OPTIMA-TBI Pilot Study (OPTIMA)

• ClinicalTrials.gov Identifier: NCT03345550
• Recruitment Status: Completed
• First Posted: November 17, 2017
• Last Update Posted: September 24, 2021
• Sponsor: University of Michigan
• Information provided by (Responsible Party): Frederick Korley, MD, PhD, University of Michigan

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Mild Traumatic Brain Injury	Drug: Omega-3 Polyunsaturated Fatty Acids (Fish Oil 1000 mg (contains 500 mg DHA & 100 mg EPA)) or placebo capsules.; Drug: Placebo - Cap	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Omega-3 Polyunsaturated Fatty Acid Treatment in Mild Acute TBI (OPTIMA-TBI Pilot)
• Actual Study Start Date: September 12, 2017
• Actual Primary Completion Date: July 27, 2021
• Actual Study Completion Date: July 27, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Omega-3 Polyunsaturated Fatty Acid Treatment Arm; 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.	Drug: Omega-3 Polyunsaturated Fatty Acids (Fish Oil 1000 mg (contains 500 mg DHA & 100 mg EPA)) or placebo capsules.; Participants will be randomized to receive fish oil 1000 mg (contains 500 mg DHA & 100 mg EPA) or placebo capsules.
Placebo Comparator: Placebo Arm; Participants randomized to this study arm will receive placebo drug for 3 months.	Drug: Placebo - Cap; 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).

Outcome Measures

Primary Outcome Measures :

1. Biomarker Endpoints (NFL) [ Time Frame: 3 months ]
   Neuronal injury measured by Neurofilament Light Chain (NFL). Samples will be analyzed using a digital immunoassay based on a single molecule counting technology.
2. Biomarker Endpoint (Inflammation) [ Time Frame: 3 months ]
   We will measure serum levels of high sensitivity CRP
3. Biomarker Endpoint (Neurogenesis) [ Time Frame: 3 months ]
   We will measure serum levels of brain derived neurotrophic factor (BDNF)

Secondary Outcome Measures :

1. Delayed Functional Recovery [ Time Frame: 3 months ]
   Delayed functional recovery will be defined as a Glasgow Outcome Scale Extended (GOSE) <8 at 3 months. Scores range from 1-8. 8 is Upper good recovery and 1 is death
2. Moderate/Severe Post-Concussive Symptoms [ Time Frame: 3 months ]
   Moderate/severe post-concussive symptoms will be defined as the presence of any one or more of the following: headaches, dizziness, general malaise, excessive fatigue, or noise intolerance, irritability, emotional lability, depression, or anxiety, subjective complaints of concentration or memory difficulty, insomnia, reduced tolerance to alcohol, preoccupation with these symptoms and fear of permanent brain damage. These will be self-reported by the patient.
3. Cognitive Impairment [ Time Frame: 3 months ]
   Cognitive impairment will be defined by a battery of neurocognitive tests including the Montreal Cognitive Assessment (MOCA), Hopkins Verbal Learning Test (HVLT), Trails A and B, Brief Visuospatial Memory Test (BVMT), Stroop Test, Wechsler Test of Adult Reading (WTAR), Brief Test of Attention, (BTA), Wisconsin Card Sorting Test (WCST) and COWAT (Controlled Oral Word Association Test). The WTAR will be used as an estimate of IQ and the neurocognitive test T-scores of interest will be compared against the subject's IQ T-score. The standard deviation (SD) of each T-score is 10. Each of the subject's neurocognitive tests is considered aberrant if it is more than 2 SD below the subject's IQ T-score. A subject is considered cognitively impaired if at least 2 (based on the .05 rule; 5 out of every 100 test scores will be outside of expected range by chance alone) out of the T-scores are aberrant.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Individuals presenting to the emergency department (ED) within 24 hours 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)
• focal neurological deficit(s) that may or may not be transient

Exclusion Criteria:

• GCS<13 at any time during ED stay.
• Significant polytrauma including: bony fracture or solid organ injury
• Study medication cannot be administered within 24 hours of injury
• Patient cannot be relied on to complete follow-up (i.e. no reliable telephone number, substance dependence, homeless)
• Cannot communicate in English
• Take an anticoagulant (coumadin or a novel oral anticoagulant) daily
• Age less than 18 years or greater than 65 years
• Patients already taking fish oil supplements daily
• History of cognitive impairment
• Allergic to fish/fish oil
• Pregnant women (self-reported)

Contacts and Locations

Locations

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

Sponsors and Collaborators

University of Michigan

Investigators

• Principal Investigator: Frederick Korley, M.D., Ph.D.; Department of Emergency Medicine

More Information

• Responsible Party: Frederick Korley, MD, PhD, Assistant Professor, University of Michigan
• ClinicalTrials.gov Identifier: NCT03345550
• Other Study ID Numbers: HUM00129045
• First Posted: November 17, 2017
• Last Update Posted: September 24, 2021
• Last Verified: September 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Brain Injuries; Brain Injuries, Traumatic; Brain Concussion; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Head Injuries, Closed; Wounds, Nonpenetrating