Clinical trial NCT01860404
Conditions: Brain Concussion
Keywords: Concussion Branched chain amino acids BCAA HIT HEADS
Sponsor: Children's Hospital of Philadelphia
Start date: 2014-01-01; Completion date: 2023-01-01
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a randomized, placebo-controlled, double-blinded, therapeutic exploratory clinical trial of branched chain amino acids (BCAA's) in the treatment of concussion. The aim of the study is to determine whether, compared to placebo treatment, administration of BCAA's, at one or more doses, after a concussion improves neurocognitive recovery at one or more time-periods post concussion.

Detailed description:
Annually, between 100,000 to 140,000 children present to the emergency department for concussion in the United States.1 The Centers for Disease Control now estimates that 1.6 - 3.8 million sports related concussions occur each year in the United States. A large proportion of these patients have enduring cognitive and neurobehavioral problems. Concussion is a heterogeneous insult to the brain that precipitates a complex pathophysiological process that can result in a cascade of deleterious side effects. At present, there are no proven therapies to mitigate or prevent the neurocognitive and neurobehavioral consequences of concussions. The limbic hippocampus, a brain structure crucial for learning and memory, is often damaged in concussion. In preclinical studies in our laboratory, analysis of ipsilateral hippocampi isolated from mice after traumatic brain injury (TBI) demonstrated that only the concentrations of the three BCAA's (valine, isoleucine, and leucine) were significantly altered (reduced) after injury. When these brain-injured animals received dietary supplementation with BCAA's, the concentrations of these amino acids were restored in the injured hippocampus and the injured animals demonstrated significant cognitive improvement to levels comparable to those obtained in non-injured control animals. In light of these results and the increasing awareness and morbidity associated with concussion, we are proposing a pilot therapeutic exploratory clinical trial to determine the effects of BCAA's in reducing the neurocognitive side effects of concussion injury.

Arms: arm 1: Placebo will be administered orally twice daily for 21 days arm 2: 27 grams of BCAA's will be administered twice-daily for 21 days arm 3: 22.5 grams of BCAA's will be administered twice-daily for 21 days arm 4: 15 grams of BCAA's will be administered twice-daily for 21 days arm 5: 7.5 grams of BCAA's will be administered twice-daily for 21 days
Interventions: intervention 1: Branched Chain Amino Acids intervention 2: Placebo solution
Intervention descriptions: intervention 1: The three BCAA's will be combined together and dissolved in a flavored solution. intervention 2: The placebo solution will have similar taste, texture, consistency and appearance as the BCAA solution.

Protocol documents:
Prot_SAP_000.pdf: 
  
Protocol No. 13-101227  
 
 
 
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i 
Title: 
HIT HEADS Trial: Head Injury Treatment with Healthy 
and Advanced Dietary Supplements: A randomized, 
placebo-controlled, double-blinded, therapeutic 
exploratory clinical trial of branched chain amino acids 
(BCAA’s) in the treatment of concussion 
Short Title 
BCAA’s in concussion 
Drug or Device 
Name(s): 
Branched chain amino acids 
FDA IND 
117570 
eIRB Number 
13-010227 
Protocol Date: 
 
Amendment 1 Date: 06/13/2014 (Full Amendment) 
 
Amendment 2 Date: 09/18/2014 (Full Amendment) 
Amendment 3 Date: 03/10/2015 (Full Amendment) 
Amendment 4 Date: 4/24/2015 (Full Amendment) 
Amendment 5 Date: 7/9/2015 (Full Amendment) 
Amendment 6 Date: 8/13/2015 (Full Amendment) 
Amendment 7 Date: 10/13/2015 (Full Amendment) 
Amendment 8 Date: 12/21/2015 (Full Amendment) 
Amendment 9 Date: 03/07/2016 (Full Amendment) 
Amendment 10 Date: 09/11/2017 (Full Amendment) 
Amendment 11 Date: 11/20/2017 (Full Amendment) 
Amendment 12 Date: 12/19/2017 (Full Amendment) 
Amendment 13 Date: 01/11/2018 (Full Amendment) 
Amendment 14 Date: 04/06/2018 (Full Amendment) 
Amendment 15 Date: 09/27/2018 (Full Amendment) 
Amendment 16 Date: 06/17/2019 (Full Amendment) 
 
 
Funding Agency: Dana Foundation  
505 Fifth Avenue, 6th floor 
New York, NY 10017 


  
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Principal Investigator 
 Sage Myers, MD, MSCE 
 Department of Emergency Medicine 
The Children's Hospital of Philadelphia 
Phone: (267)-426-7939 
Email: myerss@email.chop.edu 
 
Co-Investigator and IND Sponsor 
Akiva Cohen, PhD 
The Children’s Hospital of Philadelphia 
Abramson Research Center, Room 816-H 
Philadelphia, PA 19104 
Phone 215-590-1472 
Email: cohena@email.chop.edu 
 
Co-Investigator 
 
Matthew Kirschen, MD PhD 
Department of Anesthesia and Critical Care and  
Division of Neurology, Department of Pediatrics 
The Children's Hospital of Philadelphia 
Phone: (215) 590-7430 
Email: kirschenm@chop.edu 
 
Christina Master, MD 
Department of Pediatrics, Division of General Pediatrics 
Department of Surgery, Division of Orthopedics 
The Children’s Hospital of Philadelphia 
Phone: 215-5901527 
Email: masterc@email.chop.edu 
 
Kristy B. Arbogast 
The Children’s Hospital of Philadelphia 
3535 Market Street 
Philadelphia, PA 19104 
Phone: 215-590-6075 
Email: arbogast@email.chop.edu 
 
 
 
 


 
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TABLE OF CONTENTS 
Table of Contents .................................................................................................................. iii 
Abbreviations and Definitions of Terms ............................................................................. vi 
Protocol Synopsis ................................................................................................................. vii 
Table 1: Schedule of Study Procedures .............................................................................. xi 
1 
KEY STUDY PERSONNEL .................................................................................................................... XII 
2 
BACKGROUND INFORMATION AND RATIONALE ......................................................................... 1 
2.1 
INTRODUCTION ......................................................................................................................................... 1 
2.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ........................................ 1 
2.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ........................................................................ 2 
2.3.1 
Non-Clinical Studies ........................................................................................................................ 2 
2.3.2 
Clinical Studies ................................................................................................................................ 2 
2.4 
SELECTION OF DRUGS AND DOSAGES ...................................................................................................... 3 
2.5 
RELEVANT LITERATURE AND DATA ......................................................................................................... 4 
2.5.1 
Computerized Cognitive Testing ...................................................................................................... 4 
2.5.2 
Concussion Clinical Symptom Scales .............................................................................................. 5 
2.5.3 
Sleep Disturbances Post-Concussion ............................................................................................... 5 
2.5.4 
Balance and Vestibular Impairments Post-Concussion ................................................................... 6 
2.5.5 
Branched Chain Amino Acids .......................................................................................................... 6 
2.6 
COMPLIANCE STATEMENT ....................................................................................................................... 6 
3 
STUDY OBJECTIVES ................................................................................................................................. 8 
3.1 
PRIMARY OBJECTIVE ................................................................................................................................ 8 
3.2 
SECONDARY OBJECTIVES ......................................................................................................................... 8 
4 
INVESTIGATIONAL PLAN ...................................................................................................................... 9 
4.1 
GENERAL SCHEMA OF STUDY DESIGN ..................................................................................................... 9 
4.1.1 
Screening Phase ............................................................................................................................... 9 
4.1.2 
Study Treatment Phase ..................................................................................................................... 9 
4.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING .......................................................................... 10 
4.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES .................................................................... 10 
4.3.1 
Duration of Study Participation ..................................................................................................... 10 
4.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ................................................ 10 
4.4 
STUDY POPULATION ............................................................................................................................... 10 
4.4.1 
Inclusion Criteria ........................................................................................................................... 10 
4.4.2 
Exclusion Criteria .......................................................................................................................... 11 
5 
STUDY PROCEDURES ............................................................................................................................ 12 
5.1 
SCREENING VISIT ................................................................................................................................... 12 
5.2 
STUDY TREATMENT PHASE .................................................................................................................... 12 
5.3 
UNSCHEDULED VISITS ............................................................................................................................ 13 
5.4 
PRIOR AND CONCOMITANT MEDICATIONS ............................................................................................. 13 
5.5 
RESCUE MEDICATION ADMINISTRATION ............................................................................................... 13 
5.6 
SUBJECT COMPLETION/WITHDRAWAL ................................................................................................... 13 
5.7 
EARLY TERMINATION STUDY VISIT ....................................................................................................... 14 
6 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 15 
6.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS .................................................... 15 
6.1.1 
Demographics ................................................................................................................................ 15 


  
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6.1.2 
Concussion History ........................................................................................................................ 15 
6.1.3 
Height and weight .......................................................................................................................... 15 
6.1.4 
Laboratory Evaluations ................................................................................................................. 15 
6.2 
EFFICACY EVALUATIONS ....................................................................................................................... 15 
6.2.1 
Axon Sports Computerized Cognitive Assessment Tool (CCAT) ................................................... 15 
6.2.2 
Clinical Symptoms Checklists ........................................................................................................ 16 
6.2.3 
Cognitive and Physical Activity Assessments ................................................................................ 16 
6.2.4 
Actigraphy Sleep and Assessment .................................................................................................. 16 
6.2.5 
Computerized Dynamic Posturography (CDP) ............................................................................. 17 
6.3 
SAFETY EVALUATION ............................................................................................................................ 17 
7 
STATISTICAL CONSIDERATIONS ...................................................................................................... 18 
7.1 
PRIMARY ENDPOINTS ............................................................................................................................. 18 
7.2 
SECONDARY ENDPOINTS ........................................................................................................................ 18 
7.3 
STATISTICAL METHODS ......................................................................................................................... 18 
7.3.1 
Baseline Data ................................................................................................................................. 18 
7.3.2 
Primary Efficacy Analysis .............................................................................................................. 18 
7.3.3 
Analysis of Secondary Endpoints ................................................................................................... 20 
7.3.4 
Safety Analysis ............................................................................................................................... 21 
7.4 
SAMPLE SIZE AND POWER ...................................................................................................................... 21 
8 
STUDY MEDICATION ............................................................................................................................. 22 
8.1 
DESCRIPTION .......................................................................................................................................... 22 
8.1.1 
Packaging ....................................................................................................................................... 22 
8.1.2 
Labeling ......................................................................................................................................... 22 
8.1.3 
Dosing ............................................................................................................................................ 22 
8.1.4 
Treatment Compliance and Adherence .......................................................................................... 23 
8.1.5 
Drug Accountability ....................................................................................................................... 23 
9 
SAFETY MANAGEMENT ....................................................................................................................... 25 
9.1 
CLINICAL ADVERSE EVENTS .................................................................................................................. 25 
9.2 
ADVERSE EVENT REPORTING ................................................................................................................. 25 
9.3 
DEFINITION OF AN ADVERSE EVENT ...................................................................................................... 25 
9.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ............................................................................... 26 
9.4.1 
Relationship of Serious Adverse Events to Study Drug or Other Intervention .............................. 26 
9.5 
IRB/IEC NOTIFICATION OF SERIOUS ADVERSE EVENTS AND OTHER UNANTICIPATED PROBLEMS ....... 26 
9.5.1 
Follow-up report ............................................................................................................................ 27 
9.6 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR ............................................. 27 
9.7 
MEDICAL EMERGENCIES ........................................................................................................................ 27 
10 
STUDY ADMINISTRATION ................................................................................................................. 28 
10.1 
TREATMENT ASSIGNMENT METHODS .................................................................................................. 28 
10.1.1 
Randomization ............................................................................................................................. 28 
10.1.2 
Blinding ........................................................................................................................................ 28 
10.1.3 
Unblinding ................................................................................................................................... 28 
10.2 
DATA COLLECTION AND MANAGEMENT .............................................................................................. 28 
10.3 
CONFIDENTIALITY ................................................................................................................................ 30 
10.4 
REGULATORY AND ETHICAL CONSIDERATIONS ................................................................................... 30 
10.4.1 
Data and Safety Monitoring Plan ................................................................................................ 30 
10.4.2 
Risk Assessment ............................................................................................................................ 31 
10.4.3 
Potential Benefits of Trial Participation ...................................................................................... 31 
10.4.4 
Risk-Benefit Assessment ............................................................................................................... 31 
10.5 
RECRUITMENT STRATEGY .................................................................................................................... 31 
10.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION .............................................................. 33 


  
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10.7 
PAYMENT TO SUBJECTS/FAMILIES ....................................................................................................... 33 
10.7.1 
Reimbursement for travel, parking and meals ............................................................................. 33 
11 
PUBLICATION ........................................................................................................................................ 34 
12 
REFERENCES .......................................................................................................................................... 35 
13 
APPENDICES ........................................................................................................................................... 38 
13.1 
APPENDIX 1: CLINICAL SYMPTOM CHECKLIST ................................................................................. 38 
13.2 
APPENDIX 2: PHYSICAL AND COGNITIVE ACTIVITY ASSESSMENTS .................................................. 39 
13.3 
APPENDIX 3: SLEEP ASSESSMENT ..................................................................................................... 40 
13.4 
APPENDIX 4: DRUG ACCOUNTABILITY ASSESSMENT ......................................................................... 41 
 


  
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
BCAA’s 
 
Branched chain amino acids 
MRI 
 
Magnetic resonance imaging 
g 
 
Grams 
g/d 
 
Grams per day 
mg/d 
 
Milligrams per day 
CCAT 
 
Computerized cognitive assessment tool 
TBI 
 
Traumatic brain injury 
LFPL 
 
Lateral fluid percussion injury 
HIPAA 
 
Health Insurance Portability and Accountability Act 
IRB 
 
Institutional Review Board 
IDS 
 
Investigational Drug Service 
SAE 
 
Serious adverse event 
AE 
 
Adverse event 
CRCU 
 
Clinical research computing unit 
CHOP 
 
Children’s Hospital of Philadelphia 
HUP 
 
Hospital of the University of Pennsylvania 
CNS 
 
Central nervous system 
GABA 
 
Gamma-aminobutyric acid 
DRS 
 
Disability rating scale 
CRF 
 
Case report form 
BMI 
 
Body mass index 
PHI 
 
Personal health information 
DMS 
 
Data management system 
PI 
 
Principal investigator 
CDP 
 
Computerized dynamic posturography 
 
 
 


 
 
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PROTOCOL SYNOPSIS 
Study Title 
HIT HEADS Trial: Head Injury Treatment with Healthy and 
Advanced Dietary Supplements: A randomized, placebo-controlled, 
double-blinded, therapeutic exploratory clinical trial of branched 
chain amino acids (BCAA’s) in the treatment of concussion 
Funder 
Dana Foundation 
Clinical Phase 
Phase II 
Study Rationale 
Annually, between 100,000 to 140,000 children present to the 
emergency department for concussion in the United States.1 The 
Centers for Disease Control now estimates that 1.6 - 3.8 million 
sports related concussions occur each year in the United States. A 
large proportion of these patients have enduring cognitive and 
neurobehavioral problems. Concussion is a heterogeneous insult to 
the brain that precipitates a complex pathophysiological process that 
can result in a cascade of deleterious side effects. At present, there 
are no proven therapies to mitigate or prevent the neurocognitive 
and neurobehavioral consequences of concussions. The limbic 
hippocampus, a brain structure crucial for learning and memory, is 
often damaged in concussion. In preclinical studies in our 
laboratory, analysis of ipsilateral hippocampi isolated from mice 
after traumatic brain injury (TBI) demonstrated that only the 
concentrations of the three BCAA’s (valine, isoleucine, and leucine) 
were significantly altered (reduced) after injury. When these brain-
injured animals received dietary supplementation with BCAA’s, the 
concentrations of these amino acids were restored in the injured 
hippocampus and the injured animals demonstrated significant 
cognitive improvement to levels comparable to those obtained in 
non-injured control animals.  In light of these results and the 
increasing awareness and morbidity associated with concussion, we 
are proposing a pilot therapeutic exploratory clinical trial to 
determine the effects of BCAA’s in reducing the neurocognitive 
side effects of concussion injury. 
Study Objective(s) 
Primary  
• To determine whether, compared to placebo treatment, 
administration of BCAA’s, at one or more doses, after a 
concussion improves processing speed recovery at one or more 
time-periods post concussion. 
Secondary 
• Determine whether administration of BCAA’s improves 
neurocognitive recovery compared to placebo for the cognitive 
domains of attention, learning, and working memory. 


 
 
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• Evaluate whether BCAA supplementation improves clinical 
symptom resolution. 
• Determine whether BCAA supplementation reduces the time to 
return to normal activities, specifically school or work, and 
participation in sports. 
• Assess dose-related compliance of subjects with daily self-
administration of BCAA’s and with completion of study 
endpoints. 
• Assess feasibility of enrolling potential subjects within 72 hours 
of concussion injury. 
• Assess safety of BCAA supplementation in concussed subjects. 
Test Article(s) 
The three BCAA’s—valine, isoleucine, and leucine—will be 
combined together in a 1:1:1 ratio and administered twice daily by 
mouth. 
Study Design 
 
This study is a randomized, placebo-controlled, double-blinded 
therapeutic exploratory clinical trial to evaluate the effects of 
BCAA’s on the recovery from the neurocognitive side effects of 
concussion injury. 
Subject Population  
key criteria for 
Inclusion and  
Exclusion: 
Inclusion Criteria 
1. 
Males and females, ages 11 - 34 years, of any race.  
2. 
Weight at least 40kg. 
3. 
Subjects who had a concussion, as diagnosed by a qualified 
physician or advance practice provider, within 72 hours prior 
to enrollment.  
4. 
Ability to have daily email and internet access. 
5. 
Post-menarchal females must have a negative urine 
pregnancy test and must use an acceptable method of 
contraception. 
6. 
Subjects must, in the opinion of the referring physician, have 
the capacity to provide informed consent. 
7. 
Informed consent by the subject, or for subjects <18 years old 
both informed consent by a parent/guardian and child assent. 
Exclusion Criteria 
1. 
Witnessed seizure at the time of injury or penetrating head 
injury. 
2. 
Prior concussion or TBI within 90 days. 
3. 
Concussion or TBI severe enough to require admission to an 
intensive care unit for observation or intervention, 
specifically for the brain injury. 
4. 
Previous history of TBI or concussion requiring admission to 
the hospital, disabling stroke, epilepsy, brain tumor, 
neurodegenerative condition, or psychiatric disease. 


  
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5. 
Subjects taking neurological or psychoactive medications as a 
regular daily prescription medication. 
6. 
Known history of maple syrup urine disease or known family 
history of maple syrup urine disease.  
7. 
Any investigational drug use within 30 days prior to 
enrollment. 
8. 
Allergy to FD&C Red #40 (red dye 40) or Sucralose. 
9. 
Lactating females.  
10. Parents/guardians or subjects who, in the opinion of the 
investigators, may be non-compliant with study schedules or 
procedures.  
Number Of Subjects  
 
The study will be conducted through the Children’s Hospital of 
Philadelphia.  Recruitment will stop when approximately 72subjects 
are enrolled. It is expected that approximately 72 subjects will be 
enrolled to produce 50 evaluable subjects. 
Study Duration 
The study duration per subject will be up to 22 days, with up to 1 
day screening and up to 21 days in the treatment phase.  The entire 
study is expected to last approximately 2 years. 
Study Phases 
Screening 
Study Treatment 
(1) Screening: Physicians who evaluate patients with concussion 
will identify potential subjects. Subjects will be screened using the 
protocol inclusion and exclusion criteria. Informed consent and, if 
applicable, parental/guardian consent and child assent, will be 
obtained. 
(2) Intervention: Subjects will be randomized to receive either oral 
BCAA’s 7.5, 15, 22.5, or 27 grams twice daily or placebo for a total 
of 21 days. 
Efficacy Evaluations 
Neurocognitive function will be assessed daily through the Axon 
Sports computerized cognitive battery, which measures processing 
speed, attention, learning, and working memory. Performance will 
be measured primarily through reaction time data, but task accuracy 
data will be analyzed as well.  Clinical symptoms will be assessed 
through clinical symptom checklists, actigraphy (sleep), and 
dynamic posturography (balance testing optional). 
Safety Evaluations 
The research coordinator will ask subjects about the occurrence of 
any adverse events (AE’s) during the study visits conducted on days 
5-9, 12-16, 22-24. A standardized question will be asked of every 
subject to inquire about illnesses or accidents since the previous 
reporting period. 
Statistical And Analytic 
Plan 
The mean trajectory in decline and recovery in processing speed is 
unknown at this stage of development. Thus, the primary analysis 
will aim to determine whether there are differences in processing 
speed between the BCAA dose groups and placebo, and if so, at 


  
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what time periods the differences are most pronounced. We will 
model processing speed as a function of dose and day of study and 
will allow differences between dose groups to vary as a function of 
time through a series of interaction terms.  The primary analysis will 
consider three key time periods, Days 3-6, 7-10 and 11-14 when we 
expect differences in processing speed between the BCAA-treated 
groups and placebo to be largest.  Likelihood ratio tests will be 
employed to specifically test whether there are differences in mean 
processing speed between placebo and any of the BCAA doses at 
the three key time periods. 
Data And Safety 
Monitoring Plan 
The investigators will be responsible for data quality management 
and ongoing assessments of safety. An experienced neurologist, 
Rebecca Ichord MD will act as the Independent Medical Monitor 
for this study. 


 
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TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Evaluation 
Screening 
Day 0 
Treatment Phase 
Days 0 – 21 
Informed Consent/Assent 
Review Inclusion/Exclusion Criteria  
Pregnancy Test on Post-Menarchal 
Females 
X 
 
Demographics 
Concussion History 
Randomization 
 
X 
Axon Sports CCAT 
 
Daily 
Clinical Symptom Checklist 
 
Daily 
Cognitive and Physical Activity 
Assessments 
 
Daily 
Sleep Assessment 
 
Daily 
Drug Accountability Assessment 
 
Daily 
Actigraphy 
 
Continuous 
Computerized Dynamic 
Posturography (Optional) 
 
Days 0-4, 5-9, 12-16 
Adherence Assessment 
 
Days 0, 5-9, 12-16 
Adverse Event Assessment 
 
Days 5-9, 12-16, 22-24 
 
 
 


 
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1 
KEY STUDY PERSONNEL 
 
Principal Investigator:  Sage Myers, MD, MSCE 
Attending Physician, Division of Emergency Medicine, CHOP 
Phone: 267-426-7939 
Email: myerss@email.chop.edu 
 
Co-Investigator and IND Sponsor: Akiva Cohen, PhD  
Associate Professor 
Departments of Pediatrics and Neurology, CHOP 
Phone 215-590-1472 
Email: cohena@chop.edu 
 
Co-Investigator: Matthew Kirschen, MD PhD 
Attending Physician, Department of Anesthesia and Critical Care 
Attending Physician, Division of Neurology, Department of Pediatrics 
Phone: (215) 590-7430 
Email: kirschenm@chop.edu 
 
Co-Investigator: Christina Master, MD 
Attending Physician, Department of Pediatrics, Division of General Pediatrics 
Attending Physician, Department of Surgery, Division of Orthopedics 
Phone: 215-5901527 
Email: masterc@email.chop.edu 
 
Co-Investigator: Brian Sennett, MD 
Attending Physician, Department of Orthopaedic Surgery 
University of Pennsylvania Health System 
Phone: 215-615-4434 
Email: brian.sennett@uphs.upenn.edu 
 
Co-Investigator: Peter Le Roux, MD FACS 
The Brain and Spine Center, Lankenau Medical Center 
 
 
 
Statistician: Mary Putt, PhD 
Associate Professor, Department of Biostatistics and Epidemiology, 
University of Pennsylvania Perelman School of Medicine 
Database Administrators: Shawn Ballard, MS 
Technical Director, Software Systems Development, Research Technologies 
Independent Medical Monitor: Rebecca Ichord, MD 
Study Pharmacist: Kenneth Rockwell, PharmD 
 


 
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2 
BACKGROUND INFORMATION AND RATIONALE 
2.1 
Introduction 
The Centers for Disease Control now estimates that there are over 700 emergency 
department visits per 100,000 population for traumatic brain injury, and 1.6 - 3.8 million 
sports-related concussions occur each year in the United States. Many concussions are 
sports-related, with more than half of these concussions occur during football, particularly in 
adolescents and young adults. Annually, between 100,000 to 140,000 children present to the 
emergency department for concussion in the United States.1 However, impacts to the head, 
or sudden acceleration-deceleration events, are also common in other contact sports like 
soccer, lacrosse, hockey, rugby, and basketball and in pursuits such as horseback riding, 
cycling, roller-blading, and boxing among others. No concussion is without consequences. 
In the short-term, patients’ cognitive and athletic performance may suffer. In the long term, 
concussions, and perhaps even sub-concussive blows, are thought to cause alterations in 
cerebral structures and functions that can lead to impaired cognitive functioning and 
neurobehavioral problems. That is, there are enduring deleterious effects and a potential 
causal link between concussion and later-life cognitive and behavioral difficulties including 
a condition now known as chronic traumatic encephalopathy. 
Concussion is a heterogeneous insult to the brain, induced by traumatic biomechanical 
forces, that precipitates a complex pathophysiological process that can result in a cascade of 
deleterious side effects. Currently, there are no proven therapies to mitigate or prevent the 
neurocognitive and neurobehavioral consequences of concussions. Preclinical studies in 
mice from our laboratory have demonstrated that the hippocampus, a brain structure 
involved in higher cognitive function often injured in concussion, has reduced levels of the 
three branched chain amino acids (BCAA’s)—valine, isoleucine, and leucine— after 
traumatic brain injury (TBI).2 In vivo administration of BCAA’s restored the concentrations 
of these amino acids in the hippocampus, and these animals demonstrated cognitive 
recovery to levels comparable to non-injured animals. In light of these pre-clinical results 
and the increasing awareness of morbidity, including long-term sequela, associated with 
concussion, we propose a pilot phase II clinical trial to determine the effects of dietary 
supplementation with BCAA’s to reduce the neurocognitive effects of concussion. 
2.2 
Name and Description of Investigational Product or Intervention 
The three BCAA’s—valine, isoleucine, and leucine—will be combined together in a 1:1:1 
ratio.  Four different dose levels will be evaluated: originally,15 g/d, 30 g/d, 45 g/d, and 60 
g/d were planned, however during the original course of the study precipitation issues were 
noted at the highest ratio due to leucine precipitating at a lower concentration than expected 
due to the presence of the other solutes. After further testing, it was determined that the 
product remained in solution at a concentration of 27g/591ml bottle and therefore, the 
highest dose level was altered to give four dose levels of 15g/d, 30g/d, 45g/d, and 54g/d.  
Sodium gluconate, sucralose, and fruit punch concentrate are added to improve palatability. 


 
 
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2.3 
Findings from Non-Clinical and Clinical Studies  
2.3.1 Non-Clinical Studies 
Akiva Cohen, a Co-Investigator on this proposal, has directed the preclinical animal studies 
leading to this clinical trial. The central hypothesis of this work is that the restoration of the 
delicate balance of excitation and inhibition in central nervous system (CNS) synaptic 
circuits after TBI may improve cognitive functioning. To examine potential changes in the 
excitatory (glutamate) and inhibitory (gamma-aminobutyric acid or GABA) 
neurotransmitters after TBI, Dr. Cohen and colleagues used high pressure liquid 
chromatography (HPLC) to quantify these amino acid levels in the hippocampal formation 
of mice (adult male C57Bl/J6) after experimental TBI using lateral fluid percussion injury 
(LFPI).1 Results indicated that LPFI does not alter the concentrations of glutamate and 
GABA, but instead reduces the concentrations of the BCAA’s, valine, isoleucine, and 
leucine, by 50.8, 21.1, and 52.3%, respectively in the ipsilateral hippocampus. No other 
amino acid was affected and BCAA levels in the LFPI contralateral hippocampus were not 
significantly different from those measured in sham injured mice. 
After quantifying these changes in BCAA levels after brain injury, further research 
investigated the feasibility of using dietary treatment to restore the amino acid profile in the 
hippocampal formation.  Therefore, both LFPI and sham injured mice received water that 
was either untreated (control) or contained a cocktail of all three BCAA’s (100 mM of each 
leucine, isoleucine and valine). After consuming the treatment for 5 days, the ipsilateral 
hippocampus demonstrated BCAA levels similar to those from sham animals.  Furthermore, 
neither injury nor BCAA treatment after injury appeared to significantly alter the remaining 
14 tested amino acids, raise BCAA levels in contralateral hippocampus or hippocampi from 
sham animals, or alter the blood amino acid profile. 
LFPI mice demonstrated a significant 39.0% reduction in cognitive performance (as tested 
by the conditioned fear response task) when compared to uninjured mice. When the LFPI 
animals were assessed after BCAA treatment, their cognitive performance returned to values 
seen in sham-injured animals. Additionally, BCAA treatment restored excitability in injured 
hippocampi to levels similar to those seen in sham animals. Furthermore, there was a perfect 
(100%) correlation between BCAA-induced cognitive improvement and restoration of 
ipsilateral hippocampal excitability. To our knowledge, this is the first study to identify an 
efficacious dietary supplement that generates a measurable change in hippocampal 
excitability in injured brains and, in so doing, improves cognitive function. 
2.3.2 Clinical Studies 
2.3.2.1 Clinical Studies in Adults 
Dietary BCAA administration has been studied extensively in healthy people and in a 
variety of disease states over many decades.3  BCAA therapy has been studied most 
extensively as it relates to exercise physiology, hepatic pathology, and various neurological 
and psychiatric disorders.  Patients have been treated with BCAA’s for variable lengths of 
time including for more than 2 years. In addition, many athletes and body-builders consume 
BCAA’s as nutritional supplements.   


 
 
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A limited number of studies have examined BCAA’s in humans after TBI.  Plasma levels of 
BCAA’s and their circulating metabolites are decreased within 24 hours after injury in both 
mild and severe TBI relative to healthy volunteers.4  One study, evaluating plasma amino 
acid concentrations in patients approximately 2 months after TBI, found significantly 
reduced levels of BCAA’s, among other amino acids, relative to age-matched, non-injured 
controls.5 A follow-up study on a subsequent cohort of TBI patients found that plasma 
concentrations of amino acids were still reduced 120 days after injury, mainly driven by 
lower valine levels.6  Work by the same group demonstrated that intravenous BCAA 
administered to patients in the rehabilitation stage after severe TBI improved Disability 
Rating Scale (DRS) scores when compared to placebo.7  Additionally, they showed that 
BCAA’s may improve recovery from a posttraumatic vegetative or minimally conscious 
state.8 
2.3.2.2 Clinical Studies in Children 
The lower age limit for enrollment in the proposed study is 11 years.  Several clinical studies 
have been performed with BCAA’s in children.  BCAA’s were given to healthy children 9 
and children with cholestatic liver disease 10 to determine daily BCAA requirements.  
BCAA’s have been administered safely to children with phenylketonuria in an attempt to 
inhibit entry of phenylalanine into the brain and reduce its toxic effects on the CNS.11-13  
Beneficial effects also were seen when children with end-stage liver disease awaiting 
transplantation were fed with a BCAA-enriched formula compared with a standard 
formula.14,15  Symptoms of tardive dyskinesia were reduced in children and adolescents after 
treatment with BCAA’s and epileptic children treated with up to 20 g/d of BCAA in 
conjunction with a ketogenic diet showed reduction in seizure frequency and improvements 
in behavior and cognitive functioning.16,17  In all studies of children and adolescents treated 
with BCAA’s, the supplements were well tolerated and without side effects. 
2.4 
Selection of Drugs and Dosages 
Work from our laboratory has demonstrated that administering the equivalent of 60 g/d of 
BCAA’s (in a 1:1:1 ratio of leucine, isoleucine, and valine) mitigates injury-induced 
anterograde cognitive impairments in our mouse model. Higher doses did not offer any 
additional benefit the animals.  We originally used this dose as the maximal dose in our 
study, noting that it is within the ranges described in previous clinical studies.3  For 
example, oral doses of 60 g/d are effective in reducing mania symptoms.18  Benefit has also 
been seen in tardive dyskinesia (~15 g/d),19 spinocerebellar degeneration (6 g/d),20 anorexia 
in cancer patients (14 g/d),21 and hepatic encephalopathy (median amount of BCAA’s over 
11 randomized trials was 28 g/d; range 11 to 57 g/d).22  Aquilani and colleagues 
demonstrated that intravenous administration of 20 g of BCAA’s over 5 hours in TBI 
patients was associated with improved cognitive outcomes.7  Our preclinical work and this 
prior clinical work suggest that orally administering 30 g/d of BCAA’s twice daily will be 
safe and well tolerated.  However, during the original course of the study precipitation issues 
were noted at the highest ratio due to leucine precipitating at a lower concentration than 
expected due to the presence of the other solutes. After further testing, it was determined 
that the product remained in solution at a concentration of 27g/591ml bottle and therefore, 
the highest dose level was altered to 54 g/d. 


 
 
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Overall, BCAA’s are well tolerated and associated with minimal to no side effects. Several 
review papers have examined BCAA administration and summarized the adverse events 
(AE’s). 3,22 Many studies do not comment specifically on side effects, while others contain 
statements like “none of the subjects experienced side effects.”  A few report mild 
gastrointestinal side effects such as abdominal distention, diarrhea, and constipation.  One 
study of patients with liver cirrhosis, a group different from our proposed study population, 
found these symptoms in 12% of their BCAA treatment group.23  No serious or life 
threatening side effects have been reported.  These studies generally indicate that humans 
can consume amounts of BCAA’s that are comparable to those proposed here, without AE’s.  
Indeed, many body-builders and athletes consume large amounts of BCAA’s as nutritional 
supplements in various formulations.  There is a theoretical concern that because BCAA’s 
can alter the levels of other neurotransmitters, like dopamine and serotonin, depression or 
impairment of some cognitive functions may occur in susceptible individuals.  These 
symptoms, however, have never been reported clinically.  
It should be noted that the daily intake of BCAA’s in a 70 kg person consuming the 
recommended dietary allowance for protein (0.8 g/kg/d) would be 8.4 –11.2 g [40 kg person 
would be 4.8 - 6.4g].  In athletes, for whom a common recommendation is at least 1.2 g 
protein/kg/d, the daily BCAA intake would be 12.6 – 16.8 g [40 kg person would be 7.2 – 
9.6g].  The recommended dietary allowance of protein in adolescents is slightly higher than 
adults (1.0 g/kg/d for 11-14 year olds and 0.8-0.9 for 15-19 year olds). Therefore a 40 kg 
younger adolescent consuming the recommended dietary allowance for a non-athlete would 
be 6.0 – 8.0g and athlete would be 9.0 – 12.0g. While some studies in patients with liver 
cirrhosis 24 have used doses >100 g/d without reported side effects, the highest dose used in 
studies of neurological disease has been 60 g/d.  Additionally, a single dose finding study 
has been done in 12 healthy volunteers and showed in a randomized, double blind, crossover 
design that single oral doses of 10 g, 30 g and 60 g of BCAA’s were safe and well 
tolerated.25  At 60 g/d, this dose represents a 2 to 4 fold increase in the daily BCAA intake 
for athletes (assuming a body weight of 70 kg). Given that this dose is safe and well 
tolerated in humans, the no observable adverse effect level (NOAEL) of BCAA intake may 
be considerably higher, although this has not been formally studied to our knowledge. A 
toxicity study in rats over 13 weeks showed that rats did not exhibit any standard measures 
of potential toxicity at doses greater than 100 g/d.26   
2.5 
Relevant Literature and Data 
2.5.1 Computerized Cognitive Testing 
Neuropsychological testing provides a valuable mechanism to detect both obvious and 
subtle impairments in cognitive functioning after concussion.  Several computerized testing 
batteries are commercially available to evaluate patients after concussion.  The Axon Sports 
Computerized Cognitive Assessment Tool (CCAT) is optimal for use in a context where 
frequent repeated measurements of cognitive performance are required.  The CCAT consists 
of four computerized cognitive tests, derived from theoretical and developmentally sensitive 
principles, allowing this tool to be sensitive to any cause of cognitive performance change in 
individuals over time. The tasks themselves measure processing speed (via a simple reaction 
time task), attention (via a choice reaction time task), learning (via a one card learning task), 


 
 
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and working memory (via a one-back task).  These tests have been widely validated in both 
healthy and concussed individuals.  Normative scores exist for men and women greater than 
18 years, as well as, children and adolescents aged 10-18.  Studies have shown that task 
performance is similar between 16-18 year olds and adults.     
Prior research has demonstrated the sensitivity of the CCAT tests to neurological 
impairment, including mild TBI and concussion.27-31  The reliability and metric properties of 
the tests have been described and normative data are published.27,32-40,52  Numerous 
publications have demonstrated that the Axon Sports CCAT has minimal practice effects 
(making it ideal for repeat testing as in this proposal), and good criterion, construct, test-
retest, and ecological validity.33,34  The CCAT tasks have been shown to be sensitive to 
concussion-related cognitive decline and symptomatic athletes have greater impairments as 
measured by the CCAT than asymptomatic athletes.30,41-43 
2.5.2 Concussion Clinical Symptom Scales 
In addition to neuropsychological testing, self-reported symptoms are commonly cited as a 
means to identify concussive symptoms and a practical method to monitor recovery from 
concussion.  Piland and colleagues have demonstrated excellent factorial and construct 
validity of a 9-item self-reported symptom instrument in both high school and college 
athletes.44  The items are: headache, nausea, balance problems, sleeping more than usual, 
drowsiness, fatigue, feeling “slowed down”, feeling “in a fog”, and difficulty concentrating.  
This 9-item Head Injury Scale is a summative 7-point Likert-type scale instrument designed 
to measure the overall duration (length of symptom experienced over a 24-hour period) of 
concussion-related symptoms.  Piland also demonstrated factorial validity when athletes 
were queried on how severe each of the 9 symptoms has felt during the previous 24-hour 
period (i.e. symptom severity scale). 
2.5.3 Sleep Disturbances Post-Concussion 
Sleep disturbances are reported in up to 72% of patients with mild, moderate, and severe 
TBI up to three years post-injury.  Those TBI patients with sleep disturbances have longer 
inpatient hospital stays, a higher cost of rehabilitation, and a greater rate of functional 
disability. Current clinical practice guidelines advocate aggressive management of sleep 
hygiene after TBI to improve neurological symptoms and cognitive outcomes; however, the 
evidence behind this is lacking, and the neural mechanisms underlying sleep disturbances 
after TBI are unknown.  Moreover, our current therapeutic options for sleep disturbances are 
less effective in patients with TBI-related sleep problems than with other sleep disorders.  
Preliminary data from our laboratory suggest that after LFPI, mice show significant sleep 
disturbances for up to 30 days post-injury compared to sham surgery controls, including 
more time sleeping during the active phase and increased sleep fragmentation (defined by an 
increased number of sleep-wake transitions and shortened average length of sleep and wake 
bouts).  BCAA supplementation seems to attenuate some of these sleep disturbances after 
TBI.   


 
 
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2.5.4 Balance and Vestibular Impairments Post-Concussion 
Balance or postural control is necessary in activities of daily living and sport.  Balance 
requires the CNS to process and integrate afferent information from the visual, 
somatosensory (proprioceptive), and vestibular systems to then perform coordinated 
musculoskeletal responses.  Abnormal static and dynamic balance is well described in 
survivors of TBI and altered postural dynamics is frequently found immediately after a 
concussive injury.  Balance deficits usually resolve within 3 to 10 days after injury, 
however, they may be identified even years after injury in up to a third of patients and self-
reported balance difficulty often correlates with persistent post-concussion symptoms.  
Instrumented testing devices are considered the gold standard of balance testing since they 
attempt to objectively measure balance.  The computerized dynamic posturography (CDP) 
test as an objective means to assess balance by examining the response pattern to 
simultaneous, multimodal sensory stimulation.45 
2.5.5 Branched Chain Amino Acids 
Branched chain amino acids are essential amino acids, meaning they cannot be synthesized 
de novo and therefore must be acquired through the diet.  They are involved in numerous 
functions in the human brain including protein synthesis and energy production.  A 
significant fraction of ingested BCAA’s is not metabolized by the liver and passes directly 
into the systemic circulation, causing plasma concentrations to rise appreciably.  BCAA’s 
are important for protein metabolism throughout the body. They are transported into the 
brain by high affinity, low capacity transporters, located at the blood–brain barrier on 
capillary endothelial cells.  Leucine enters the brain faster than any other amino acid, but 
valine and isoleucine also readily cross the blood-brain barrier. 
Once in the brain, BCAA’s are key amino acids involved in de novo glutamate (the major 
excitatory neurotransmitter in the CNS) synthesis, as approximately 50% of brain glutamate 
contains BCAA-derived nitrogen.  Furthermore, de novo glutamate synthesis contributes 
approximately 40% of the releasable synaptic glutamate. It is believed that astrocytes 
remove released glutamate from the synaptic cleft, and amidate it to form glutamine for 
return to the neuron. This process, known as the glutamate:glutamine cycle, requires de novo 
glutamate synthesis to maintain sufficient presynaptic releasable neurotransmitter pools.  If 
this process continued unabated, it would lead to a net transfer of nitrogen from astrocytes to 
neurons.  Nature prevents this by shuttling BCAA’s in the opposite direction (i.e., from the 
neuron to the astrocyte).  Due to the intrinsic role for BCAA’s in glutamate and subsequent 
GABA (the major inhibitory neurotransmitter in the mammalian CNS) synthesis, and the 
interrelationship between the glutamate:glutamine cycle and the presumed BCAA-
dependent astroglial:neuronal nitrogen shuttle, changes in these three specific amino acids 
likely contribute to post-traumatic alterations in both hippocampal excitability and cognitive 
performance. 
2.6 
Compliance Statement 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia (CHOP) Research Policies and Procedures and all applicable federal and state 
laws and regulations. The investigators will perform the study in accordance with this 


 
 
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protocol, will obtain consent and assent, and will report unanticipated problems involving 
risks to subjects or others in accordance with CHOP’s Institutional Review Board (IRB) 
Policies and Procedures and all federal requirements. Collection, recording, and reporting of 
data will be accurate and will ensure the privacy, health, and welfare of research subjects 
during and after the study.  


 
 
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3 
STUDY OBJECTIVES 
The purpose of this study is to determine whether dietary administration of BCAA’s shows 
evidence of improving the recovery of neurocognitive symptoms after concussion injury, 
and to determine which of several doses of dietary BCAA’s shows the highest promise of 
efficacy. 
3.1 
Primary Objective 
The primary objective of this study is to determine whether, compared to placebo treatment, 
administration of BCAA’s, at one or more doses, after a concussion improves processing 
speed recovery at one or more time-periods post concussion.  In the event that differences 
are observed, we will determine whether differences in processing speed between BCAA-
treated and placebo-treated groups reflect differences in the maximum level of impairment 
and/or increases in the subsequent speed of improvement. 
3.2 
Secondary Objectives 
The secondary objectives are to: 
• Determine whether administration of BCAA’s improves neurocognitive recovery 
compared to placebo for the cognitive domains of attention, learning, and working 
memory, and if so determine whether the results reflect differences in maximum levels 
of impairment or increases in subsequent speed of improvement. 
• Evaluate whether BCAA supplementation improves clinical symptom resolution. 
• Determine whether BCAA supplementation reduces the time to return to normal 
activities, specifically school or work, and participation in sports. 
• Assess dose-related compliance of subjects with daily self-administration of BCAA’s 
and with completion of study endpoints. 
• Assess feasibility of enrolling potential subjects within 72 hours of concussion injury. 
• Assess safety of BCAA supplementation in concussed patients. 


 
 
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4 
INVESTIGATIONAL PLAN 
4.1 
General Schema of Study Design 
The proposed study is a therapeutic exploratory clinical trial that will evaluate the effects of 
BCAA’s on the magnitude and recovery of neurocognitive deficits following concussion 
injury. 
4.1.1 Screening Phase 
Physicians and advanced practice providers who have experience in diagnosing concussion, 
will identify potential subjects.  The investigators and co-investigators will inform the 
groups of physicians who will be referring patients to the study (e.g. CHOP and Penn Sports 
Medicine, CHOP and HUP Emergency Medicine) about the study procedures and their role 
in referring patients via email and presentations at local conferences.  For these groups of 
physicians, the diagnosis of concussion is informed by the commonly published guidelines 
for the diagnosis of concussion.  The most widely used is the Consensus Statement on 
Concussion in Sport: The 5th International Conference on Concussion in Sport, Berlin, 
October 2016.46  Others societies and professional organizations including the American 
Academy of Neurology, American Academy of Pediatrics, and the American Medical 
Society for Sports Medicine have publications which contain similar diagnostic guidelines.  
A potential subject is a patient who has had a concussion, as diagnosed by a physician, 
within the prior 72 hours, is between the ages of 11 and 34, and, in the opinion of the 
physician, has capacity to consent to participate in the study.  Verification of the diagnosis 
of concussion will be made by obtaining written documentation from the referring physician 
or advanced practice provider.  This documentation may come in several forms including a 
copy of a clinic note, a copy of an ED or hospital note, summary statement or discharge 
document, or an email sent directly from the physician confirming the diagnosis. This 
documentation will be reviewed by a physician from the study staff to confirm that the 
patient was diagnosed by a qualified physician or advanced practice provider to have a 
concussion. The source document and documentation of the PI’s review and confirmation of 
the diagnosis will be maintained in the subject’s file.  
Potentially eligible subjects will be referred to the study coordinator and subsequently 
screened by a study staff member using the protocol inclusion and exclusion criteria during 
an in-person interview.  Post-menarchal females will have a urine pregnancy test performed, 
or documented as negative within 72 hours prior to enrollment.  Informed consent and, if 
applicable, parental/guardian consent and child assent, will be obtained prior to any study 
related procedures being performed.  If enrolled, subjects will be randomized to receive one 
of four different dose levels of BCAA’s or placebo.  
4.1.2 Study Treatment Phase 
Subjects enrolled in the trial will be randomized to receive either oral BCAA’s at doses of 
7.5, 15, 22.5, or 27 g BID or an oral placebo BID for a total of 21 days. Subjects will 
complete five on-line computerized assessments daily: 
 
1. Axon Sports Computerized Cognitive Assessment Tool 
2. Clinical symptom checklists (Appendix 1) 


 
 
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3. Cognitive and physical activity assessments (Appendix 2) 
4. Sleep assessment (Appendix 3) 
5. Drug accountability assessment (Appendix 4) 
 
Subjects will wear an actigraphy monitor for the duration of the trial to assess sleep patterns.  
Computerized Dynamic Posturography may be conducted at 3 time points (days 0-4, 5-9, 
and 12-16) during the study treatment phase. 
4.2 
Allocation to Treatment Groups and Blinding 
The study biostatistician, Dr. Putt, will generate a randomization schedule for 
implementation in the randomization module of the study database system. The 
randomization scheme will be based on an equal allocation of each of the possible doses or 
placebo, and stratified based on sex.  The randomization schedule is uploaded into the data 
management system (DMS) and provided to the Investigational Drug Service (IDS).  The 
IDS will use the randomization schedule to prepare kits of BCAA doses or placebo for 
distribution.  Upon confirmation of eligibility, the DMS will provide study personnel with a 
number that is then given to the IDS and corresponds to the kit number to be distributed.  All 
study team members will be blinded to treatment assignment. The Database Administrator 
will have access to the link between the kit number and the treatment arm and will provide 
this information to the Investigational Drug Service (IDS) so that kits are prepared according 
to this scheme. BCAA and placebo treatment kits will appear identical. 
4.3 
Study Duration, Enrollment and Number of Sites 
4.3.1 Duration of Study Participation 
The study duration per subject will be up to 22 days, with up to 1 day screening and up to 21 
days in the treatment phase.  
4.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted through the Children’s Hospital of Philadelphia and the 
Hospital of the University of Pennsylvania.  Recruitment will stop when 50 subjects who are 
evaluable for efficacy are enrolled. A subject who is evaluable for efficacy is one who 
completes the study up until at least day 10 of the study. It is expected that approximately 72 
subjects will be enrolled to produce 50 such subjects.  All subjects who enroll and receive 
study medication will be evaluable for safety.  
4.4 
Study Population 
4.4.1 Inclusion Criteria 
1) 
Males and females, ages 11 - 34 years, of any race.  
2) 
Weight at least 40kg. 
3) 
Subjects who had a concussion, as diagnosed by a qualified physician or advanced 
practice provider, within the 72 hours prior to enrollment.   
4) 
Ability to have daily email and internet access. 


 
 
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5) 
Post-menarchal females must have a negative urine pregnancy test and must use an 
acceptable method of contraception including abstinence, a barrier method (diaphragm 
or condom), Depo-Provera, or an oral contraceptive for the duration of the study. 
6) 
Subjects must, in the opinion of the referring physician, have the capacity to provide 
informed consent, defined by: 1) the ability to communicate; 2) the ability to assess 
their understanding of the treatment; 3) the ability to understand the risks and benefits 
of the treatment; and 4) the ability to understand the risks and benefits of not 
embarking on the treatment. 
7) 
Informed consent by the subject, or for subjects <18 years old both informed consent 
by a parent/guardian and child assent. 
4.4.2 Exclusion Criteria 
1) 
Witnessed seizure at the time of injury or penetrating head injury. 
2) 
Prior concussion or TBI within 90 days.   
3) 
Concussion or TBI severe enough to require admission to an intensive care unit for 
observation or intervention, specifically for the traumatic brain injury.   
4) 
Previous history of TBI or concussion requiring admission to the hospital, disabling 
stroke, epilepsy, brain tumor, neurodegenerative condition, or psychiatric disease. 
5) 
Subjects taking neurological or psychoactive medications as a regular daily 
prescription medication (e.g. stimulants, antidepressants, anticonvulsants, 
benzodiazepines, etc.). 
6) 
Known history of maple syrup urine disease or known family history of maple syrup 
urine disease.  
7) 
Any investigational drug use within 30 days prior to enrollment. 
8) 
Allergy to FD&C Red #40 (red dye 40) or Sucralose. 
9) 
Lactating females.  
10) Parents/guardians or subjects who, in the opinion of the investigators, may be non-
compliant with study schedules or procedures. 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  


 
 
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5 
STUDY PROCEDURES 
5.1 
Screening Visit 
• Informed consent 
• Review of inclusion and exclusion criteria 
• Urine pregnancy test (for post-menarchal females only) 
5.2 
Study Treatment Phase 
At the start of the treatment phase at Visit 1, the study coordinator or study staff member 
will obtain demographic information, a concussion history and measure height and weight.  
The study drug will be dispensed in 42 bottles at the time of enrollment.  The assessments 
during the study treatment phase will be web-based and completed daily through the study 
website:   
 
 
1. Axon Sports Computerized Cognitive Assessment Tool 
2. Clinical symptom checklists (Appendix 1) 
3. Cognitive and physical activity assessments (Appendix 2) 
4. Sleep assessment (Appendix 3) 
5. Drug accountability assessment (Appendix 4) 
 
Subjects will wear an actigraphy monitor for the duration of the trial to assess sleep patterns.  
Subjects will have the option to complete computerized dynamic posturography (CDP) 
measured on visits 1, 2, and 3, which correspond to study, days 0-4, 5-9 and 12-16.  If 
enrollment occurs on a Saturday or Sunday, CDP can be conducted the following Monday or 
Tuesday.  The actigraph monitor will be downloaded during the CDP visits, and after being 
returned at the conclusion of the study (Visit 4, Days 22-24).  Subjects will be screened for 
drug accountability via a urine assay on visits 2 and 3, which correspond to study days 5-9 
and 12-16. 
We recognize that the data collection we are requesting of subjects may be onerous, and 
return visits for study procedures are a significant burden for subjects. Early subject 
recruitment has demonstrated issues with consistent compliance with study procedures.  
Therefore, we will institute graduated rewards for continued participation during the study.  
Using a token economics approach, study subjects will be rewarded by text- or email-based 
reinforcement for each data entry completed, including visual representations of compliance 
to serve as reminders/motivators for sustained compliance.52-55  These will graphically 
and/or by text show how close they are to meeting the 3-day-in-a-row and 7-day-in-a-row 
endpoints, which will have associated monetary incentives (see subject payment section). 
 
Visit 
Purpose 
Main Procedures 
Duration 
Visit 1, Day 0 
Screening 
 
Informed consent 
Review inclusion/exclusion criteria 
Urine pregnancy test (post-menarchal 
women only) 
15 minutes 
Visit 1, Day 0 
Orientation 
Start Study Drug 
Orientation to study & study website 
Demographics & concussion history 
Baseline compliance urine test 
2 hours 


 
 
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Computerized balance testing (optional)* 
Distribute actigraphy sleep monitor 
Distribute study drug 
Days 0-21 
Daily 
assessments via 
study website 
Computerized cognitive testing 
Clinical symptom checklists  
Cognitive & physical activity assessments  
Sleep assessment 
15 minutes 
Visit 2, Day 5-9 
Routine Visit 
Computerized balance testing (Optional) 
Compliance urine test 
20 minutes 
Visit 3, Day 12-16 
Routine Visit 
Computerized balance testing (Optional) 
Compliance urine test 
20 minutes 
Visit 4, Day 22-24 
End of Study 
Return used and unused drug bottles 
Return actigraphy monitor 
10 minutes 
* - If enrollment occurs on a Saturday or Sunday, balance testing can be conducted the following Monday or Tuesday. 
 
5.3 
Unscheduled Visits 
The study coordinator and investigators will be available to address any concerns or 
questions that may arise during the study.  Any medically related questions will be referred 
to their primary treating physician.  
5.4 
Prior and Concomitant Medications 
All medications used within 7 days prior to the screening visit and through the end of the 
study will be recorded.  The dates of administration and reason for use will be included.  
Participation in the study will not preclude subjects from receiving symptomatic 
management for concussion related symptoms (e.g. non-steroidal anti-inflammatory drugs 
for headaches) or other disorders.  However subjects will be discontinued from the study if 
they use neurological or psychoactive medications (e.g. stimulants, antidepressants, 
anticonvulsants, benzodiazepines, etc.) during the study.  While subjects will be prohibited 
from using dietary supplements during the study, there will be no dietary restrictions.  
5.5 
Rescue Medication Administration 
Subjects who experience side effects from the study medication, to a level that the subject 
requests medication to manage these symptoms, will be discontinued from the study.  
5.6 
Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may be discontinued from the study at the discretion of the investigators for safety concerns 
related to any adverse event.  Any subject who sustains a second concussion during the 
study period will be withdrawn.  Additionally, any female subject who becomes pregnant 
while enrolled in the study will be withdrawn. Date of termination will be documented for 
each subject.  


 
 
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5.7 
Early Termination Study Visit 
The study coordinator will contact subjects who terminate early and request that they return 
all of the study drug bottles (used and unused). 


 
 
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6 
STUDY EVALUATIONS AND MEASUREMENTS 
6.1 
Screening and Monitoring Evaluations and Measurements 
6.1.1 Demographics 
• Demographic characteristics will be obtained via interview: date of birth, gender, 
ethnicity, racial background, native language, handedness, and highest educational 
level attained. 
6.1.2 Concussion History 
• Concussion history will be obtained via interview: number of times diagnosed with a 
concussion and date of last concussion. 
• History of current concussion obtained from the subject and family members, if 
necessary, via interview including: mechanism of injury, for sports-related 
concussions: sport and position and specific mechanism (head-to-head, head-to-
ground, hit-to-body, etc), day and time of the injury, was the subject helmeted, 
presence and duration of loss of consciousness.  The subject may bring a clinic note 
from their referring physician and refer to it for answers to these questions if they are 
unsure or sustained amnesia from their concussion.  For CHOP patients, data may be 
collected directly from the medical record of their CHOP visits if subjects/parents 
are unable to provide. 
6.1.3 Height and weight 
Height and weight will be measured, or taken from the most recent visit documentation if 
visit was within 1 week of enrollment. 
6.1.4 Laboratory Evaluations 
6.1.4.1 Pregnancy Testing 
A urine pregnancy test will be performed through the Translational Core Laboratories for all 
post-menarchal female subjects.  Results will be available to the study coordinator and 
investigators in less than 5 minutes. If the study team is unable to access Translational Core 
Laboratories and/or it is not possible to obtain pregnancy test results within 5 minutes, the 
pregnancy test will be done by the enrolling study team member. The enrolling study team 
member must have documented training to do the pregnancy test. If a pregnancy test was 
performed by a medical facility within 72 hours prior to enrollment, and documentation can 
be provided or found in the CHOP medical record, then a second pregnancy test will not be 
required. Pregnant subjects will be excluded from the trial. Should a subject become 
pregnant while enrolled in the study, they will be withdrawn.  
6.2 
Efficacy Evaluations 
6.2.1 Axon Sports Computerized Cognitive Assessment Tool (CCAT) 
The Axon Sports CCAT will be completed daily over an 8-10 minute period using any 
computer with internet access.  The CCAT consists of four computerized cognitive tests, 


 
 
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derived from theoretical and developmentally sensitive principles and aims to be sensitive to 
any cause of cognitive performance change in individuals over time. The tasks themselves 
measure processing speed (via a simple reaction time task), attention (via a choice reaction 
time task), learning (via a one card learning task), and working memory (via a one-back 
task).  All of the four tasks are based on a ‘playing-card’ paradigm. Within each of the 
playing-card tasks, participants are shown a picture of a playing card and asked to answer a 
question about the card. Different tests are created by changing the question. For example, in 
the attention test the question ‘Is the card red?’ elicits a simple binary choice and is 
equivalent to a choice reaction time test. The question ‘Is the card exactly the same as the 
previous card?’ is used in the working memory paradigm to produce a 1-back version of the 
commonly used n-back working memory paradigm. In all tasks, responses are indicated by 
pressing the ‘YES’ or ‘NO’ buttons on a computer keyboard. Subjects will be reminded to 
choose an environment with minimal distractions for completing the cognitive battery.  
Subjects will complete a single short practice session, as previous research has demonstrated 
that a single practice test is sufficient to eliminate the majority of practice effects.  
6.2.2 Clinical Symptoms Checklists 
A 9 item clinical symptom checklist, designed to measure the overall duration and severity 
of concussion-related symptoms, will be administered daily over a 1-2 minute period via the 
study website. This summative 7-point Likert-type scale instrument incorporates aspects of 
the two scales commonly used in the literature (Post-concussion Symptom Scale [included 
in the Sport Concussion Assessment Tool 2 (SCAT2)] and Graded Symptom Checklist) to 
capture the overall severity of symptoms. The checklist will be administered twice: first to 
address the duration and second the severity of symptoms including headache, nausea, 
balance problems, sleeping more than usual, drowsiness, fatigue, feeling “slowed down” or 
“in a fog”, and difficulty concentrating.   
6.2.3 Cognitive and Physical Activity Assessments 
Subjects will be asked daily to indicate their level of cognitive and physical activity via the 
study website.  The physical activities are based on the “Graduated Return to Play” protocol 
recommended in the Consensus Statement on Concussion in Sport.  The cognitive activities 
are based on return to school guidelines used at CHOP. 
6.2.4 Actigraphy Sleep and Assessment  
Subjects will complete a daily brief questionnaire on their sleep via the study website and 
will be asked to wear an actigraphy monitor throughout the trial on the non-dominant wrist, 
with the exception of bathing or swimming.  Actigraphy has been shown to provide a valid 
estimate of sleep patterns in children and adolescents.  An actigraph is a non-invasive small, 
wristwatch sized activity monitor that provides an estimate of sleep patterns based on data 
collected by an internal accelerometer, and can record and store the data over an extended 
period of time.  The data are collected continuously and then translated into epochs 
(typically 30 sec or 1 min) of activity.  Using validated algorithms, epochs are then scored as 
sleep or wake.  Subjects will be instructed to push the event button on the device each time 
they go to bed, get out of bed, take the watch off or put the watch back on if not permitted in 


 
 
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an academic or athletic event.  The study coordinator will download the data from the 
actigraph device onto a study computer at each study visit and the conclusion of the study. 
The actigraph monitor used in this study is called the ActiSleep+ Monitor and is produced 
by the ActiGraph Company from Pensacola, FL.  This product is approved for marketing in 
the US and is an FDA cleared Class II medical device within the US (see attached material).  
This product is currently deployed in other concussion research studies at CHOP.  
6.2.5 Computerized Dynamic Posturography (CDP) 
Computerized dynamic posturography (CDP) will be measured over a 15 minute period at 
visits 1, 2, and 3 at The Balance Center at the Hospital of the University of Pennsylvania. 
CDP is a postural control test utilized to assess function balance ability.45  The Sensory 
Organization Test of CDP evaluates a person’s ability to effectively utilize the visual, 
somatosensory, and vestibular systems for the maintenance of balance.  It also provides 
information regarding the patient’s ability to maintain balance in the presence of inaccurate 
visual information that can confuse orientation.  The motor control test measures, time to 
respond to a disruption of equilibrium.  Testing is performed by standing a subject on a 
computerized support surface to measure their ability to sustain upright stance while the 
support surface and/or visual surround move in response to their own postural movements.  
Six sensory conditions are performed to assess ability to use visual, proprioceptive, and 
vestibular information in isolation and in concert for the preservation of balance.  Medium 
and large forward translations for each leg will be recorded for the motor control test.  
CDP will be performed on an EquiTest® system (manufactured by NeuroCom®, a division 
of Natus®) which is an FDA approved product.  CDP will be conducted by a trained 
audiologist A report will be issued to the investigators who will subsequently input the 
results into the study database. 
Balance testing is now available at CHOP, as of fall 2017, and if equivalence can be 
determined between the results gathered at HUP and CHOP and access can be gained to this 
equipment/lab then CHOP will also be added as a potential site for balance testing of 
subjects. 
6.3 
Safety Evaluation 
Subject safety will be monitored by tracking AE’s.  See Section 8.1 for details. 


 
 
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7 
STATISTICAL CONSIDERATIONS 
7.1 
Primary Endpoints 
We hypothesize that neurocognitive function in concussed subjects will initially worsen and 
then improve in a non-linear fashion over the course of the study, and that, compared to the 
placebo group, one or more of the BCAA dose level groups will show a reduced nadir in 
cognitive performance and/or a more rapid recovery.  Currently, the time course of the 
worsening and improvement of neurocognitive function after concussion is not well 
understood.  Thus, part of our study will aim to identify times when maximal differences 
between groups may be observed. The primary analysis in this exploratory study will 
consider three key time periods, Days 3-6, 7-10 and 11-14 when we expect differences in 
processing speed between the BCAA-treated groups and placebo to be largest. 
7.2 
Secondary Endpoints 
• Repeated measurements of neurocognitive functioning (CCAT test of attention, 
learning, and working memory) sampled over a period of 21 days. 
• Clinical symptoms. 
• Time to return to school/work, and sports participation. 
• Tolerability of BCAA’s based on AE’s. 
• Compliance. 
• Safety and incidence of AE’s and serious adverse events (SAE’s). 
7.3 
Statistical Methods 
7.3.1 Baseline Data  
The characteristics of the dose and placebo groups will be described using standard statistics 
(e.g. means, medians, standard deviations, or proportions).  For all analyses, high dose group 
will continue to be evaluated together, despite slight change in concentration.  Subgroup 
analysis will be done to evaluate any differences in those subjects who received the full 60 
g/d dosing before this dose was decreased, versus the current 54 g/d dosing. Graphical 
procedures will be used to assess distributional assumptions and particularly the assumption 
of normality of outcome.  
7.3.2 Primary Efficacy Analysis 
The primary intent to treat analysis will include all subjects who enroll and contribute at 
least 10 days of data to the study. The mean trajectory in decline and recovery in processing 
speed is unknown. Thus the primary analysis will aim to determine whether there are 
differences in processing speed between the BCAA dose groups and placebo, and if so, at 
what time periods the differences are most pronounced. The primary analysis will focus on 
results for the first 10 days of the study when we anticipate that the majority of subjects will 
be highly compliant. We will model processing speed as a function of dose and day of study 
and will allow differences between dose groups to vary as a function of time through a series 
of interaction terms.  To ensure that the number of interaction terms does not become too 
large, we will consider groups of two to four time points, looking specifically at whether 


 
 
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there are differences between any of the dose groups and placebo at Days 1-2, 3-6, 7-10, 11-
14, 15-18, 19-21. The primary analysis will consider three key time periods, Days 3-6, 7-10 
and 11-14 when we expect differences in processing speed between the BCAA-treated 
groups and placebo to be largest. Since processing speed differs with age, the model will be 
adjusted for age to account for any imbalances in age between dose groups. A mixed effects 
model will be used to account for correlations between repeated measurements on individual 
subjects. Likelihood ratio tests will be employed to specifically test whether there are 
differences in mean processing speed between placebo and any of the BCAA doses at the 
three key time periods. These three global tests will be conducted at a family-wise error rate 
of 0.05, using a Bonferroni correction to account for the three individual global tests. If 
statistical significance is achieved for the global test, we will then compare individual dose 
levels to placebo within time periods, again using a correction for four multiple tests per key 
time period.  
We note that with five treatment groups and 21 time points, there are a very large number of 
possible hypothesis tests that can be carried out with these data. If all of these tests were 
carried out without adjusting for multiple comparisons, we would undoubtedly find spurious 
associations. On the other hand, adjusting for large numbers of multiple comparisons 
substantially reduces the statistical power of a study. By focusing our testing for the primary 
efficacy analysis on three key periods where we adjust for a limited number of tests, we 
balance the need for a rigorous statistical testing procedure with a need to maintain 
statistical power. 
An analysis of the Day 1-2, 15-18 and 19-21 data will follow the same format, but will be 
considered secondary and will not be formally corrected for multiple testing. In addition to 
hypothesis testing, we will estimate and plot means and confidence intervals for each group 
at each time point.  This analysis will guide the recommendation for dose levels and 
evaluation times for the primary analysis in future efficacy studies.  
With concerted efforts from our study coordinators and study staff we are hopeful that we 
can maintain excellent compliance throughout the study. In particular we expect good 
compliance early in the study when patients are highly motivated to feel better and return to 
school, work and play. However, we allow that some patients may have difficulty with 
compliance due to their injury, or become non-compliant once their symptoms improve. As 
part of this feasibility study, we will explore patterns of missing data, in particular how they 
may relate to the observed response (e.g. more missing data in those subjects who show 
better or worse processing speed) to compliance (e.g. more missing data in subjects who 
regularly fail to consume their supplements) and to demographics e.g. gender, age.  This 
information will be valuable in planning future efficacy trials, and will guide our efforts to 
adjust for missing data.  For example if the probability of missing data is associated with 
outcome, then non-ignorable missing data methods will be needed, whereas missing at 
random assumptions will be valid if the missing data can be explained by covariate 
information. 
In addition to the primary analysis, this feasibility study will consider several approaches to 
modeling a smooth function for the trajectories of the individual processing speeds.  The 
first model will fit non-linear curves to the trajectory of processing speed for the dose groups 


 
 
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and then compare the mean curve for the BCAA dose groups to the placebo group, using an 
interaction term that allows differences between groups to vary over time. The basis for this 
model will be a smoothing spline. This first model assumes that the trajectories are smooth 
over time, albeit somewhat different between groups. We will carry out a hypothesis test of 
the difference between the groups using a likelihood ratio test for models with and without 
terms for the treatment effect and treatment by time interactions.  A second model 
conceptualizes an initial increase in processing speed followed by a period of gradual 
improvement and by a transition where processing speed plateaus.  This transition is of 
interest as we hypothesize that it represents the time when processing speed has returned to 
baseline. Here we anticipate a model using a quadratic with a change-point,47,48 with 
separate baseline functions for the dose and placebo groups and separate change-points.  
Correlation between repeated measurements on the same individual over time will be 
modeled using random effects i.e., a mixed effects model will also be used for these 
analyses.  
7.3.3 Analysis of Secondary Endpoints 
Secondary endpoints, including clinical symptoms such as the posturography and sleep 
assessments, and the learning, attention and working memory components of the 
neurocognitive battery will be modeled using a similar approach as described above for the 
primary efficacy analysis (Section 7.3.2), with the goal of assessing differences between 
groups over time, after adjustment for age differences. We will assess the distribution of the 
outcome and either use a transformation to achieve approximate normality or use a 
generalized mixed effects model. Time to event outcomes (e.g. time to return to school or 
sports participation) will be modeled using a Cox proportional hazards model. We will 
secondarily adjust our primary models for body mass index (BMI) and compliance to obtain 
information on whether individuals with lower BMI, and presumably higher BCAA/kg 
dosing have better outcome.  
We will also monitor compliance including adherence to treatment and daily completion of 
neurocognitive testing.  It is of interest to determine whether there are differences in 
compliance among the dosage groups versus placebo whether compliance decreases as a 
function of time, and whether compliance differs among groups over time. Adherence to 
treatment is measured in terms of number of bottles of consumed per day (0, 1, or 2) and 
will be modeled as an ordinal outcome. Adherence to treatment will be assessed using 
generalized estimating equations (GEE) models as we have repeated measures on adherence 
for each subject across all time points in the study and are primarily interested in differences 
between groups. In particular we anticipate that with regular prompting and encouragement, 
subjects will consistently complete their neurocognitive functioning tests up until about 10 
to 14 days into the study. We anticipate that compliance may begin to decrease around the 
10 to 14 day point as subjects begin to feel better and return to their normal routines. 
Assessment of compliance will be key information needed to design the anticipated pivotal 
trial of subsequent research studies.  


 
 
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7.3.4 Safety Analysis 
All subjects enrolled into the study, who receive study medication, are evaluable for safety. 
The frequencies of AEs by type, body system, severity, patient BMI, and relationship to 
study drug will be summarized. SAEs (if any) will be described in detail.  AE incidence will 
be summarized by dose and placebo along with the corresponding exact binomial 95% two-
sided confidence intervals. 
7.4 
Sample Size and Power 
The primary analysis of the processing speed data is broadly based, reflecting the fact that 
that this is a feasibility study in which we have limited knowledge regarding the temporal 
patterns of decline and recovery in human neurocognitive functioning following concussion. 
We hypothesize that BCAA-treated groups will differ from placebo at specific time periods. 
The power calculation is based on comparisons of each dose group to placebo at each of the 
key time periods. These time periods each encompass three daily measurements per subject. 
With 10 subjects per dose group, and three repeated measurements per subject we have 80% 
power to detect mean differences in processing speeds between the BCAA group and the 
placebo group on the order of 0.122 seconds. Putting this in the context of a mean 
processing speed for healthy individuals of ages 14 to 34 of 2.46 to 2.51 seconds (Axon 
Sports unpublished), means that detectable differences between groups are on the order of 
5% of the mean of a healthy individual. The analysis is based on a standard deviation in 
healthy individuals of 0.08, which we inflated to 0.10 based on our experience with injured 
or sick subjects, where variances are generally larger than their healthy counterparts. The 
intra-class correlation coefficient was set to 0.5. The calculation assumes a two-sided 
family-wise Type I error rate of 0.05 and uses a Bonferroni correction with four contrasts for 
each time period. The overall sample size is thus 50 subjects. We will consider a subject 
who contributes data up until and including at least Day 10 to be “evaluable for efficacy.” 
We conservatively anticipate that no more than 72 subjects will be enrolled in order to 
achieve 50 evaluable subjects.  We anticipate that it will take us approximately 12-18 
months to recruit these subjects.   
 


 
 
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8 
STUDY MEDICATION 
8.1 
Description 
The three BCAA’s, valine, isoleucine, and leucine, will be dissolved in water and combined 
with sodium gluconate, Tropical Punch Kool-Aid® powder, and sucralose to improve 
palatability.   
8.1.1 Packaging 
Study product will be packaged by the Investigational Drug Service (IDS) at the Hospital of 
the University of Pennsylvania (HUP) into 20 oz bottles containing 591 mL of blinded doses 
active drink (containing valine, isoleucine and leucine) or matching placebo (similar in 
appearance and taste but absent the three amino acids).  Each bottle will be individually 
labeled and sealed with a tamper-evident cap, then packaged in corrugated cartons (with a 
carry handle) in sets of 14 (representing a one-week supply). 
8.1.2 Labeling 
Study product will carry labeling that clearly identifies the study, treatment code and 
directions, as well as the statement ‘Caution: For Investigational Use Only’.  Each label will 
identify the study day (Day 1, Day 2, etc.) and the labels will be color coded for MORNING 
dose (yellow) and EVENING dose (blue).  A detailed label on the outside of the carton will 
identify the subject, date, prescriber, emergency phone number, study, federal caution 
statement (noted above) and detailed directions for use.  A smaller removable label, will be 
placed on the carton and will be peeled off and pasted into the subject’s study records at the 
time of dispense, as a clear record of which kit was issued to which subject. 
8.1.3 Dosing 
Four different doses of BCAA’s will be used in this study, 15, 30, 45, and 54 grams per day 
(divided BID).  Originally, 60 grams per day (divided BID) was used as the highest dose, 
however during the study precipitation issues were noted at the highest ratio due to leucine 
precipitating at a lower concentration than expected in to the presence of the other solutes. 
After further testing, it was determined that the product remained in solution at a 
concentration of 27g/591ml bottle and therefore, the highest dose level was altered to 54 
grams per day. For each dose, the three BCAA’s - valine, isoleucine and leucine - will be 
combined together in a 1:1:1 ratio and dissolved in 591 ml (20 ounces) of water (see table 
below).  Additionally, 13 g sodium gluconate, 1.75 g unsweetened Tropical Punch Kool-Aid 
powder, and 9 g sucralose are added to the mixture to improve palatability.  This mixture 
will be administered twice daily.   
BCAA 27 g/bottle 
Valine 9 g 
Leucine 9 g 
Isoleucine 9 g 
Sodium Gluconate 13 g 
Unsweetened flavoring 
1.75 g 
Sucralose 9 g 
BCAA 22.5 g/bottle 
Valine 7.5 g 
Leucine 7.5 g  
Isoleucine 7.5 g 
Sodium Gluconate 13 g 
Unsweetened flavoring 
1.75 g 
Sucralose 9 g 
BCAA 15 g/bottle 
Valine 5 g  
Leucine 5 g  
Isoleucine 5 g  
Sodium Gluconate 13 g 
Unsweetened flavoring 
1.75 g 
Sucralose 9 g 
BCAA 7.5 g/bottle 
Valine 2.5 g 
Leucine 2.5 g  
Isoleucine 2.5 g 
Sodium Gluconate 13 g 
Unsweetened flavoring 
1.75 g 
Sucralose 9 g 


 
 
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QS to 591 mL 
QS to 591 mL 
QS to 591 mL 
QS to 591 mL 
 
The solution may be chilled or at room temperature, and should be shaken prior to 
consumption.  The bottles may not be frozen or heated.  Subjects are instructed to consume 
exactly 2 bottles in a 24-hour period.  The recommended time between the two daily doses is 
6 hours. The exact time given to consume a given bottle is not prescribed, although less than 
60 minutes is recommended.  If less than 2 bottles are consumed in a 24-hour period, the 
subject is instructed not to complete the remainder of the solution the following day and 
proceed to the bottles scheduled for that day.  A study member is available 24 hours per day, 
7 days per week by email and cell phone to answer dosing and other administrative 
questions. 
The placebo solution will contain 1.2 g sucrose octaacetate (NF grade) and 30 g of 
microcrystalline cellulose (NF grade) dissolved in 591 ml of water.  Additionally, 13 g 
sodium gluconate, 1.75 g unsweetened Tropical Punch Kool-Aid powder, and 9 g sucralose 
are added to the solution.  This will ensure that the placebo solution has similar taste, 
texture, consistency and appearance as the BCAA solution. 
BCAA’s will be supplied by Spectrum Chemical and Laboratory Products.  All ingredients 
in both BCAA and placebo solutions are USP/NF grade (see attached material). 
8.1.4 Treatment Compliance and Adherence 
Each day, subjects will self-report the number of bottles of the study medication that were 
consumed the prior day.  Subjects will return all used, partially used, and unopened 
medication bottles at the conclusion of the study.   
The study supplement will contain 500 mg/bottle of deuterium oxide that can be detected in 
the urine using isotope ratio mass spectrometry.  Deuterium oxide has been used to assess 
drug compliance in both adult and pediatric research studies.49-51  Urine samples will be 
collected from all subjects for a baseline measure of deuterium oxide on Day 0 and then 
again on days 7 and 14 of the trial to assess adherence.  These samples will be frozen and 
stored in the laboratory of Dr. Cohen.  Isotope ratio mass spectrometry will be conducted by 
the CHOP Metabolomics Core facility in a batched fashion at several points throughout the 
study.  Deuterium oxide will be supplied by Cambridge Isotope Laboratories and is of 
suitable quality for use in human subjects (see attached material). 
To assist with treatment compliance, subjects will be sent text, email or in-app alert 
messages twice a day to remind subjects to consume their study drink, and to reward them 
for compliance if they have documented consuming their drink. 
 
8.1.5 Drug Accountability 
Adequate records of study drug receipt and disposition will be maintained by the IDS 
Pharmacy at HUP.  Records of receipts, investigational drug orders, dispensing records, and 


 
 
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disposition forms will be examined during the course of the study.  The IDS at HUP will 
prepare treatment kits in advance of enrollment for rapid distribution when a subject enrolls. 
The purpose of these records is to ensure regulatory authorities and the trial sponsor, the 
Dana Foundation, that the investigational new drug will not be distributed to any person who 
is not a study subject under the terms and conditions set forth in this protocol.  The study 
medication is to be prescribed by the investigator or designee and may not be used for any 
purpose other than that described in this protocol.  At study completion, all study products 
including partially used and empty containers will be destroyed on-site by the IDS Pharmacy 
and complete documentation will be maintained, with copies given to the 
investigator/sponsor. 
 


 
 
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9 
SAFETY MANAGEMENT 
9.1 
Clinical Adverse Events 
Clinical AE’s will be monitored throughout the study.  
The study coordinator will ask the subject about the occurrence of any AE’s during the 
scheduled study visits conducted on days 7, 14, and 22 and during unscheduled visits. A 
standardized question will be asked of every subject to inquire about illnesses or accidents 
since the previous reporting period. The study coordinator will collect complete information 
about AE’s from subjects including: 
• 
Descriptive text and key words of the event 
• 
Assessment of the event severity (grade)  
• 
Indication if the event is serious and type  
• 
Relationship to study drug 
• 
Start date and end date (if applicable) 
The investigators, with input from the independent medical monitor, will evaluate all AE’s 
to determine the relationship to the study drug.  All recorded AE’s will be followed until 
resolution or stabilization. An AE Log will be used to collect this information across study 
visits and prompt follow-up of previously reported events.  
Additionally, at the final study visit, subjects will be asked to call the study coordinator and 
report any serious AE’s that they experience following the last visit, and that they believe 
may be related to their treatment.   
9.2 
Adverse Event Reporting 
The investigator is responsible for recording and reporting unanticipated problems related to 
research that occurs during and after study treatment. All on-site SAEs (CHOP or related 
sites) will be reported to the IRB in accordance with CHOP IRB policies. AE’s that are not 
serious will be summarized in narrative or other format and submitted to the IRB at the time 
of continuing review.  Since this is an FDA regulated study, Dr. Cohen (IND Sponsor) will 
monitor AEs and report them to the FDA. 
9.3 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a subject who has received an intervention 
(drug, biologic, or other intervention). An AE is any unfavorable or unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
All AE’s (including SAE’s) will be noted in the study records and on the case report form 
with a full description including the nature, date and time of onset, determination of non-
serious versus serious, intensity (mild, moderate, severe), duration, causality, and outcome 
of the event. 


 
 
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9.4 
Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
• Death, 
• A life-threatening event (at risk of death at the time of the event),  
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• A persistent or significant disability/incapacity 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AE’s.  A severe AE is a major 
event of its type.  A severe AE does not necessarily need to be considered serious.  For 
example, nausea that persists for several hours may be considered severe nausea, but would 
not be an SAE.  On the other hand, a stroke that results in only a limited degree of disability 
may be considered a mild stroke, but would be an SAE.  
9.4.1 Relationship of Serious Adverse Events to Study Drug or Other Intervention 
The relationship of each SAE to the study intervention will be characterized using one of the 
following terms: definitely, probably, possibly, unlikely, or unrelated.  
9.5 
IRB/IEC Notification of Serious Adverse Events and Other Unanticipated 
Problems 
The investigator will promptly notify the IRB of all on-site unanticipated, SAE’s that are 
related to the research activity. Other unanticipated problems related to the research 
involving risk to subjects or others will also be reported promptly to the IRB. Written 
reports will be filed using the eIRB system and in accordance with the timeline below. 
External SAE’s that are both unexpected and related to the study intervention will be 
reported promptly after the investigator receives the report. 
Type of Unanticipated Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems Related 
to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important AEs 
may be reported at time of 
continuing review 


 
 
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9.5.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. The investigator is responsible for ensuring that all SAE’s are 
followed until either resolved or stable.  
9.6 
Investigator Reporting of a Serious Adverse Event to Sponsor 
Reporting will be consistent with regulatory and sponsor requirements. 
9.7 
Medical Emergencies 
If a medical emergency occurs during the screening process, the subject will immediately be 
referred to the CHOP or HUP emergency department.  If the study coordinator or 
investigators learns of a medical emergency while communicating with a subject who is not 
on-site, the subject will immediately be referred to a local hospital emergency department.  


 
 
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10 STUDY ADMINISTRATION 
10.1 Treatment Assignment Methods 
10.1.1 Randomization 
The study biostatistician, Dr. Putt, will generate a randomization schedule that will be 
implemented in the randomization module of the study database system. The randomization 
scheme will be based on equal allocation of BCAA’s to placebo and stratified based on sex. 
Upon confirmation of eligibility in the DMS, the randomization module will be programmed 
to generate a randomization number that corresponds to a unique kit number of BCAA or 
placebo treatment. This kit number will be used to distribute treatment. 
10.1.2 Blinding 
All primary study team members will be blinded to treatment arm. The Database 
Administrator will have access to the information that links the kit number to the treatment 
arm. He/she will provide this information to the Investigational Drug Service (IDS) so that 
kits are prepared according to this scheme. BCAA and placebo treatment kits will appear 
identical. They will be labeled with the following information: 
1. 
Kit number 
2. 
Study name and number 
3. 
Bottle # X of 42. 
4. 
Subject ID # [blank line to record this number] 
10.1.3 Unblinding 
Unblinding can occur if the PI instructs the IDS to reveal this information.  A direct request 
from the PI to IDS must be documented. 
10.2 Data Collection and Management 
Procedures to assure confidentiality will be strictly observed.  All identifiable personal 
health information (PHI) data will be 1) kept in confidential locked files; 2) identified by 
subject number only; and 3) kept separately from identifying information used for subject 
tracking and follow-up contact. Identifying information will be kept in separate locked files. 
No identifying information will be disclosed in reports, publications, or presentations. 
Protection of subjects depends on the joint activities of all clinical staff as well as the 
database administrative team. Extensive efforts will be made to ensure that subjects’ 
confidentiality is maintained. Each subject will be assigned a unique study identification 
number and is never tracked through the study by name, medical record number, or any 
other personal identifier. A log of the subject names, ID numbers, and pertinent registration 
information (e.g., home address, telephone number, and emergency contact information) is 
maintained in a separate, locked area at the clinical site. The database administrative staff 
will not have access to this information. Only the subject ID number and date of birth are 
given to the database administrative staff and registered in the study database. Any 
communication between the database administrative staff and investigators regarding subject 


 
 
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data will occur via the subject ID number. Any forms or documents sent to the IRB or other 
regulatory authorities will have all personal information removed.  
Study data will be entered into a web based data management system (DMS).  This DMS 
uses a secure connection between the client browser at the clinical site and the web server at 
the Penn Clinical Research Computing Unit (CRCU).  Data transmitted over this connection 
is authenticated by the use of digital certificates and is encrypted as it travels the internet to 
the CRCU.  Data is being gathered and stored through the CRCU because the expertise of 
the CRCU staff was required to construct the secure website subjects will access to complete 
daily assessments and to build the DMS on an Oracle platform so it can communicate in a 
subject-specific manner directly and securely with the Axon Sports system.  The Oracle 
development tools integrate seamlessly with the DMS to allow a full range of programming 
functionality which allow us to: 1) capture data from remote locations over the internet 
using secure connections, 2) incorporate data quality checks at entry and after entry using 
simple or complex rule sets as needed, 3) assign specific privileges for users to reflect their 
role and needs on the project, to provide an electronic audit trail of all data changes, 4) 
incorporate and enforce workflow logic where appropriate, 5) integrate with external data 
and software systems, and 6) provide secure and convenient access to data for authorized 
study personnel.  Using this platform, the DMS automatically transmits a subject’s ID 
number and date of birth to the Axon Sports system.  The Axon Sports system then securely 
sends coded data to the DMS where it is stored.  At no point is PHI except date of birth (for 
the purposes of computing a participant’s age) collected by the Axon Sports system or 
stored in the DMS.  The Axon Sports system does not have direct access to the DMS.  All 
information transmitted between the Axon Sports system and the DMS is coded solely by 
subject ID number.   
The DMS will be designed to prevent unauthorized access to trial data and to prevent data 
loss due to equipment failure or catastrophic events. The procedures to do so encompass 
user account management, user privilege assignment, data loss prevention (database 
backup), computer systems validation, performance monitoring, and the DMS change 
management. User access will be controlled by assignment of confidential usernames, 
passwords, and role assignment. The system will meet the applicable Federal regulatory 
requirements and those described in the E6 Good Clinical Practice Guidelines to ensure the 
confidentiality of trial subjects.  
CRCU data networks comprise a set of physical data networks all linked in a point-to-point 
configuration to form a single logical data network.  The network is protected through the 
use of several Juniper® firewall devices.  These devices perform as firewalls and logging 
devices for data network traffic, as Intrusion Detection to alarm information technology 
personnel to possible network attack scenarios, and as an email spam filter and eliminator. 
Security requirements at the computer systems’ level start with separation of duties with the 
system administrators.  Administrators each are assigned specific accounts that dictate what 
services they have access to.  All accounts are individually assigned and logged, regardless 
of access level.   The systems are configured to vendor specification with the published 
operating system releases and published patches, before connected to any data network.  
Once configured, the systems operating system is imaged and TripWire® software is loaded 


 
 
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to ensure all system and operating files maintain their current configurations.  Any changes 
to the recorded and monitored files results in an alert being sent to the responsible 
administrator. 
All users of the database applications have unique and permanent user identifications 
assigned to them for use to gain access to the systems and to the appropriate databases.  
Passwords are aged and also restricted so good password creation and usage are enforced.  
Users are trained on log-in procedures and also application usage.  A support helpdesk is 
maintained during normal business hours to ensure problems are quickly discovered and 
resolved for the users. 
The data is stored in several disk storage subsystems that are backed up and stored off site, 
depending on the critical nature of the data. Standard operating procedures are in place to 
provide business continuity, disaster recovery, and file restoration.  All hardware/system 
software components are covered by vendor supported maintenance contracts with a 4-hour 
or less turn-around on parts and assistance. 
Computer system security will be enhanced for the applications through the use of the 
Oracle database repositories.  Users of the applications will not be allowed to log into any of 
the project servers directly.  All users of the project will only log into specific applications 
where access is controlled and limited. 
10.3 Confidentiality 
Patient confidentiality will be maintained at all times and study information will be 
protected against release to unauthorized people. All data and records generated during this 
study will be kept confidential in accordance with institutional policies and the Health 
Insurance Portability and Accountability Act (HIPAA) on subject privacy.  The investigator 
and all other personnel will not use such data and records for any purpose other than 
conducting the study. Subjects will be assigned study numbers for entry into the protocol; 
this number alone will identify them. Subjects are free to refuse participation in the study 
and can withdraw at any time without compromising clinical care.  The investigator will 
obtain a data use agreement between the provider (the PI) of the data and any recipient 
researchers (including others at CHOP) before sharing a limited dataset (PHI limited to dates 
and zip codes).  
10.4 Regulatory and Ethical Considerations 
10.4.1 Data and Safety Monitoring Plan 
Rebecca Ichord MD, an experienced neurologist, will act as the independent Medical 
Monitor for adverse events during this study.  Dr. Ichord has served in prior and ongoing 
clinical trials as endpoint adjudicator and was on the Clinical Event Committee for the 
pediatric EXCOR Berlin heart trial.  She is presently a member of the endpoint adjudication 
committee for the Thrombolysis in Pediatric Stroke trial.  The Medical Monitor will review 
all acute AE’s regardless of how the investigator reports the relationship between the event 
and the study intervention. All patient deaths will be similarly reviewed.  The study will also 
undergo monitoring by the CHOP Office of Research Compliance and Regulatory Affairs 


 
 
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after each subject for the next six subjects enrolled and then at least annually throughout the 
duration of the study. 
10.4.2 Risk Assessment 
Risks for this study are a minor increase above minimal.  Subject safety will be monitored 
by AE’s on a weekly basis.  Expected adverse experiences during this study may include 
gastrointestinal symptoms such as dyspepsia either from the BCAA’s themselves or the 20 
ounces of fluid consumed.  Prior studies have shown that these symptoms when related to 
BCAA’s are mild and transient.   An informal inquiry of athletes (both male and female) 
from many sports indicated that drinking 20 ounces of fluid twice daily is not burdensome 
and within the volume typically consumed while training or competing.  Should a subject 
report new onset gastrointestinal symptoms while on therapy, the subject will be monitored 
to see if these symptoms either have an alternative explanation (e.g. development of acute 
gastroenteritis from an identifiable source) or spontaneously resolve in less than 24 hours.  
The study therapy will not be held unless these symptoms persist for more than 24 hours or 
are severe enough to require medical attention.  In this case the subject will be removed 
from the study and the therapy not restarted.  Taking the CCAT or CDP may temporarily 
exacerbate concussion symptoms, which typically resolve after a short period of rest.  
Neurological and psychiatric symptoms induced by changes in neurotransmitters like 
serotonin, dopamine, norepinephrine are theoretically possible with BCAA therapy but have 
never been observed clinically.  Emergence of any of these symptoms will result in 
discontinuation of the subject’s participation in the study.  BCAA therapy will be 
discontinued for any SAE related to its use.  
10.4.3 Potential Benefits of Trial Participation 
By taking BCAA supplementation subjects may accelerate the recovery of cognitive 
symptoms after concussion injury.  Successful development of this compound may modify 
clinical protocols for treating concussion and other types of TBI.  
10.4.4 Risk-Benefit Assessment 
Although this study involves more than minimal risk (i.e. administration of a test substance), 
there is the potential for benefit directly or through new knowledge.  We believe that the risk 
to benefit ratio is favorable and the risks are reasonable in relation to the potential benefit 
and new broadly applicable knowledge. 
10.5 Recruitment Strategy 
Physicians with experience in diagnosing patients with concussion, will identify potential 
subjects and refer them to the study coordinator for participation in the study.  These 
providers typically see patients within a few days of their suspected concussion.  
Recruitment will primarily occur through CHOP Sports Medicine, the CHOP Emergency 
Department, University of Pennsylvania Sports Medicine, the Hospital of University of 
Pennsylvania (HUP) Emergency Department, and Penn Presbyterian Medical Center 
Emergency Department (Presby ED).   


 
 
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For CHOP Sports Medicine, providers will identify potential subjects and with subject’s 
permission, the provider will contact the study coordinator with the subject’s contact 
information.  Physicians in the CHOP Emergency Department will identify potential 
subjects for this study. Once a patient has been diagnosed by an ED physician with a 
concussion, a referral will be made to the study coordinator and a HIT-HEADS Study 
informational sheet will be provided to the patient. The study coordinator will arrange to 
complete the remainder of the screening process in a designated office or clinical exam after 
discharge from the ED.  
For Penn Sports medicine, providers will identify potential subjects and with the subject’s 
permission, the provider will contact the study coordinator with the subject’s contact 
information. 
Providers in the HUP ED, and Presby ED may also identify potential subjects for this study.  
They will provide a HIT-HEADS informational sheet to a patient once they have been 
diagnosed with a concussion.  The patient will then contact the study coordinator if they are 
interested in study participation.  Providers from these entities will not collect or transmit 
patient information to the study coordinator.  Once the study coordinator has made contact 
with a potential subject, he or she will make arrangements with the potential subject to 
complete the remainder of the screening process in a designated office or clinical exam 
room. 
Subjects may self-refer to the study. Informational flyers will also be displayed and 
distributed in University of Pennsylvania campus, including student gathering places, locker 
rooms, training facilities and sports medicine clinics to inform subjects about the study.  
Patients greater than 10 years of age that had a sports physical in the last year will be 
contacted and will receive an informational flyer, a letter from the PI, and a business card in 
the mail.  Those patients that selected to receive CHOP emails will also receive an email 
from the PI. 
Marianne Chilutti, Department of Biomedical and Health Informatics (DBHi) will query the 
CHOP EPIC system for patients, ages 11 - 34 years, who, in the previous 24 hours, have 
been diagnosed with a concussion (ICD-9-CM codes 850, 850.0, 850.1, 850.10, 850.11, 
850.5, 850.9) or made a call to the triage nurse after business hours with the complaint of a 
concussion .  The search will be limited by those departments listed above. The report will 
be run daily and the results emailed to the study team.  A medical record review using the 
EPIC database will be conducted by the study team to determine which patients are eligible 
for contact about the study.  Specifically, the medical record will be searched for the manner 
and time of the concussion to determine which patients are eligible for contact.  A study 
team member will then contact potential subjects via phone to provide information about the 
study. 
High school administrative and athletic personnel from the school districts in the greater 
Philadelphia area will be given information about the study through informational fliers. 
Additional information about how to refer concussed players to the study will be 
communicated to nurses, coaches and team medical staff if the school is interested in 
participation. As with recruitment from other domains, potential subjects will be required to 


 
 
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contact the study coordinator directly and the diagnosis of concussion will be confirmed by 
a physician prior to enrollment. 
Upon approval from high school administrative personnel, a member of the study team will 
attend back to school night to distribute approved study materials including flyers and 
business cards.  Approval will be documented in the form of a letter/email of confirmation 
from a high school administrator. 
The UNTOLD Foundation will display the approved flyer on the organization’s homepage, 
http://www.theuntoldfoundation.org/. 
The Recruitment Enhancement Core (REC) may provide assistance with recruitment plan 
development and may assist in identifying and contacting potential participants using the 
CRU, the CHOP Recruitment Registry, social media and internal communication resources. 
The REC also may engage community partners and facilitate outreach on behalf of the 
Research Institute and this CHOP research study. 
10.6 Informed Consent/Assent and HIPAA Authorization 
Informed consent is an ongoing process that takes place between the investigator/study staff 
and study participants. The PI or their designee (physician co-investigators) will obtain 
informed consent for this research study.  The consent process will occur in a designated 
office or clinical exam room at CHOP or Penn. It is the responsibility of the PI to ensure that 
informed consent has been properly obtained.  The consent will include use of the 
information obtained during the clinical battery before enrollment and all data obtained after 
enrollment.  Subjects may take any additional time needed to review the consent document, 
however, initiating the trial may not begin more than 72 hours after the time of injury.  Adult 
subjects age ≥18 will sign the Informed Consent after full review and verbalized 
understanding of the protocol. If the subject is a <18 years old, enrollment will require both 
parental permission and subject assent.  
10.7 Payment to Subjects/Families 
Subjects will receive a possible total of $100 for participation in this study.  Amount 
received will depend on compliance with study procedures and will be offered in a 
graduated schema to encourage ongoing participation.56  Payment will be placed on a 
reloadable CHOP-issued card and money added throughout the study.  Subjects will receive 
$20 on the card at the time of visit 1.  Each day that they input all required study data will 
add $1, with a bonus of $2 each time 3 days in a row are met and $5 each time 7 days in a 
row are met, for a possible total of $50 if all 21 days of data are entered completely.  $10 
will be added for each in-person research visit that they attend (possible total of $30 for 3 
visits)..  
10.7.1 Reimbursement for travel, parking and meals 
Subjects who park at a CHOP facility that requires paid parking for any of their 4 research 
visits will receive parking vouchers.  
 


 
 
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11 PUBLICATION 
The principal investigator and co-investigators will prepare the data for publication.   
 
 


 
 
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22. Als-Nielsen B, Koretz RL, Kjaergard LL, Gluud C. Branched-chain amino acids for hepatic 
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25. Gijsman HJ, Scarna A, Harmer CJ, et al. A dose-finding study on the effects of branch chain amino acids 
on surrogate markers of brain dopamine function. Psychopharmacology (Berl) 2002;160:192-197. 
26. Tsubuku S, Hatayama K, Katsumata T, et al. Thirteen-week oral toxicity study of branched-chain amino 
acids in rats. Int J Toxicol 2004;23:119-126. 
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32. Collie A, Maruff P, Makdissi M, McCrory P, McStephen M, Darby DG. CogSport: Reliability and 
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33. Falleti MG, Maruff P, Collie A, Darby DG. Practice effects associated with the repeated assessment of 
cognitive function using the CogState battery at 10-minute, one week and one month test-retest intervals. 
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34. Falleti MG, Maruff P, Collie A, Darby DG, McStephen M. Qualitative similarities in cognitive 
impairment associated with 24 h of sustained wakefulness and a blood alcohol concentration of 0.05%. J 
Sleep Res 2003;12:265-274. 
35. Fredrickson J, Maruff P, Woodward M, et al. Evaluation of the usability of a brief computerized 
cognitive screening test in older people for epidemiological studies. Neuroepidemiology 2010;34:65-75. 
36. Maruff P, Falleti MG, Collie A, Darby D, McStephen M. Fatigue-related impairment in the speed, 
accuracy and variability of psychomotor performance: comparison with blood alcohol levels. J Sleep Res 
2005;14:21-27. 
37. Mollica CM, Maruff P, Collie A, Vance A. Repeated assessment of cognition in children and the 
measurement of performance change. Neuropsychol Dev Cogn C Child Neuropsychol 2005;11:303-310. 
38. McKay J, Betts J, Maruff P, Anderson V. An examination of developmental trajectories for attention 
skills in children. The Australian Educational and Developmental Psychologist 2011;27:76-89. 
39. Betts J, McKay J, Maruff P, Anderson V. The development of sustained attention in children: the effect 
of age and task load. Child Neuropsychol 2006;12:205-221. 
40. Straume-Naesheim TM, Andersen TE, Bahr R. Reproducibility of computer based neuropsychological 
testing among Norwegian elite football players. Br J Sports Med 2005;39 Suppl 1:i64-69. 
41. Makdissi M, Collie A, Maruff P, et al. Computerised cognitive assessment of concussed Australian Rules 
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42. Makdissi M, Collie A, Maruff P, McCrory P, Brukner P, Bennell K. Does baseline neuropsychological 
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43. Collie A, Makdissi M, Maruff P, Bennell K, Brukner P, McCrory P. Post-concussion cognitive function 
in symptomatic and asymptomatic athletes.  Second International Conference on Concussion in Sport; 
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44. Piland SG, Motl RW, Guskiewicz KM, McCrea M, Ferrara MS. Structural validity of a self-report 
concussion-related symptom scale. Med Sci Sports Exerc 2006;38:27-32. 
45. Cohen HS, Kimball KT. Usefulness of some current balance tests for identifying individuals with 
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45. McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 5th 
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Medicine 2017;51(11):found at http://bjsm.bmj.com/content/51/11/838. Last accessed December 7, 2017. 
46. Pauler DK, Laird NM. A mixture model for longitudinal data with application to assessment of 
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47. Hall CB, Lipton RB, Sliwinski M, Stewart WF. A change point model for estimating the onset of 
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48. Rodewald LE, Pichichero ME. Compliance with antibiotic therapy: a comparison of deuterium oxide 
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50. Fusch C, Moeller H. Measurement of D2O concentrations at tracer levels in small samples obtained from 
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56.   Haff N, Patel MS, Lim R, Zhu J, Troxel AB, Asch DA, Volpp KG. The role of behavioral economic 
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13 APPENDICES 
13.1 APPENDIX 1: Clinical Symptom Checklist 
 
 
 
 


 
 
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13.2 APPENDIX 2: Physical and Cognitive Activity Assessments 
Please indicate your level of cognitive activity in the past day [insert date]: 
1. Cognitive Activity: 
q0 Complete cognitive rest 
 
q1 Not attending school/work, but doing light cognitive activity, (e.g. 
watching TV, pleasure reading or using the Internet) 
 
q2 Not attending school/work, but doing moderate cognitive activity, (e.g. 
homework, academic reading, school/work-related computer use) 
 
q3 Attending school/work with decreased workload (e.g. not taking exams, 
taking a reduced number of courses) 
 
q4 Full unrestricted participation in school/work including all exams, 
assignments, and homework 
 
Please indicate your level of physical activity in the past day [insert date]: 
2. Physical Activity: 
q0 Complete physical rest 
 
q1 Light aerobic activity (e.g. walking, swimming or stationary cycling) 
 
q2 Moderate non-contact exercise (e.g. running, skating drills in hockey, 
running drills in soccer or football) 
 
q3 Complex activity or drills involving partial participation (e.g. passing or 
shooting drills in sports, partial participation in gym class or exercise 
classes) 
 
q4 Complex activity or drills with full participation (e.g. full contact 
practice, normal training activities, full participation in gym class or exercise 
classes) 
 
q5 Normal activity level without limitation, including normal game or 
scrimmage play 
 
 
 
 


 
 
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13.3 APPENDIX 3: Sleep Assessment 
 
 
 
 
 


 
 
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13.4 APPENDIX 4: Drug accountability assessment 
 
 

ICF_001.pdf: 
CHOP IRB#: IRB 13-010227
Effective Date: 12/21/2020
Expiration Date: 12/20/2021 
Page 1 of 12
Informed Consent Form and HIPAA Authorization
Study Title: 
HIT HEADS Trial: Head Injury Treatment with Healthy and 
Advanced Dietary Supplements: A randomized, placebo-controlled, 
double-blinded, therapeutic exploratory clinical trial of dietary 
supplements in the treatment of concussion
Version Date:  
June 17, 2019 V.09
Principal Investigator:
Dr. Sage Myers
  Telephone: (267) 436-7939
Emergency Contacts:
Dr. Sage Myers
Telephone: (203) 907-8589
You, or your child, may be eligible to take part in a research study. This form gives you 
important information about the study. It describes the purpose of this research study, and 
the risks and possible benefits of participating. 
If there is anything in this form you do not understand, please ask questions. Please take 
your time. You do not have to take part in this study if you do not want to. If you do 
decide to take part, you can leave the study at any time. 
In the sections that follow, the word “we” means the study doctor and other research 
staff. If you are a parent or legal guardian who is giving permission for a child, please 
note that the word “you” refers to your child.
Why are you being asked to take part in this study?
You are being asked to take part in this research study because you have been diagnosed 
with a concussion within the past three days.  There are several inclusion and exclusion 
criteria for this study which will be reviewed with you by a study team member.  If you 
do not meet these criteria you will not be allowed to continue with this study.
What is the purpose of this research study? 
The purpose of this research study is to study the effects of dietary supplements on the 
recovery from a concussion injury.  A concussion is a type of traumatic brain injury 
(TBI), caused by a bump, blow, or jolt to the head that can change the way your brain 
normally works. It is common to experience symptoms after concussion such as having 
difficulty thinking clearly, feeling slowed down, or having difficulty concentrating or 
remembering new information. Some people also have symptoms like headache, feeling 
off balance, irritability and difficulty sleeping.  Recent research in mice has shown that 
taking these dietary supplements after a concussion injury can reduce the amount of time 
to recover from a concussion injury.  The purpose of this study is to measure the recovery 


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Expiration Date: 12/20/2021 
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of patients after a concussion injury, and to see whether dietary supplements may speed 
the recovery.
The study drug, which is often used as a dietary supplement, has been used in over 100 
scientific studies over the past several decades to treat thousands of patients with a 
multitude of medical conditions.  They are generally regarded as safe and well tolerated.  
The US Food and Drug Administration (FDA) has given their approval for these 
supplements to be studied in people with concussions.  However, the study drug being 
used in this study is not approved by the FDA.  The use of the study drug is considered 
“investigational.” 
How many people will take part?
About 70 subjects will take part in this study.
What is involved in the study?
As a participant in this study, you will be asked to drink 20 ounces or 2.5 cups of a 
flavored liquid twice per day for 21 days.  Not everyone will receive the study drug.  
Some people will get a drink called a “placebo” which looks and tastes the same as the 
drink with the study drug but doesn’t contain the drug in it.  There are four different 
concentrations of the study drug being evaluated, thus you have a four out of five chance 
of getting a beverage that includes some concentration of the study drug, and a one in 
five chance of getting a beverage that is essentially flavored water.  Whether you receive 
the study drug or the flavored water will be decided at random.  
There are no dietary restrictions while participating in this trial.  However, you cannot 
take any dietary supplements (e.g. protein powder, whey powder, amino acids, etc.) 
during the 3 weeks of this study.
In addition to the drink, you will be asked to take around 10-15 minutes each day to 
complete a web-based program to measure how your brain is recovering from the 
concussion along with a web-based questionnaire to understand how you are feeling.  
Specifically, we will measure brain functions like processing speed, attention and 
memory, ask about symptoms like headache and tiredness, and ask about how much 
physical and brain-related activity you have done each day.  To understand how your 
sleep has been affected by the concussion, you will wear a motion monitor on your wrist 
during the study.  Lastly, to measure how your balance has been affected by the 
concussion, you may undergo balance testing three times during the study. 
How long will you be in this study?
If you agree to take part, your participation will last for 22 days. You will be required to 
complete a web-based program every day for the duration of the study that will take 
about 10-15 minutes.  There will be two additional in-person visits where you may have 
the option to complete dynamic balance testing. You will also be required to return the 
motion monitor and used, partially used, or empty dietary supplement bottles after the 
study is done on day 22.


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What are the study procedures? 
The study involves the following tests and procedures. 
Interview:  A team member will ask you about any prior concussions or traumatic brain 
injuries you have had and what the outcomes were.  The team member will gather 
details about your current concussion including the time of the concussion, the way 
that you were injured, whether you were wearing any protective equipment, and the 
mechanism of your concussion (i.e. head to head, foot to head, head to ground, head 
to object, blow to body, etc.).  
Physical Examination: You will have your weight and height measured. 
Pregnancy Test:  All post-menarchal women will be asked to take a urine pregnancy test 
before starting this study.  For children: the results will be shared with you and not 
with your parent(s).  We strongly encourage you to share the results with your 
parents.  If you are found to be pregnant, you will not be able to continue 
participation in the study. 
Administration of the study drug or placebo:  You will be asked to drink 20 ounces, 
which is equal to 2.5 cups or 590 milliliters of a flavored liquid twice per day for 21 
days.  There are four different concentrations of the study drug that are being tested 
in this study, in addition to a placebo that is essentially flavored water.  All 
concentrations of the study drug, as well as the placebo, will look and taste the 
same.  Whether you receive the study drug or placebo will be decided at random.  
Each bottle must be finished in no more than 60 minutes.  The recommended time 
between the two daily beverages is 6 hours, however, the minimum time between 
beverages is 2 hours.  You should not consume more than 2 of the beverages 
supplied by this study in a 24-hour period.  If a beverage is missed and you do not 
have time to drink another beverage the same day, then you should skip the 
beverage and begin your regular schedule again the following day.
Axon Sports Computerized Cognitive Assessment Tool (CCAT):  You will be asked to 
spend 8-10 minutes on tests designed to measure your brain function. These tests, 
called the CCAT, consist of 4 computerized tests which measure processing speed, 
attention, learning, and working memory.  All of the tests involve a card-playing 
game. You will be shown a picture of a playing card and asked to answer a question 
about the card. For each test you will respond by pressing the ‘YES’ or ‘NO’ 
buttons on a computer keyboard.  Different tests are created by changing the 
question.  The entire CCAT takes 8-10 minutes to complete and can be accessed 
from any computer with internet access.  We request that you choose a computer 
that is in a quiet, calm environment.  You will complete a single short practice 
session with the study coordinator so you will have the chance to practice the tests 
and ask any questions. The CCAT will be completed daily during the trial.
Clinical Symptom Checklist:  You will also be asked to take 1 or 2 minutes each day to 
complete a symptoms checklist via the study website. The checklist will be given 
twice, first to ask how long the symptoms affect you each day, and second to 
understand how bad the symptoms are. The symptoms are: headache, nausea, 


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balance problems, sleeping more than usual, drowsiness, fatigue, feeling “slowed 
down”, feeling like “in a fog”, and difficulty concentrating. 
Physical and Cognitive Activity Assessment:  You will be asked to spend no more than 1 
minute each day to tell us, via the study website, about your level of physical 
activity and brain activity.
Sleep Assessment and Motion:  You will be required to wear a motion monitor on your 
wrist for the duration of the study.  The motion monitor is a small non-invasive, 
wristwatch sized activity monitor.  The monitor will be worn at all times on your 
non-dominant wrist, with the exception of bathing or swimming.  You will be 
instructed to push a button on the device each time you go to bed, get out of bed, 
take the watch off or put the watch back on, and for any unusual events that occur. 
The device may also be removed if it is not permitted in an academic or athletic 
situation.  You will also take1-2 minutes each day to complete a questionnaire on 
your sleep via the study website.
Computerized Dynamic Balance Testing (Optional):  Computerized dynamic balance 
testing will be used to measure your ability to balance.  Testing is performed by 
standing on a computerized support surface to measure how well you sustain 
upright stance while the support surface and/or visual surround moves in response 
to your own postural movements. The evaluation takes about 15 minutes and can be 
conducted when you enroll, and on days 7 and 14 of the study. If you enroll on a 
Saturday or Sunday, you will have the option to complete the balance testing on a 
week day.
Supplement Accountability Assessment:  You will need to take the study dietary 
supplement by mouth twice a day for 21 days.  You will be asked daily on the study 
website to indicate whether or not you have taken the supplement.  Additionally, a 
small concentration of deuterium oxide or heavy water will be added to each bottle.  
This compound is not dangerous to your health in any way.  Your urine will be 
collected at the beginning of the study and then weekly to measure the 
concentration of this compound to determine how much of the study drug you have 
been taking.  Throughout the study you will be also asked to report if you think that 
anything bad has happened as a result of the study drug or the study. 
The study physicians will not be responsible for the medical management of your 
concussion or your routine medical care. They are available to answer general questions 
about concussion or concussion management. 


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Expiration Date: 12/20/2021 
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Visit Schedule
The table below provides a brief description of the purpose and duration of each part of 
the study.
Visit
Purpose
Main Procedures
Duration
Visit 1, Day 0
Screening
Informed consent
Review inclusion/exclusion criteria
Urine pregnancy test (post-menarchal 
females only)
15 minutes
Visit 1, Day 0
Orientation
Start Study Drug
Orientation to study & study website
Demographics & concussion history
Baseline compliance urine test
Computerized balance testing (optional)*
Distribute actigraphy sleep monitor
Distribute study drug
2 hours
Days 0-21
Daily assessments 
via study website
Computerized cognitive testing
Clinical symptom checklists 
Cognitive & physical activity assessments 
Sleep assessment
15 minutes
Visit 2, Day 5-9
Routine Visit
Computerized balance testing (Optional) 
Compliance urine test
20 minutes
Visit 3, Day 12-16
Routine Visit
Computerized balance testing (Optional) 
Compliance urine test
20 minutes
Visit 4, Day 22-24
End of Study
Return used and unused drug bottles 
Return actigraphy monitor
10 minutes
* - If enrollment occurs on a Saturday or Sunday, balance testing will be conducted the following Monday or Tuesday.
What are the risks of this study?
Taking part in a research study involves inconveniences and risks.  If you have any 
questions about any of the possible risks listed below, you should talk to your study 
doctor or your regular doctor. 
While in this study, you are at risk for the following side effects:
Risks associated with study dietary supplements:
•
Gastrointestinal symptoms such as an upset stomach, abdominal distention or 
bloating, diarrhea, or constipation.
•
Allergic reactions (e.g. rash, runny nose, watery eyes, or itching).
•
If you have maple syrup urine disease or family history of maple syrup urine 
disease should not participate in this study as the supplement can potentially be 
dangerous for individuals with this condition.
Risks associated with interview:


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•
There are no physical risks with the medical interview but you might 
experience momentary embarrassment or discomfort.  You do not have to 
answer any questions that make you too uncomfortable.
•
There are no risks to the physical exam.  Only your height and weight will be 
measured. You will not be required to remove your clothes.  
Risks associated with Axon Sports CCAT:
•
Performing the CCAT may make your concussion symptoms worse.  If this 
occurs, you may stop the program.  This will not result in your removal from 
the study.  We request that you attempt the CCAT each day. 
Risks associated with Clinical Symptoms Checklist and Physical and Cognitive 
Activity Assessments:
•
Performing the clinical symptom checklists and the physical and cognitive 
activity assessments may make your concussion symptoms worse temporarily. 
Risks associated with the Sleep and Motion Assessments:
•
Some individuals with sensitive skin may have irritation of their skin from the 
motion monitor strap.  You will be permitted to wear the motion monitor over 
long sleeves or a wristband.  You can remove the motion monitor at any time if 
it becomes uncomfortable or painful to wear.  
Risks associated with Computerized Dynamic Balance Testing
•
Balance testing may temporarily exacerbate your concussion symptoms, 
particularly feeling dizzy, being off balance or disoriented.  Since you are 
harnessed into the testing device, the risk of falling is minimal. 
Reproductive Risks
For female subjects:  If you are pregnant or nursing, you will not be allowed to 
participate in this study.  You should not become pregnant while in this study.  You will 
need to take safety measures to prevent pregnancy (such as not having sexual intercourse, 
or using a medically accepted form of contraception such as condoms or birth control 
pills) during the study.  If you have questions about how to avoid pregnancy, talk to your 
doctor or the researcher and they will provide you with information on contraceptive 
choices.  You should contact the study investigator at once if you become pregnant 
during this research study.
Are there any benefits to taking part in this study?
You might benefit by having symptoms of your concussion affect you less severely and 
or resolve more quickly.  However, we cannot guarantee or promise that you will receive 
any direct benefit by participating in this study.  The knowledge gained from this 
research may help doctors understand how the brain recovers from concussion injury, 
treat other individuals with concussions or traumatic brain injuries, and may help develop 
further treatments for concussion.


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Do you need to give your consent in order to participate? 
If you decide to participate in this study, you must sign this form.  A copy will be given 
to you to keep as a record.  Please consider the study time commitments and 
responsibilities as a research subject when making your decision about participating in 
this study.  You will need to follow the study doctor’s instructions, complete your web-
based assessments daily, and take the study dietary supplement as directed. 
What happens if you decide not to take part in this study? 
Participation in this study is voluntary. You do not have to take part in order to receive 
care at CHOP or Penn.  If you decide not take part or if you change your mind later there 
will be no penalties or loss of any benefits to which you are otherwise entitled. 
Can you stop your participation in the study early?
You can stop being in the study at any time.  You do not have to give a reason.
Can the study doctor take you out of the study early?
The study doctor may take you off of the study if:
•
Your condition worsens.
•
The study is stopped.
•
The dietary supplement is no longer available.
•
You cannot meet all the requirements of the study.
•
New information suggests taking part in the study may not be in your best 
interest.
What choices do you have other than this study?
There are options for you other than this study including:
•
Not participating in this study. 
•
You may discuss other options available to you with your doctor.
What about privacy, authorization for use of Personal Health Information (PHI) and 
confidentiality? 
As part of this research, health information about you will be collected.  This will include 
information about your medical history, as well as cognitive and symptom assessments. 
Laboratory test results will appear in your medical record.  We will do our best to keep 
your personal information private and confidential.  However, we cannot guarantee 
absolute confidentiality.  Your personal information may be disclosed if required by law. 
The results of this study may be shown at meetings and published in journals to inform 
other doctors and health professionals.  We will keep your identity private in any 
publication or presentation.


C H O P I R B #: I R B 1 3- 0 1 0 2 2 7
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E x pirati o n Date: 1 2/ 2 0/ 2 0 2 1 
Pa ge 8 of 1 2
Se veral pe o ple a n d or ga nizati o ns ma y re vie w or recei ve y o ur i de ntifia ble i nf or mati o n. 
T he y will nee d t his i nf or mati o n t o c o n d uct t he researc h, t o ass ure t he q ualit y of t he data, 
or t o a nal yze t he data or sa m ples. T hese gr o u ps i ncl u de: 
•
Me m bers of t he researc h tea m a n d ot her a ut h orize d pers o n nel at C H O P or 
Pe n n;
•
Pe o ple fr o m a ge ncies a n d or ga nizati o ns t hat perf or m i n de pe n de nt accre ditati o n 
a n d/ or o versi g ht of researc h; s uc h as t he U. S. De part me nt of Healt h a n d 
H u ma n Ser vices a n d t he Office f or H u ma n Researc h Pr otecti o ns;
•
Gr o u ps m o nit ori n g t he safet y of t his st u d y, i ncl u di n g t he Me dical M o nit or;
•
T he data base ma na ge me nt tea m at t he Pe n n Cli nical Researc h C o m p uti n g U nit 
will k n o w y o ur date of birt h, b ut n o ot her i de ntif yi n g i nf or mati o n;
•
A x o n S p orts will k n o w y o ur date of birt h, b ut n o ot her i de ntif yi n g i nf or mati o n 
 T he F o o d a n d Dr u g A d mi nistrati o n.
B y la w, C H O P is re q uire d t o pr otect y o ur healt h i nf or mati o n.  T he researc h staff will 
o nl y all o w access t o y o ur healt h i nf or mati o n t o t he gr o u ps liste d a b o ve.  B y si g ni n g t his 
d oc u me nt, y o u are a ut h orizi n g C H O P t o use a n d/ or release y o ur healt h i nf or mati o n f or 
t his researc h.  S o me of t he or ga nizati o ns liste d a b o ve ma y n ot be re q uire d t o pr otect y o ur 
i nf or mati o n u n der Fe deral pri vac y la ws.  If per mitte d b y la w, t he y ma y be all o we d t o 
s hare it wit h ot hers wit h o ut y o ur per missi o n.  
T here is n o set ti me f or destr o yi n g t he i nf or mati o n t hat will be c ollecte d f or t his st u d y. 
Y o ur per missi o n t o use a n d s hare t he i nf or mati o n a n d data fr o m t his st u d y will c o nti n ue 
u ntil t he researc h st u d y e n ds a n d will n ot e x pire.  Researc hers c o nti n ue t o a nal yze data 
f or ma n y years a n d it is n ot p ossi ble t o k n o w w he n t he y will be c o m pletel y d o ne. 
C a n y o u c h a n ge y o ur mi n d a b o ut t he use of pers o n al i nf or m ati o n ?
Y o u ma y c ha n ge y o ur mi n d a n d wit h dra w y o ur per missi o n t o use a n d discl ose y o ur 
healt h i nf or mati o n at a n y ti me. T o ta ke bac k y o ur per missi o n, it is preferre d t hat y o u 
i nf or m t he i n vesti gat or i n writi n g. 
Dr. Sa ge M yers
T he C hil dre n's H os pital of P hila del p hia
3 4 0 0 Ci vic Ce nter Bl v d
P hila del p hia, P A 1 9 1 0 4
I n t he letter, state t hat y o u c ha n ge d y o ur mi n d a n d d o n ot wa nt a n y m ore of y o ur healt h 
i nf or mati o n c ollecte d.  T he pers o nal i nf or mati o n t hat has bee n c ollecte d alrea d y will be 
use d if necessar y f or t he researc h.  N o ne w i nf or mati o n will be c ollecte d.  If y o u 
wit h dra w y o ur per missi o n t o use y o ur pers o nal healt h i nf or mati o n, y o u will be 
wit h dra w n fr o m t he st u d y.
A d diti o n al I nf or m ati o n
A me dical m o nit or, a n i n de pe n de nt p h ysicia n w h o is a n e x pert i n cli nical trials, will be 
re vie wi n g t he data fr o m t his researc h t hr o u g h o ut t he st u d y.  Y o u will be i nf or me d if 


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Expiration Date: 12/20/2021 
Page 9 of 12
changes to the study are needed to protect your health.  You will be told about any new 
information that could affect your willingness to stay in the study, such as new risks, 
benefits or alternative treatments. 
One of the Investigators on this study, Dr. Akiva Cohen, is the author of a “provisional 
application for patent” (35 U.S.C. §111(b)) pertaining to the study agent. Dr. Cohen may 
gain financial benefit from this technology if it is successful.
Financial Information 
While you are in this study, the cost of your usual medical care – procedures, medications 
and doctor visits – will continue to be billed to you or your insurance.
Will there be any additional costs? 
The Dana Foundation is providing financial support for this study and the following 
research procedures, study medication, and study visits: 
•
Cost of parking
•
Cost of study medication
•
Urine pregnancy test (post-menarchal females only)
•
Cost of study assessments including Axon Sports CCAT, Actigraphy, and 
Computerized Dynamic Posturography
Will you be paid for taking part in this study? 
•
You will be paid as an incentive for participation in this study.  At time of visit 
1, you will receive $20.You will also receive $1 for each day that you 
complete all study procedures (drink 2 drinks and complete online assessment), 
with an additional bonus of $2 if you complete 3 days in a row and $5 if you 
complete 7 days in a row.  You will be provided $10 for each in person 
assessment (for a possible total of $30 for 3 visits).  In total, if all study 
procedures are completed fully, you could be paid $100. All payments will be 
given via gift card. If you receive payment using a bankcard, the bank will 
have access to identifiable information. The bank will not have access to any 
medical information.   
•
If you drive to and park at CHOP for any visits, you will also receive a parking 
voucher.
Who is funding this research study?
The Dana Foundation is providing funding for this study. 
Please ask Dr. Myers if you have any questions about how this study is funded. 
What if you have questions about the study?
If you have questions about the study, call the study doctor, Dr. Myers at 267-426-7939.  
You may also talk to your own doctor if you have questions or concerns.


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The Institutional Review Board (IRB) at The Children’s Hospital of Philadelphia has 
reviewed and approved this study.  The IRB looks at research studies like these and 
makes sure research subjects’ rights and welfare are protected.  If you have questions 
about your rights or if you have a complaint, you can call the IRB Office at 215-5902830. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
What happens if you are injured during the study? 
If you are hurt or get sick from something that was done as part of this study, doctors at 
the clinic or hospital can arrange for emergency medical care.  The Hospital does not 
offer financial compensation or payment for injuries due to participation in this research. 
No funds have been set aside to compensate you in the event of injury. 
You and your insurance company will be billed for the costs of any care or injuries. 
If you think you have been injured from taking part in this study, call Dr. Myers at 267-
426-7939.  She can go over things with you, let you know of resources that may be 
available and give you information on what you need to do.
In case of injury resulting from this study, you will not lose any legal rights by signing 
this form.


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Consent to Take Part in this Research Study and Authorization to Use and Disclose Health 
Information for the Research
The research study and consent form have been explained to you by:
Person Obtaining Consent
Signature of Person Obtaining Consent
Date:
By signing this form, you are indicating that you have had your questions answered and 
agree to take part in this research study.  If your child is participating, you are indicating 
that you are legally authorized to consent to your child’s participation.  You are also 
agreeing to let CHOP and Penn use and share your health information or your child’s 
health information as explained above.  If you don’t agree to the collection, use and 
sharing of your health information or your child’s health information, your child cannot 
participate in this study. NOTE: A foster parent is not legally authorized to consent for a 
foster child’s participation.
Name of Subject
Signature of Subject (18 years or older)
Date
Name of Authorized Representative 
Relation to subject:
(if different than subject)
 Parent
 Legal Guardian
Signature of Authorized Representative
Date


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Child Assent to Take Part in this Research Study
For children capable of providing assent:
I have explained this study and the procedures involved to __________________ in 
terms he/she could understand and that he/she freely assented to take part in this study.
Person Obtaining Assent
Signature of Person Obtaining Assent
Date
This study has been explained to me and I agree to take part.
Signature of Subject (optional)
Date