
patients. 
The CAARS is a well validated diagnostic instrument to identify ADHD, which is a predictor 
of PPCS.  
7.4.7 Center for Epidemiologic Studies - Depression Scale 
The Center for Epidemiologic Studies - Depression Scale (CES-D) is a brief self-report scale 
designed to measure self-reported symptoms associated with depression. The items of the 

 
 
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scale are symptoms associated with depression which have been used in previously validated 
longer scales. 
The CES-D is a well validated diagnostic instrument to identify depression, which is a 
predictor of PPCS.  
7.5 
Autonomic Tests 
7.5.1 Cold Pressor Test (Ice Bucket and ClearHeart© Testing) 
The cold pressor test measures the cardiovascular response to acute cooling of the hand. The 
cold pressor test will be performed using 2 different tests, with a break in-between each test 
(refer to Section 8.1 for details of the order of assessments to achieve this).  
Ice Bucket Testing: The subject will rest in the supine position for at least 3 minutes. The 
subject will be fitted with the Caretaker4® device which attaches to right arm and right finger 
and measures continuous beat to beat HR and BP. Once connected, 5 minutes of baseline data 
collection will occur, followed by 2 minutes data collection while the subjects’ left hand will 
be submerged in ice water for 120 seconds (ice bucket testing), and a further 2 minutes post-
ice bucket data collection.  
Testing with ClearHeart©: ClearHeart© is ANSwers Neuroscience Pty Ltd commercial 
prototype for cold pressure testing. The subject will rest in the supine position for at least 3 
minutes. The subject will be fitted with the Caretaker4® device which attaches to right arm 
and right finger and measures continuous beat to beat HR and BP. Once connected, 5 minutes 
of baseline data collection will occur, followed by 2 minutes data collection while the 
subjects’ left hand will be placed in the hand cooling device (ClearHeart©) for 120 seconds, 
and a further 2 minutes ClearHeart© data collection. 
7.5.2 Buffalo Concussion Bicycle Test 
The BCBT measures the exacerbation of post-concussive symptoms during 15 minutes of 
graded exercise. 
The subject will be fitted with the Caretaker4® device which attaches to right arm and right 
finger and measures continuous beat to beat HR and BP. Once connected, 5 minutes of 
baseline data collection will occur, during this time, the subject will record their rating of 
perceived exertion (RPE) on a scale of 6 to 20, and symptom severity using a 10--point visual 
analog scale. 
Exercise will be initiated, and at each minute RPE and symptom severity will be recorded and 
the bike grade increased to next stage. This will be repeated every minute until termination 
by: 
• Maximum exertion (i.e., exhaustion); 
• Three-point increase in symptom severity compared to pre-test, addition of new 
symptom, or increase in severity resulting in difficulty continuing test; 
• Rapid progression of complaints, subject appears faint or unsteady or staff 
determines inability to continue test safely. 

 
 
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On completion of the exercise, subjects will complete a 5-minute cool down (if safe to do so), 
during which RPE and symptom severity assessment will continue at 1-minute intervals. 
7.6 
Evaluation of Neck Range and Motion 
The evaluation of neck range and motion will be performed using 2 different tests. The 
neurologic examination will be completed first followed by the ClearNeck© assessment. 
7.6.1 Whiplash Test (Whiplash Testing (ClearNeck©) 
The ClearNeck© is ANSwers Neuroscience Pty Ltd commercial prototype for cervico-genic 
proprioception measurement. The subject will be seated 40 to 50 cm from a bullseye target, 
and the ClearNeck© (cap with inbuilt laser) will be placed on the subject’s head. During 
testing, the subject will direct the laser onto the target from zero angle (by looking straight 
ahead with eyes open), and 8 trials (4 left and 4 right) of proprioception (eyes closed, rotate 
head 90 degrees to the left or right, then back to starting point). 
7.6.2 Neurologic Examination 
The neurologic examination, by an allied health professional, will include performing the 
following neurological tests:  
• Orthostatic Vital signs: Blood pressure, Heart Rate and Symptoms are measured 
Supine after 2 minutes rest and Standing after 1 minute rest. Test results are deemed 
clinically significant if they include at least one of the following AND symptomatic:  
(1) systolic BP drop of ≥ 20mmHg or (2) diastolic BP drop of ≥10mmHg. 
• Neck and Sub-Occipital Region Exam: Evaluation of neck muscle spasm, tenderness, 
and range of motion, to evaluate for any signs or symptoms of whiplash 
• Oculomotor/Ophthalmologic Evaluation: Evaluations of visual tracking, smooth 
pursuits, repetitive saccades, gaze stability, and near point of convergence (NPC) and 
accommodation. 
• Postural Control and Motor Coordination: Evaluation of tandem gait with eyes open 
and closed, and tandem stance. 
7.7 
Post Study Survey 
On completion of the study only, subjects will be invited to comment on study participation 
and provide suggestions for improvement. Subjects will also be asked to provide a summary 
of school or work absence during study. 
 
 

 
 
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8 
STUDY SCHEDULE OF EVENTS 
8.1 
Order of Assessments 
The order of assessment for each subject is dependent on their assigned subject identification 
numbers. Refer Table 4 for detail.  
Table 4: Order of Assessments :  
 
Subjects Assigned to ODD numbered 
subject identification numbers  
 
Subjects Assigned to EVEN numbered 
subject identification numbers 
Biomarker sample collection 
Biomarker sample collection 
Ice Bucket Test  
ClearHeart© 
Neuropsychology Testing (CAARS, CES-
D, BAI, ASI [Pre/Post mTBI], BSI-18 
[Pre/Post mTBI].   
Neuropsychology Testing (CAARS, CES-
D, BAI, ASI [Pre/Post mTBI], BSI-18 
[Pre/Post mTBI].   
Neurologic Evaluation  
Neurologic Evaluation 
ClearNeck© 
ClearNeck© 
ClearHeart© 
Ice Bucket Test 
Buffalo Concussion Bike Test 
 Buffalo Concussion Bike Test 
Randomize subject to Exercise or Stretching Group 
Dispense i-touch or i-phone with 
appropriate software loaded (whether 
randomized to graded exercise vs. passive 
stretching).  
Subject to enter test PCSS and Godin score 
via ClearPlay App©; to ensure subject is 
able to use this App.  
Dispense i-touch or i-phone with 
appropriate software loaded (whether 
randomized to graded exercise vs. passive 
stretching). 
Subject to enter test PCSS and Godin score 
via ClearPlay App©; to ensure subject is 
able to use this App. 
Adverse Events  
Adverse Events  
 
Post-study survey to be completed at Day 56 only 
Abbreviations: ASI = Anxiety Sensitivity Index, BAI = Beck Anxiety Inventory, BESS = 
Balance Error Scoring System, BSI = Brief Symptom Inventory, CAARS = Conners’ Adult 
Attention Deficit Hyperactivity Disorder Rating Scale, CES-D = Center for Epidemiologic 
Studies - Depression Scale, DNA = deoxyribonucleic acid, PCSS = Post-Concussion 
Symptom Scale, RNA = ribonucleic acid, VOMS = Vestibular-Oculomotor Screening 
 
 
 
 
 
 

 
 
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Table 5: Schedule of Events 
Study Assessments 
Baseline Visit 
Therapy Period 
Telephone 
Safety Visit 
Follow-Up/ET  
Day 0 (within 3 to 14 days of concussion) 
Day 1 to Day 55 
Day 14, Day 28, 
Day 42 (±2 days) 
Day 56 
(±3 days) 
Screening Evaluation 
Study Evaluation 
Study Assessments 
Informed consent 
X 
 
 
 
 
Allocate unique subject study identification 
X 
 
 
 
 
Inclusion/exclusion criteria review 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Medical and medication history  
X 
 
 
 
 
Review of CT or MRI (if obtained) 
X 
 
 
 
 
Height and weighta 
X 
 
 
 
X 
Subject Completed Questionnaires 
Post-Concussion Symptom Scale 
(pre- and post-mTBI) 
 
X 
X 
 
 
Godin leisure time exercise questionnaireb 
 
X 
X 
 
X 
Brief Symptom Inventory 
(pre- and post-mTBI) 
 
X 
 
 
Xf 
Anxiety Symptom Index 
(pre- and post-mTBI) 
 
X 
 
 
Xf 
Beck Anxiety Inventory 
 
X 
 
 
X 
CAARS (Attention) 
 
X 
 
 
 
CES-D (Depression) 
 
X 
 
 
 

 
 
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Study Assessments 
Baseline Visit 
Therapy Period 
Telephone 
Safety Visit 
Follow-Up/ET  
Day 0 (within 3 to 14 days of concussion) 
Day 1 to Day 55 
Day 14, Day 28, 
Day 42 (±2 days) 
Day 56 
(±3 days) 
Screening Evaluation 
Study Evaluation 
Post-study survey 
 
 
 
 
X 
Autonomic Tests 
Ice Bucket Testing 
 
X 
 
 
X 
ClearHeartÓ Testing 
 
X 
 
 
X 
Buffalo Concussion Bike Test 
 
X 
 
 
X 
Other Physical Tests 
 
 
 
 
 
ClearNeckÓ Testing 
 
X 
 
 
X 
Neurologic Testing 
 
X 
 
 
X 
Biomarkers/BioBank 
Biomarker sample collection 
 
X 
 
 
X 
DNA and RNA sample collection 
 
X 
 
 
Xd 
Therapeutic Intervention 
Dispense i-touch or i-phone.  
 
X 
 
 
 
Waveband® – dispense and instruct 
 
X 
 
 
 
ClearPlay© - dispense and instruct via initial entry 
of PCSS and Godin data on i-touch or i-phone  
 
X 
 
 
 
Enter/Review ClearPlay© mobile application 
entries 
 
 
Xe 
 
 
Return of Waveband® 
 
 
 
 
X 

 
 
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Study Assessments 
Baseline Visit 
Therapy Period 
Telephone 
Safety Visit 
Follow-Up/ET  
Day 0 (within 3 to 14 days of concussion) 
Day 1 to Day 55 
Day 14, Day 28, 
Day 42 (±2 days) 
Day 56 
(±3 days) 
Screening Evaluation 
Study Evaluation 
Safety Assessments 
Vital signs including beat to beat BP 
 
X 
 
 
X 
Adverse event monitoring 
 
X 
X 
X 
X 
Concomitant medications 
 
X 
X 
X 
X 
Concomitant therapies  
 
X 
X 
X 
X 
Abbreviations: AE = Adverse Event, ASI = Anxiety Sensitivity Index, BAI = Beck Anxiety Inventory, BESS = Balance Error Scoring System, BP = blood pressure; BSI = Brief Symptom 
Inventory, CAARS = Conners’ Adult Attention Deficit Hyperactivity Disorder Rating Scale, CES-D = Center for Epidemiologic Studies - Depression Scale, CT = DNA = deoxyribonucleic 
acid, , ET = early termination, MRI = magnetic resonance imaging, mTBI = mild traumatic brain injury, PCSS = Post-Concussion Symptom Scale, RNA = ribonucleic acid, VOMS = 
Vestibular-Oculomotor Screening 
Footnotes for Table 5 
a) 
Height will only be captured at the Screening Visit; 
b) 
Godin leisure time exercise questionnaire to be administered weekly;  
c) 
Optional consent required; 
d) 
RNA collection only; 
e) 
Site to monitor AEs and symptom escalation. Subjects who do not upload data for 3 consecutive days are to be contacted. Subjects who do not upload data for 5 consecutive days are 
to be contacted again. Subjects who do not upload for 7 consecutive days are to be withdrawn from the study for poor compliance. 
f) 
Questionnaires to be completed at Day 56, based on subject’s current condition.  
 

 
 
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9 
STATISTICAL METHODS 
9.1 
Determination of Sample Size 
The sample size for this study is 400 subjects: 200 to be randomized to graded exercise, and 
200 to be randomized to passive stretching. A power calculation was conducted with the 
minimum difference in probability of symptom recovery of 13%. Specifically, the probability 
of symptom resolution of passive stretching and graded exercise groups were set to be 80% 
and 93%, respectively. In order to achieve power of 90% with α=0.05, a sample of 
316 subjects is required. Allowing the attrition rate of 15%, a total of 363 subjects is required. 
To be conservative we plan to enroll 400 subjects to appropriately power this study. 
9.2 
Statistical and Analytical Plans 
A Statistical Analysis Plan (SAP) will be written after finalizing the protocol and prior to 
database lock. The SAP will detail the implementation of all the planned statistical analysis in 
accordance with the principal features stated in the protocol. Any deviations from the SAP 
will be presented in the final clinical study report. 
In general, data will be summarized using descriptive statistics (mean, median, standard 
deviation, minimum and maximum) or frequency counts and percentages, as appropriate to 
the type of data. Baseline will be defined as the last available, valid, non-missing assessment 
prior to dosing.  
Only data from protocol scheduled visits/time points will be included in the summary tables. 
Data from unscheduled visits/time points will not be included in the summary tables but will 
be included in the figures and listings. 
All analyses will be performed using Statistical Analysis Software 9.4 (SAS Institute, Cary, 
NC) and R 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria; http://www.r-
project.org/). 
9.3 
Analysis Populations 
9.3.1 All Subjects Population 
The all subject’s population will include all enrolled subjects and will be based on the 
randomized intervention regardless of which intervention the subject actually completed. The 
all subject’s population will be used for all summaries of baseline and demographic data.  
9.3.2 Safety Population 
The safety population will include all randomized subjects who completed at least Day 1 of 
therapeutic intervention and will be based on the actual therapy received, if this differs from 
that to which the subject was randomized to. The safety population will be used for the 
summaries of all safety data. 
9.3.3 Efficacy Population 
The efficacy population will include all randomized subjects who completed, at least Day 1 
of therapeutic intervention, who had PCSS data at baseline and at least 1 post-baseline 
assessment and will be based on the actual therapy received. The efficacy population will be 

 
 
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used for the summaries of all neuropsychology and autonomic data, and for the validation of 
ClearHeart© and ClearNeck© performance. 
9.4 
Demographic and Other Baseline Characteristics 
Subject enrolment and disposition will be summarized by randomized treatment group and 
will include the total number of subjects randomized into the study and in each analysis 
population. The number of subjects prematurely discontinuing from the study, along with the 
reason for early discontinuation will also be summarized. 
Demographic and baseline data recorded at screening and prior to dosing will be summarized, 
by randomized treatment group.  
9.5 
Safety Analysis 
9.5.1 Adverse Event Analysis 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). AEs will be grouped by system organ class and preferred term and summarized, 
by treatment group at the time of onset of the AE (ie, the therapeutic intervention most 
recently prior to the onset of the AE). The summary tables will present the number and 
percentage of total subjects and number of events, by system organ class and by preferred 
term. 
All AE summaries will be restricted to treatment emergent AEs only. Treatment emergent 
AEs are defined as AEs which commence on or after the time of start of therapeutic 
intervention.  
For the summaries of AEs, subjects who experience the same AE (in terms of the MedDRA 
preferred term) more than once will only be counted once for that event in the number of 
subjects but all occurrences of the same event will be counted in the number of events. 
Separate summaries will be provided for AEs by severity and relationship to study 
intervention. 
Serious adverse events will be summarized and listed separately. 
9.5.2 Vital Signs Analysis 
Vital signs will be summarized at each protocol scheduled time point, by treatment group at 
each time point. Where vital signs were captured as continual measures, mean values for that 
time interval will be recorded. Actual values and actual changes from baseline will be 
presented.  
9.5.3 Prior and Concomitant Medication Analysis 
Prior and concomitant medications will be coded using the World Health Organization Drug 
coding dictionary. Prior and concomitant medications will be grouped by preferred term. 
Prior medications are those medications that were stopped prior to commencing the 
therapeutic intervention. Concomitant medications are medications that are taken at least 

 
 
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once after commencing the therapeutic intervention. Medications stopping on the same day as 
commencing therapeutic intervention will be considered as concomitant medications. 
9.6 
Efficacy Analysis 
The full presentation of the analysis of efficacy data will be presented in the SAP. 
For all subjects, daily reported PCSS scores collected from ClearPlay© mobile application 
will be utilized to determine the resolution of symptoms. The resolution of symptoms is 
defined as a symptom-severity score of less than each subject’s pre-injury PCSS score for 
3 consecutive days. To assess differences in the probability of symptom resolution between 
graded exercise and passive stretching during the 8 weeks of therapy, both unadjusted and 
adjusted logistic regression models will be used. The primary outcome of the study will be to 
confirm or refute the superiority of sub-threshold aerobic exercise versus passive stretching to 
result in resolution of symptoms following mTBI. Confounders for the adjusted models will 
include age, gender, anxiety at baseline, history of migraine, cardiovascular fitness, the 
presence or absence of neurologic findings, and site of enrollment.  
The survival probability will be compared using Kaplan-Meier (log rank test) analyses 
between the 2 treatment arms. Cox proportional hazards regression models will be used to 
evaluate the differences in time to symptom resolution. Adjusted treatment effects will be 
estimated in Cox proportional hazards regression models, controlling for the variables listed 
above. To identify that our randomization strategy was effective, analysis of variance will be 
used to assess for group-wise differences in age, days since injury to initial visit, initial PCSS 
score, resting HR, and ΔHR during the BCBT and resting BP and ΔBP during the ice bucket 
test on Day 1. Non-parametric tests of medians will be used to compare the non-normally 
distributed variable duration of clinical recovery. Chi-squared tests will be used to assess 
group-wise differences in gender, history of concussions, and incidence of PPCS. 
9.6.1 Biomarker Data Analysis 
Biomarkers will be summarized at each protocol scheduled time point by treatment group, 
using either summary statistics or frequency tabulations, as applicable to the type of data. 
Changes from baseline will also be presented where applicable. 
9.6.2 Neuropsychology Testing Analysis 
Neuropsychology testing will be assessed using the patient reported outcomes and will be 
summarized at each protocol scheduled time point by treatment group, using either summary 
statistics or frequency tabulations, as applicable to the type of data. Changes from baseline 
will also be presented where applicable. 
Results of the cold pressor test, whiplash test and BCBT will be summarized at each protocol 
scheduled time point by treatment group, using either summary statistics or frequency 
tabulations, as applicable to the type of data. Changes from baseline will also be presented 
where applicable. 
9.7 
Interim Analyses 
There are no formal interim analyses planned for this study. 

 
 
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9.8 
Handling of Missing Data 
For subjects who are withdrawn from the study prior to their completion for any reason, all 
data compiled up to the point of discontinuation will be used for analysis. All withdrawals 
will be included in all analyses up to the time of withdrawal. 
Subjects who are withdrawn prematurely from study intervention will be included in all 
analyses regardless of the duration of intervention. 
There will be no imputation for missing data, unless otherwise stated. 
10 STUDY DOCUMENTATION 
10.1 Data Management 
A comprehensive data management plan will be prepared to support the study.  
10.2 Access to Source Documents  
In compliance with local regulations and ICH GCP guidelines, it is required that the 
investigator and institution permit authorized representatives of the sponsor, the regulatory 
agency(s), and the HREC direct access to review the subject’s original medical records for 
verification of study-related procedures and data. Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study. The investigator is obligated to inform the subject and obtain their 
consent to permit named representatives to have access to his/her study-related records 
without violating the confidentiality of the subject. 
10.3 Protocol Amendments  
No changes (amendments) to the protocol may be implemented without prior approval from 
the sponsor and the appropriate HREC, except where necessary to eliminate an immediate 
hazard to subjects, or when the change involves only logistical or administrative aspects of 
the study. If a protocol amendment requires changes to the Patient Information and Consent 
Form (PICF), the revised PICF, prepared by the investigator, must be approved by the HREC. 
10.4 Protocol Deviations  
If any issue relating to the safety of study subject arises which requires a deviation from the 
protocol, the study unit through the investigator may immediately make such a deviation.  If 
there is a need for such a deviation the study unit must notify the sponsor and the responsible 
IEC of the facts and circumstance causing the deviation as soon as is reasonably practical, but 
in any event no later than 5 working days after the change is implemented. The nature and 
reasons for the protocol deviations will be recorded in the subject’s eCRF. 
The sponsor may not reimburse the investigator for cases in which the study procedures and 
evaluations are conducted such that they result in major protocol violations. 

 
 
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11 QUALITY ASSURANCE AND QUALITY CONTROL 
11.1 Audit and Inspection 
Study sites and study documentation may be subject to quality assurance audit during the 
course of the study by the sponsor or its nominated representative. In addition, inspections 
may be conducted by regulatory authorities at their discretion. 
11.2 Monitoring 
Data for each subject will be recorded on a eCRF. Data collection must be completed for 
each subject who signs a PICF and is commences therapeutic intervention. 
In accordance with the ICH GCP guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the eCRF are 
accurate and reliable.  
The investigator must permit the monitor, the HREC, the sponsor’s internal auditors, and 
representatives from regulatory authorities’ direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs. 
12 ETHICS 
12.1 Human Research Ethics Committee Approval 
The protocol will be submitted for approval to the appropriate HREC. Prior to initiation of 
the study, the investigator must provide the sponsor with a copy of the written HREC 
approval of the protocol and study PICF. This approval letter will identify the study PICF by 
date and the study protocol by protocol number, title and date. The investigators will receive 
all the documentation needed for submitting the present protocol to the HREC. The 
composition of the HREC will also be provided to the sponsor. If approval is suspended or 
terminated by the HREC, the investigator will notify the sponsor immediately. 
It is the responsibility of the investigator to report study progress to the HREC as required or 
at intervals not greater than 1 year. 
The investigator at the study site or his/her nominee, will be responsible for reporting any 
SAEs to the HREC as soon as possible, and in accordance with the guidelines of the HREC. 
12.2 Regulatory Approval 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local requirements, for review and approval before the 
beginning of the study. On completion of the study, the regulatory authorities will be notified 
that the study has ended 
The investigator will ensure that this study is conducted in full compliance with the protocol, 
the Declaration of Helsinki, the ICH GCP guidelines, Therapeutic Goods Administration 
regulations, and all other applicable local laws and regulations. Compliance with these 
standards provides assurance that the rights, safety, and well-being of subjects are protected. 

 
 
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In agreeing to the provisions of the protocol, these responsibilities are accepted by the 
investigator. 
12.3 Ethical Conduct of the Study  
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, ICH GCP guidelines, 
and the applicable local laws and regulatory requirements. 
12.4 Subject Information and Consent  
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to ICH GCP guidelines. 
The investigator is responsible for ensuring that no subject undergoes any study related 
examination or activity before that subject has given written informed consent to participate 
in the study. 
The investigator or designated personnel will inform the subject of the objectives, methods, 
anticipated benefits and potential risks and inconveniences of the study. The subject should 
be given every opportunity to ask for clarification of any points s/he does not understand and, 
if necessary, ask for more information. At the end of the interview, the subject will be given 
ample time to consider the study. Subjects will be required to sign and date the PICF. After 
signatures are obtained, the PICF will be kept and archived by the investigator in the 
investigator’s study file. A signed and dated copy of the subject PICF will be provided to the 
subject or their authorized representative. 
It should be emphasized that the subject may refuse to enter the study or to withdraw from 
the study at any time, without consequences for their further care or penalty or loss of 
benefits to which the subject is otherwise entitled. Subjects who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study, a new PICF will be approved by the HREC (and 
regulatory authorities, if required). The study subjects will be informed about this new 
information and reconsent will be obtained. 
13 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit evaluation 
of the study and quality of the data produced. After completion of the study (end of study 
defined as the date of the last visit of the last subject), all documents and data relating to the 
study will be kept in an orderly manner by the investigator in a secure study file. This file 
will be available for inspection by the sponsor or its representatives. Essential documents 
should be retained for 2 years after the final marketing approval in an ICH region or for at 
least 2 years since the discontinuation of clinical development of the therapeutic intervention. 
It is the responsibility of the sponsor to inform the study site when these documents no longer 
need to be retained. The investigator must contact the sponsor before destroying any study 
related documentation. In addition, all subject medical records and other source 
documentation will be kept for the maximum time permitted by the hospital, institution, or 
medical practice. 

 
 
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The sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the investigator(s). Published data must not compromise the objectives 
of the study. Data from individual study sites in multicenter studies must not be published 
separately. 
14 FINANCING AND INSURANCE 
Financing of this study will be outlined in a separate agreement. 
Subjects may be compensated for the costs associated with travel to and from and parking at 
the study site for the 2 study visits. 
Insurance will be provided in conformity with the Medicines Australia Guidelines for all 
subjects involved in the study. The subject should not take part in any other clinical study 
whilst enrolled in this study. The subject should report any health injury that could have 
occurred as a result of the clinical study to the investigator without delay. 
 
 

 
 
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16. Leddy et al. Use of graded exercise testing in concussion and return-to-activity 
management. Curr Sports Med Rep, v. 12, n. 6, p. 370-6, 2013 Nov-Dec 2013. 
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16 APPENDICES 
16.1 Post-Concussion Symptom Scale 
16.2 Godin Leisure Time Exercise Questionnaire 
16.3 Beck Anxiety Inventory 
16.4 Brief Symptom Inventory 
16.5 Reiss-Epstein-Gursky Anxiety Sensitivity Index 
16.6 CAARS (Attention) 
16.7 CES-D (Depression) 
16.8 Post-study survey