Clinical trial NCT03345550
Conditions: Mild Traumatic Brain Injury
Sponsor: University of Michigan
Start date: 2017-09-12; Completion date: 2021-07-27
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, randomized controlled trial comparing the effect of omega-3 fatty acid versus placebo on blood biomarkers of brain injury, inflammation and neurogenesis.

Detailed description:
Primary brain injury, the initial physical injury to brain tissue post-trauma, responds only to measures that prevent TBI from occurring in the first place. However, secondary brain injury, a complex cascade of events causing additional brain injury following primary brain injury, is more amenable to pharmacologic treatment. Neuroinflammation is one of the recognized mechanisms of secondary brain injury. In response to primary brain injury, activated microglia and injured neurons both release signaling proteins including cytokines and chemokines. Ω-3 and ω-6 fatty acids are major components of immune cells and neuronal cell membranes. They are also precursors to neuromodulatory lipids such as eicodanoids, endovanilloids and endocannabinoids that have antinociceptive and anxiolytic properties. Docosahexaenoic acid (DHA) is one of the most abundant fatty acid components of brain cell membrane phospholipids. In rodent model studies, dietary supplementation with omega-3 fatty acids (eicosapentaenoic acid \[EPA\] and docosahexaenoic acid \[DHA\]) decreased secondary axonal injury, attenuated endoplasmic reticulum stress response, decreased neuroinflammation post-TBI, and improved short and long-term neurologic outcomes. Additionally, DHA supplementation post-TBI enhances neurogenesis by counteracting reductions in neuroplasticity biomarkers such as brain-derived neurotrophic factor. Furthermore, DHA deficient rodents are more likely to have a greater amount of axonal injury and slower recovery neurologic recovery post-TBI. To our knowledge there are no human studies examining the effect of omega-3 fatty acid supplementation post-TBI on functional, symptomatic and neurologic outcomes. However, a study of collegiate football players who were randomized to 2, 4 or 6g/day of DHA or placebo for a total of 189 days (including 80 pre-season days). Irrespective of the dose of DHA supplementation, those receiving DHA had lower values of serum neurofilament light chain, a biomarker of axonal injury, than those receiving placebo.

Arms: arm 1: Participants randomized to this study arm will receive 6g DHA+EPA for one month followed by 1.2 g DHA+EPA for two months. Capsules contain fish oil 1000 mg (contains 500 mg DHA \& 100 mg EPA) or placebo capsules. arm 2: Participants randomized to this study arm will receive placebo drug for 3 months.
Interventions: intervention 1: Omega-3 Polyunsaturated Fatty Acids (Fish Oil 1000 mg (contains 500 mg DHA & 100 mg EPA)) or placebo capsules. intervention 2: Placebo - Cap
Intervention descriptions: intervention 1: Participants will be randomized to receive fish oil 1000 mg (contains 500 mg DHA \& 100 mg EPA) or placebo capsules. intervention 2: Participants will be randomized to receive fish oil 1000 mg (contains 500 mg DHA \& 100 mg EPA) or placebo capsules (olive oil capsules that look identical to the intervention DHA+EPA).

Protocol documents:
Prot_SAP_000.pdf: 
 
Pilot Study of Omega-3 Polyunsaturated Fatty Acid 
Treatment in Mild Acute TBI (OPTIMA-TBI pilot). 
 
 
 
 
NCT03345550 
 
Date of Notification from IRB: January 29, 2018  
Date of IRB Approval: January 8, 2018 
 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
Version 2.000
Protocol HUM00129045 
06 July 2017
NIH-FDA Clinical Trial Protocol Template – v1.0 5 Apr 2017 
2
Pilot Study of Omega-3 Polyunsaturated Fatty Acid 
Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
Protocol Number: HUM00129045 
Principal Investigator: Frederick Korley, M.D., Ph.D. 
IND Sponsor: NA 
Funded by: No 
Version Number: 2.000 
06 July 2017 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
  
  
  
  
  
  
 
 
Table of Contents 
Statement of Compliance .............................................................................................................................................. 5 
1 Protocol Summary ...................................................................................................................................................... 6 
1.1 Synopsis ............................................................................................................................................................... 6 
1.2 Schema ................................................................................................................................................................ 8 
1.3 Schedule of Activities (SoA) ................................................................................................................................. 9 
2 Introduction .............................................................................................................................................................. 10 
2.1 Study Rationale .................................................................................................................................................. 10 
2.2 Background ........................................................................................................................................................ 10 
2.3 Risk/Benefit Assessment.................................................................................................................................... 10 
2.3.1 Known Potential Risks ................................................................................................................................. 10 
2.3.2 Known Potential Benefits ........................................................................................................................... 11 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................................... 11 
3 Objectives and Endpoints ......................................................................................................................................... 12 
4 Study Design ............................................................................................................................................................. 13 
4.1 Overall Design .................................................................................................................................................... 13 
4.2 Scientific Rationale for Study Design ................................................................................................................. 13 
4.3 Justification for Dose ......................................................................................................................................... 13 
4.4 End of Study Definition ...................................................................................................................................... 13 
5 Study Population ...................................................................................................................................................... 14 


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5.1 Inclusion Criteria ................................................................................................................................................ 14 
5.2 Exclusion Criteria ............................................................................................................................................... 14 
5.3 Screen Failures ................................................................................................................................................... 15 
5.4 Strategies for Recruitment and Retention ......................................................................................................... 15 
6 Study Intervention .................................................................................................................................................... 16 
6.1 Study Intervention(s) Administration ................................................................................................................ 16 
6.1.1 Study Intervention Description ................................................................................................................... 16 
6.1.2 Dosing and Administration ......................................................................................................................... 16 
6.2 Preparation/Handling/Storage/Accountability .................................................................................................. 16 
6.2.1 Acquisition and accountability .................................................................................................................... 16 
6.2.2 Formulation, Appearance, Packaging, and Labeling ................................................................................... 16 
6.2.3 Product Storage and Stability ..................................................................................................................... 16 
6.2.4 Preparation ................................................................................................................................................. 16 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 16 
6.4 Study Intervention Compliance ......................................................................................................................... 17 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................................. 18 
7.1 Discontinuation of Study Intervention .............................................................................................................. 18 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 18 
7.3 Lost to Follow-Up ............................................................................................................................................... 19 
8 Study Assessments and Procedures ......................................................................................................................... 20 
8.1 Efficacy Assessments ......................................................................................................................................... 20 
8.2 Safety and Other Assessments .......................................................................................................................... 20 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 21 
8.3.1     Definition of Adverse Events (AE) ........................................................................................................... 21 
8.3.2     Definition of Serious Adverse Events (SAE) ............................................................................................. 21 
8.3.3     Classification of an Adverse Event .......................................................................................................... 21 
8.3.4     Time Period and Frequency for Event Assessment and Follow-Up ........................................................ 22 
8.3.5     Serious Adverse Event Reporting ............................................................................................................ 23 
8.4 Unanticipated Problems .................................................................................................................................... 24 
8.4.1     Definition of Unanticipated Problems (UP) ............................................................................................. 24 
8.4.2      Unanticipated Problem Reporting ......................................................................................................... 24 
9 Statistical Considerations ......................................................................................................................................... 25 
9.1 Statistical Hypotheses ........................................................................................................................................ 25 
9.2 Sample Size Determination................................................................................................................................ 25 
9.3 Statistical Analyses............................................................................................................................................. 25 
9.4.1 General Approach ....................................................................................................................................... 25 
10 Supporting Documentation and Operational Considerations ................................................................................ 26 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 26 
10.1.1     Informed Consent Process .................................................................................................................... 26 
10.1.2     Study Discontinuation and Closure ....................................................................................................... 26 
10.1.3     Confidentiality and privacy ................................................................................................................... 27 
10.1.4     Future Use of Stored Specimens and Data ........................................................................................... 28 
10.1.5     Key Roles and Study Governance .......................................................................................................... 28 
10.1.8     Quality Assurance and Quality Control ................................................................................................. 28 
10.1.9     Data Handling and Record Keeping ....................................................................................................... 29 
10.1.10  Protocol Deviations ................................................................................................................................ 29 


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10.1.12  Conflict of Interest Policy ....................................................................................................................... 30 
10.2 Abbreviations ................................................................................................................................................... 30 
10.4 Protocol Amendment History .......................................................................................................................... 31 
11 References .............................................................................................................................................................. 32 
 
 
 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following: 
  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
 Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild 
Acute TBI (OPTIMA-TBI pilot). 
Study Description: 
 This is a double-blinded randomized control trials comparing the effect of 
omega-3 fatty acid versus placebo on blood biomarkers of brain injury, 
inflammation and neurogenesis. 
Objectives: 
Primary Objective: Biomaker endpoints include: neuronal injury measured 
by Neurofilament light chain (NFL), Neurogranin (NRGN) and Intercellular 
adhesion molecule 5 [ICAM5]; inflammation measured by high sensitivity 
C-reactive protein (CRP), IL-6 and IL-10 and neurogenesis measured by 
brain derived neurotrophic factor (BDNF) 
Secondary Objectives:  
1. Delayed functional recovery defined as Glasgow Outcome Scale 
Extended (GOSE)<8 at 3 months 
2. Moderate/severe post-concussive symptoms at 3 months defined as 
having at symptoms in at least three following ICD-10 symptom categories 
obtained from the Rivermead Post-Concussion Questionnaire (RPQ): (1) 
headaches, dizziness, general malaise, excessive fatigue, or noise 
intolerance; (2) irritability, emotional labiality, depression, or anxiety; (3) 
subjective complaints of concentration or memory difficulty; (4) insomnia; 
(5) reduced tolerance to alcohol; (6) preoccupation with these symptoms 
and fear of permanent brain damage.  
3. Cognitive impairment at 3 months is defined based on a battery of 13 
neurocognitive tests. Subjects are deemed cognitively impaired if their 
scores on at least 2 neurocognitive tests are more than 2 standard 
deviations below their IQ T-Score ascertained by the Wechsler Test of 
Adult Reading (WTAR). 
4. Serious adverse events (SAEs): Life-threatening bleed including upper GI 
bleed, intracranial hemorrhage; hypotension; severe allergic reaction, 
blood glucose and LDL cholesterol levels 
Endpoints: 
Primary Endpoint: Serum levels of neurofilament light chain, C-reactive 
protein, IL-6, IL-10, Brain derived neurotrophic factor over a 3-month 
period 
Secondary Endpoints: Functional recovery (measured by Glasgow Coma 
Scale Extended), symptomatic recovery (measured by the Rivermead Post-
concussive Symptoms Questionnaire) and cognitive impairment 
(measured by a cognitive battery) at 3 months post injury 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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Study Population: 
Individuals presenting to the emergency department (ED) within 7 days of 
injury, who meet the American Congress of Rehabilitation Medicine 
(ACRM)’s definition of having mild traumatic brain injury (mTBI) will be 
eligible. The ACRM defines mTBI as a traumatically-induced physiological 
disruption of brain function as a consequence of the head being struck, 
striking an object, or undergoing an acceleration/deceleration movement 
without direct external head trauma and resulting in at least one of the 
following: any period of loss of consciousness (LOC); any loss of memory 
for events immediately before or after the injury; any alteration in mental 
state at the time of the injury (eg, feeling dazed, disoriented, or confused); 
and focal neurological deficit(s) that may or may not be transient. 
Subjects will be excluded if they have any of the following findings: 
1. GCS<13 at any time during ED stay 
2. Significant polytrauma including: bony fracture or solid organ injury 
3. Study medication cannot be administered within 7 days of injury 
4. Patient cannot be relied on to complete follow-up (i.e. no reliable 
telephone number, substance dependence, homeless) 
5. Cannot communicate in English 
6. Take an anticoagulant (coumadin or a novel oral anticoagulant) daily 
7. Age less than 18 years or greater than 65 years 
8. Patients already taking fish oil supplements daily 
9. History of cognitive impairment 
10. Allergic to fish/fish oil 
11. Pregnant women (self-reported) 
Phase: 
 II 
Description of 
Sites/Facilities Enrolling 
Participants: 
 University of Michigan Emergency Department 
Description of Study 
Intervention: 
The intervention group will receive 6g/day of omega-3 fatty acids (fish oil) 
for 1 month followed by 1.2g/day for two additional months. The control 
group will receive placebo (olive oil) treatment for 3 months.  
Study Duration: 
 1 year 
Participant Duration: 
 3 months 
  


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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1.2 SCHEMA 
  
  
  
 
 
6g DHA+EPA/day x 
1 month; 1.2 g/day 
x 2 months
Placebo for 3 
months
Randomize to study intervention
Screen potential participants by inclusion and exclusion criteria
Eligibility 
Met?
Obtain Informed consent
Exclude from study
No
Yes
Follow-up assessment 1
Follow-up assessment 2
Follow-up assessment 3
Prior to 
enrollment
2 week visit
3 month visit
1 month visit


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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1.3 SCHEDULE OF ACTIVITIES (SOA) 
 Activity 
Enrollment 
2 week visit 
1 month visit 
3 month visit 
Screening 
X 
 
 
 
Demographics 
X 
 
 
 
Medical History 
X 
 
 
 
Pre-hospital Events 
X 
 
 
 
Informed consent 
X 
 
 
 
Clinical data elements 
X 
 
 
 
Rivermead Post-Concussion Questionnaire 
X 
X 
X 
X 
Blood draw 
X 
X 
X 
X 
Study medication 
X 
X 
X 
X 
Glasgow Outcome Scale Extended 
 
X 
X 
X 
Montreal Cognitive Assessment 
 
 
X 
X 
Brief Test of Attention (BTA) 
 
 
X 
X 
Trail Making Test, Part A, Part B 
 
 
X 
X 
Stroop Test 
 
 
X 
X 
Controlled Oral Word Association Test (COWAT) 
 
 
X 
X 
Wisconsin Card Sorting Test (WCST) 
 
 
X 
X 
Hopkins Verbal Learning Test (HVLT) 
 
 
X 
X 
Brief Visual Memory Test (BVMT) 
 
 
X 
X 
Wechsler Test of Adult Reading (WTAR) 
 
 
X 
X 
Patient Health Questionnaire 9  (PHQ9) 
 
 
X 
X 
Generalized Anxiety Scale GAD 7 
 
 
X 
X 
Davidson Trauma Scale to assess PTSD 
 
 
X 
X 
Pittsburg Sleep Questionnaire  
 
 
X 
X 
Satisfaction with life scale 
 
 
X 
X 
Social Ties Check List 
 
 
X 
X 
McGill pain scale 
 
 
X 
X 
 
  
  
 
 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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2 INTRODUCTION 
2.1 STUDY RATIONALE 
The objective of this study is to determine whether the treatment of traumatic brain injury patients with 
omega-3 fatty acids results in a decrease in blood biomarkers of neuronal injury and inflammation and 
an increase in biomarkers promoting neurogenesis. 
 
 
2.2 BACKGROUND 
Primary brain injury, the initial physical injury to brain tissue post-trauma, responds only to measures 
that prevent TBI from occurring in the first place. However, secondary brain injury, a complex cascade of 
events causing additional brain injury following primary brain injury, is more amenable to pharmacologic 
treatment. Neuroinflammation is one of the recognized mechanisms of secondary brain injury. In 
response to primary brain injury, activated microglia and injured neurons both release signaling proteins 
including cytokines and chemokines. Ω-3 and ω-6 fatty acids are major components of immune cells and 
neuronal cell membranes. They are also precursors to neuromodulatory lipds such as eicodanoids, 
endovanilloids and endocannabinoids that have antinociceptive and anxiolytic properties. 
Docosahexaenoic acid (DHA) is one of the most abundant fatty acid components of brain cell membrane 
phospholipids.1 In rodent model studies, dietary supplementation with omega-3 fatty acids 
(eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) decreased secondary axonal injury,2,3 
attenuated endoplasmic reticulum stress response,4 decreased neuroinflammation post-TBI,5 and 
improved short and long-term neurologic outcomes.3 Additionally, DHA supplementation post-TBI 
enhances neurogenesis by counteracting reductions in neuroplasticity biomarkers such as brain-derived 
neurotrophic factor.6,7 Furthermore, DHA deficient rodents are more likely to have a greater amount of 
axonal injury and slower recovery neurologic recovery post-TBI.8 To our knowledge there are no human 
studies examining the effect of omega-3 fatty acid supplementation post-TBI on functional, symptomatic 
and neurologic outcomes. However, a study of collegiate football players who were randomized to 2, 4 
or 6g/day of DHA or placebo for a total of 189 days (including 80 pre-season days). Irrespective of the 
dose of DHA supplementation, those receiving DHA had lower values of serum neurofilament light 
chain, a biomarker of axonal injury, than those receiving placebo.9 
 
 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
 Gastrointestinal distress (nausea, vomiting, diarrhea), low risk of bleeding 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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2.3.2 KNOWN POTENTIAL BENEFITS 
 Improvement in functional, cognitive and symptomatic recovery from traumatic brain injury; 
cardiovascular benefits 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
 Omega-3 fatty acids have an excellent safety profile. It is FDA approved for treating 
hypertriglyceridemia. The potential risks from taking omega-3 fatty acids are minimal. Gastrointestinal 
symptoms resolve upon stopping the medication. The risk of bleeding is minimal and at times disputed. 
There are currently no treatments for traumatic brain injury. Animal studies have demonstrated that 
omega-3 fatty acid supplementation may hasten recovery from TBI. Therefore the potential benefits 
from taking this medication outweigh the risks.  
 
 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
To determine the effect of omega-3 
polyunsaturated fatty acids (PUFA) 
treatment on blood biomarkers of 
neuronal injury and blood biomarkers 
of inflammation and a blood 
biomarker of neurogenesis 
Neurofilament light chain [NFL], 
Neurogranin [NRGN] and Intercellular 
adhesion molecule 5 [ICAM5], high 
sensitivity C-reactive protein [CRP], IL-
6, IL-10, and brain derived 
neurotrophic factor [BDNF] 
If omega-3 fatty acid 
supplementation decreases 
the levels of biomarkers of 
neuronal injury and 
inflammation and increases 
the levels of biomarkers of 
neurogenesis, then there is 
a strong likelihood it will 
improve clinical outcome 
Secondary 
1. To demonstrate the feasibility of 
enrolling, treating and 
conducting follow-up 
assessments on mTBI patients 
presenting to the University of 
Michigan 
2. To acquire preliminary data on 
the effect of omega-3 PUFA 
treatment on delayed functional 
recovery, moderate/severe post-
concussive symptoms and 
cognitive impairment. 
3. To acquire preliminary data on 
the types and incidence of 
serious adverse events (SAEs) in 
the Omega-3 PUFA treatment 
arm compared to the placebo 
arm 
1. Successful enrollment of 50 
subjects within 1 year 
2. Measurement of functional 
recovery using the Glasgow 
Outcome Scale Extended (GOSE), 
measurement of symptomatic 
recovery using the Rivermead 
Post-concussive symptoms 
questionnaire (RPQ) and 
cognitive impairment using a 
neurocognitive battery of tests 
3. Measurement of the incidents of 
gastrointestinal distress and 
clincally significant bleeding 
  
These endpoints will help 
inform the design of a 
multi-center phase II trial 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
We hypothesize that treatment of traumatic brain injury patients with omega-3 fatty acids will result in 
a decrease in blood concentrations of biomarkers of neuronal injury and inflammation and an increase 
in the blood concentration of biomarkers of neurogenesis. This is a randomized, placebo-controlled, 
double-blinded pilot phase II clinical trial.Participants will be randomized either a single dose of  6g of 
DHA+EPA for 1 month followed by 1.2g/day of DHA+EPA for two additional months or to placebo 
treatment for 3 months. Blood samples will be drawn at enrollment, 2 weeks, 1 month and 3 months 
post-injury. Biomarkers of neuronal injury, inflammation, and neurogenesis will be measured in batches. 
Functional and symptomatic recovery will be assessed at 2 weeks, 1 month and 3 months. Additionally, 
cognitive impairment will be assessed at 3 months. 
 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
There are limited data on treatment of TBI with omega-3 fatty acids. The performance of a randomized 
control trial will allow an unbiased determination of the efficacy of omega-3 fatty acids in treating TBI 
 
 
4.3 JUSTIFICATION FOR DOSE 
Some animal studies have used a dose of 40mg/kg. Human studies of high dose omega-3 fatty acids for 
preventing cardiovascular disease have used our study dose of 4g. The maximum tolerable dose of 
omega-3 fatty acids is 21g/day. Case reports of severe TBI treatment with omega-3 fatty acids have 
reported using up to 19g/day.  In our population of mild TBI patients we have selected a dose of 6g/day 
which is about 2 times the dose used in animal studies but significantly below the maximum tolerable 
dose or the dose used in other TBI studies.   
 
 
4.4 END OF STUDY DEFINITION 
 A participant is considered to have completed the study if he or she has completed all phases of the study 
including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 1.3. 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Individuals presenting to the emergency department (ED) within 7 days of injury, who meet the 
American Congress of Rehabilitation Medicine (ACRM)’s definition of having mild traumatic brain injury 
(mTBI) will be eligible. The ACRM defines mTBI as a traumatically-induced physiological disruption of 
brain function as a consequence of the head being struck, striking an object, or undergoing an 
acceleration/deceleration movement without direct external head trauma and resulting in at least one 
of the following: any period of loss of consciousness (LOC); any loss of memory for events immediately 
before or after the injury; any alteration in mental state at the time of the injury (eg, feeling dazed, 
disoriented, or confused); and focal neurological deficit(s) that may or may not be transient. 
 
 
5.2 EXCLUSION CRITERIA 
Subjects will be excluded if they have any of the following findings: 
1. GCS<13 at any time during ED stay. 
2. Significant polytrauma including: bony fracture or solid organ injury 
3. Study medication cannot be administered within 7 days of injury 
4. Patient cannot be relied on to complete follow-up (i.e. no reliable telephone number, substance 
dependence, homeless) 
5. Cannot communicate in English 
6. Take an anticoagulant (coumadin or a novel oral anticoagulant) daily 
7. Age less than 18 years or greater than 65 years 
8. Patients already taking fish oil supplements daily 
9. History of cognitive impairment 
10. Allergic to fish/fish oil 
11. Pregnant women (self-reported) 
 
 
 
 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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5.3 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
  
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a may 
be rescreened. Rescreened participants should be assigned the same participant number as for the 
initial screening. 
 
 
5.4 STRATEGIES FOR RECRUITMENT AND RETENTION 
Potential subject for this trial will be recruited from all patients with mild TBI (GCS 13-15) presenting 
within 7 days of injury to the University of Michigan Emergency Department. Trained research personnel 
will perform enrollment of subjects. 
Target sample size: 50 participants 
Anticipated accrual rate: 5-10 patients per month 
Anticipated number of sites: 1 
Source of participants: Emergency Department and Inpatient admissions of the University Hospital, 
University of Michigan 
How potential participants will be identified and approached: Trained research coordinators will 
screen the Emergency Department Dashboard of MiChart for eligible patients. They will then approach 
emergency physicians/physician assistants taking care of eligible patients and ask for permission to 
approach their patient to further discuss the study and obtain informed consent. This will occur in the 
emergency department. If the potential subject agrees to the referral, the research coordinator will 
approach the potential subject and begin the consent process. This process will help maintain patient 
privacy, by allowing potential subjects to have control over who has access to them. For patients lacking 
the capacity to consent, an authorized legal representative will be identified for consent purposes. 
Participation in the study will be voluntary. 
Incentives for visit attendance: A cash incentive of $75 will be provided for attending the 2 week visit, 
$75 for attending the 1 month visit and $150 for attending the 3 month visit. 
Inclusion of women and minorities: Traumatic brain injury occurs more frequently in men. However, 
efforts will be made to ensure that all eligible women are included. Additionally, efforts will be made to 
ensure an adequate representation of under-represented minorities.   
 
 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
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6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 The study intervention is an omega-3 fatty acid capsules manufactured by Wiley's Finest. We will utilize 
a formulation that contains 500 mg of docosahaxaenoic acid (DHA) and 100 mg of eicosapentaenoic acid 
(EPA) in one capsule 
6.1.2 DOSING AND ADMINISTRATION 
Every attempt will be made to start treatment as soon as possible after enrollment. The first dose will be 
administered within 7 days of injury. The intervention group will receive 6g per day of DHA+EPA for 1 
month followed by 1.2 g/day of EPA+DHA for two additional months. The control group will receive 
placebo treatment for 3 months. 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 Study medications will be acquired from Wiley's Finest and stored and dispensed by the University of 
Michigan Research Pharmacy Group 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Study medication will be supplied as soft-gelatin capsules filled with light-yellow oil. 
6.2.3 PRODUCT STORAGE AND STABILITY 
• 
Store study medications at room temperature between 68°F to 77°F (20°C to 25°C). 
• 
Do not freeze study medication 
• 
Safely throw away medicine that is out of date or no longer needed  
6.2.4 PREPARATION 
 The study drug will not need additional preparation 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
A web-based central randomization system will be developed and utilized. Study team members will be 
blinded to study group allotment. 
 
 


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6.4 STUDY INTERVENTION COMPLIANCE 
Adherence to protocol will be assessed by measuring plasma levels of EPA and DHA and red blood cell 
index of omega-3 fatty acids at each follow-up visit. 


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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from taking the study medication does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
  
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Blood samples, functional, symptomatic and cognitive outcomes data 
 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
  
• 
Pregnancy (self-reported)  
• 
Significant study intervention non-compliance 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation 
• 
Participant unable to receive the study medication for 2 weeks or more 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will be replaced. 
 
 


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7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for a scheduled visit and is 
unable to be contacted by the study site staff. 
  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 2 weeks and 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter 
to the participant’s last known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record or study file. 
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
 
 


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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
Biomarker Assays: Neurofilament light chain, Intercellular adhesion molecule 5 and brain derived 
neurotrophic factor will be measured using a single molecule counting technology from Quanterix. 
Neurogranin will be measured using an ELISA assay made by ADx Neurosciences. 
high-sensitivity C-reactive protein, IL-6 and IL-10 will be measured using standard ELISA assays. 
  
Other outcome measures: Functional outcome will be assessed with the Glasgow Outcome Scale 
Extended (GOSE). Symptomatic outcome will be assessed with the Rivermead Post-concussion Symptom 
Questionnaire (RPQ). Depressive symptoms will be assessed with the Patient Health Questionnaire 9 
(PHQ9). These outcomes will be measured at 2 weeks, 1 month, and 3 months. 
Neurocognitive impairment will be assessed based on a battery of neurocognitive test. These include: 
• 
the Wechsler Test of Adult Reading (WTAR) 
• 
the Hopkins Verbal Learning Test (HVLT) (3 scores), 
• 
the Brief Visuospatial Memory Test - Revised (BVMT-R) (3 scores), 
• 
the Brief Test of Attention (BTA) (1 scores), 
• 
the Trail making test A and B (1 scores), 
• 
the stroop test (2 scores), and 
• 
the Wisconsin Card Sorting Test (WCST) (2 scores), 
Using the WTAR (word pronunciation) as an estimate of IQ, we will compare the 13 neurocognitive test 
T-scores of interest against the subject’s IQ T-score. The standard deviation (SD) of T-score is 10. Each of 
the subject’s 13 neurocognitive test T-scores is considered as aberrant if it is more than 2 SD below this 
subject’s IQ T-score. A subject is considered cognitively impaired if at least 2 (based upon .05 rule; 5 out 
of every 100 test scores will be outside of expected range by chance alone) out the 13 T-scores are 
aberrant. 
8.2 SAFETY AND OTHER ASSESSMENTS 
At each study visit, we will evaluate patients for the following: 
1. Gastrointestinal distress (nausea, vomiting, diarrhea) 
2. Clinically significant bleeding such as intracranial hemorrhage and upper GI bleed 
 
 


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8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1     DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
  
8.3.2     DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
  
8.3.3     CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1    SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity. 
  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. Of note, the term 
“severe” does not necessarily equate to “serious”. 
  
8.3.3.2    RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect. 


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• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
after administration of the study intervention, is unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although an 
AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the event 
did not occur within a reasonable time after administration of the study intervention) and in which other 
drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician. 
  
8.3.3.3    EXPECTEDNESS 
Study research coordinators will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study intervention. 
  
8.3.4     TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
  
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 


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training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
  
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE. 
  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
  
Study research coordinators will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or stabilization. 
  
8.3.5     SERIOUS ADVERSE EVENT REPORTING 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
  
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
  
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information. In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
  
  
 
 


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8.4 UNANTICIPATED PROBLEMS 
8.4.1     DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in 
the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
  
8.4.2      UNANTICIPATED PROBLEM REPORTING 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB 24 hours of the investigator 
becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 7 days of the investigator 
becoming aware of the problem. 
  
 
 


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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
• 
Primary Efficacy Endpoint(s): 
 Omega-3 fatty acid supplementation results in a decrease in the area under the concentration versus 
time curve for neurofilament light chain, CRP, IL-6 and IL-10 during the 3 months following TBI and an 
increase in the area under the concentration curve for brain derived neurotrophic factor.  
• 
Secondary Efficacy Endpoint(s): 
 Omega-3 fatty acid supplementation improves functional outcome, post-concussive symptoms and 
cognitive decline post-TBI 
 
9.2 SAMPLE SIZE DETERMINATION 
This is a pilot study of 50 patients. 
 
9.3 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
 We will examine blood levels of biomarkers of omega-3 intake, axonal injury, and inflammation (red 
blood cell and plasma omega-3 index, NFL, ICAM5, CRP, IL-6 and IL-10) at baseline and at 3 months in 
both the intervention and the control groups and test the hypothesis that omega-3 PUFA treatment 
increases omega-3 PUFA blood levels and decreases levels of biomarkers of axonal injury and 
inflammation. To examine the effect of omega-3 PUFA treatment on biomarkers of neuronal injury and 
inflammation, we will construct multiple linear regression models with generalized estimating equations 
(GEE) and robust variance estimation to account for correlations within repeated measurements. This 
will allow us to determine whether variations in the levels of NFL, ICAM5, CRP, IL-6 and IL-10 over the 3 
month study period differ among those receiving omega-3 PUFA supplementation versus those 
receiving placebo.  
  
  
  
  
  
  
 
 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1     INFORMED CONSENT PROCESS 
10.1.1.1    CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The written informed consent document is submitted 
with this protocol. 
10.1.1.2    CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research 
participants.  Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The participants will have the opportunity to discuss the study with their 
family or surrogates or think about it prior to agreeing to participate. The participant or legally 
authorized representative will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants must be informed that participation is voluntary and that they 
may withdraw from the study at any time, without prejudice. A copy of the informed consent document 
will be given to the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the participant 
undergoes any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study. 
  
10.1.2     STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the IRB, and sponsor and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 


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• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping   
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
  
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
  
10.1.3     CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
  
All research activities will be conducted in as private a setting as possible. 
  
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
  
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
  
Study participant research data will be stored in a secure password protected and data-encrypted online 
database (REDCap). This will not include the participant’s contact or identifying information. At the end 
of the study, all study databases will be de-identified and archived at the on a University of Michigan 
password protected computer.  


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10.1.4     FUTURE USE OF STORED SPECIMENS AND DATA 
Data collected for this study will be analyzed and stored at the University of Michigan. Study data will be 
available for use by other researchers including those outside of the study. Permission to transmit data 
to the other collaborators will be included in the informed consent. 
  
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at the University of Michigan with the same goal as the 
sharing of data with other collaborators. These samples could be used for research the causes of 
traumatic brain injury, its complications and other conditions for which individuals with traumatic brain 
injury are at increased risk, and to improve treatment. Collaborators will also be provided with a code-
link that will allow linking the biological specimens with the phenotypic data from each participant, 
maintaining the blinding of the identity of the participant. 
  
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed. 
  
  
10.1.5     KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator  
Principal Investigator 
Frederick Korley, M.D., Ph.D. 
Department of Emergency Medicine 
University of Michigan 
24 Frank Lloyd Wright Drive, H3100 
Ann Arbor, MI 48105 
  
  
10.1.8     QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management. 
  
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
  
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 


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Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
  
10.1.9     DATA HANDLING AND RECORD KEEPING 
10.1.9.1    DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
  
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.  
  
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents. 
  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into REDCap. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
  
10.1.9.2    STUDY RECORDS RETENTION 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
  
10.1.10  PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or MOP requirements. The noncompliance may be 


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either on the part of the participant, the investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly. 
  
These practices are consistent with ICH GCP: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the principal investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working days of 
the scheduled protocol-required activity.   
  
10.1.12  CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.   
10.2 ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 


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GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
  
  
  
  
 
 


Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI pilot).  
Version 2.000
Protocol HUM00129045 
06 July 2017
NIH-FDA Clinical Trial Protocol Template – v1.0 5 Apr 2017 
32
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