Nutrition for Post-Traumatic Headache

October 4, 2021 updated by: Kimbra Kenney, Uniformed Services University of the Health Sciences

Targeted Alteration in Omega-3 and Omega-6 Fatty Acids for Post-traumatic Headache (Nutrition for PTH)

The purpose of this multi-site study is to evaluate the efficacy of a high omega-3/low omega-6 dietary intervention (the H3-L6 Diet) vs. a Control Diet in reducing headache pain and improving function in soldiers, veterans and military healthcare beneficiaries with post-traumatic headache (PTH). In addition, the study will examine the effects of the diet interventions on anti-nociceptive and pro-nociceptive lipid mediators derived from omega-3 and omega-6 fatty acids.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Migraine-like PTH is an ideal patient population to test the effects of the H3-L6 intervention for several reasons. First, although PTH is considered a secondary headache syndrome, the fact that migraine-like PTH has a phenotype indistinguishable from primary migraine disorders and shares common pain-related comorbidities (e.g. anxiety, depression) suggests that shared biochemical mechanisms may underlie both conditions. Second, many PTH patients experience poor or incomplete therapeutic responses to available treatments, often while suffering from drug-related adverse effects. The prospect of improved headache outcomes with concurrent reduction in medication use (as seen in the Chronic Daily Headache Trial) may be particularly beneficial in PTH, since certain headache medications (e.g. opiates, muscle relaxants, sleep aids) have cognitive side effects, which may worsen residual cognitive impairment from Traumatic Brain Injury (TBI).

While PTH is an important cause of disability after TBI, problems with memory, executive function, depression, anxiety, irritability, fatigue, post-traumatic stress, and other neurobehavioral disorders are also common after TBI and contribute to disability. The H3-L6 (High Omega-3 Low Omega-6) intervention increased circulating concentrations of several key bioactive mediators which could hypothetically also have favorable effects on these TBI-associated non-headache impairments associated with TBI combat injuries. Omega-3 fatty acids have been widely studied in pre-clinical models and human TBI and demonstrate promising evidence of both neuroprotective and neurorestorative efficacy.

Potential mechanisms include antioxidant, anti-inflammatory, and pro-neurogenic effects. In our pilot study, the H3-L6 intervention significantly increased circulating levels of docosahexaenoic acid-eicosapentaenoic acid (DHA-EPA) , a potent stimulator of neurite growth and synaptogenesis in hippocampus and other central nervous system (CNS) tissues. Corresponding increases in the synaptamide biosynthesis in central nervous system tissues could hypothetically assist cognitive and functional neurorecovery associated with traumatic brain injury. Further, the reduction of proinflammatory metabolites of omega-6 fatty acids may provide additional benefits beyond what can be achieved through omega-3 supplementation alone.

Study Type: Interventional, Phase 2, double blind Study Design: Allocation: Randomized, parallel group Masking: Double Blind (Participant, Investigator, Outcomes Assessor) Primary Purpose: Treatment

Primary Outcome Measures:

Hypothesis and Objective: The investigators will obtain support for the following hypotheses through three specific aims:

Specific Aim 1: To compare the efficacy of the H3-L6 Diet to the Control Diet, in reducing headache pain and improving headache-related quality of life.

Hypothesis 1: Compared to the Control Diet, the H3-L6 Diet will produce significant improvement in:

(1a) the Headache Impact Test-a headache-specific quality of life measure-Primary Clinical Outcome);

(1b) mean total Headache Hours per day; and

(1c) mean Severe Headache Hours per day.

Secondary Outcomes Measures:

Specific Aim 2: To evaluate whether the H3-L6 Diet can increase circulating anti-nociceptive omega-3 metabolites, and reduce pro-nociceptive omega-6 metabolites, in patients with Posttraumatic Headaches.

Hypothesis 2: Compared to the Control Diet, the H3-L6 Diet will produce significant increases in anti-nociceptive omega-3 metabolites including 17-hydroxy DHA (Primary Biochemical Aim), and reductions in pro-nociceptive omega-6 metabolites.

Other Outcomes Measures Specific Aim 3: To explore the potential of the H3-L6 intervention for improving non-headache TBI outcomes.

Hypothesis 3: Compared to the Control Diet, the H3-L6 Diet will produce significant improvement in:

(3a) non-headache pain; (3b) depression/anxiety; (3c) symptoms of post-traumatic stress disorder; (3d) cognitive function; (3e) sleep quality; and (3f) will significantly reduce the use of acute pain medications. Enrollment: Up to 300 total participants enrolled among the 3 military sites for 120 12-week diet completers

Study Type

Interventional

Enrollment (Anticipated)

300

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • In order to be included in the study, you must be a person of either gender who is at least 18 years of age, meets criteria of having had a traumatic brain injury, a physiological disruption of brain function, as manifested by at least one of the following:

    1. . Any period of loss of consciousness
    2. . Any loss of memory for events immediately before or after the accident
    3. . Any alteration of mental state at the time of the accident (e.g., feeling dazed, disoriented, and confused)

    4. . Focal neurologic deficits that may or may not be permanent.

      • Traumatically induced includes the head being struck, the head striking an object, or the brain undergoing an acceleration/deceleration movement (i.e. whiplash) without direct external trauma to the head.
  • Meets Internation Classification of Headache Disorders-version III (ICHD-III) criteria for persistent post-traumatic headache which is defined as a headache of at least 3 months duration caused by a traumatic injury to the head.

  • Meets ICHD-III criteria for episodic/chronic migraine, with or without aura (excepting exclusion for organic disease):

    1. . Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)

    2. . Headache has at least 2 of the following characteristics:

      1. unilateral location
      2. pulsating quality
      3. moderate or severe pain intensity
      4. aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)

    3. . During headache at least 1 of the following:

      1. nausea and/or vomiting
      2. photophobia and phonophobia
  • A potential candidate for this study must be under the care of a physician for headaches and have an incomplete response to standard headache treatments.
  • Must have headache frequency of more than 8 days per month.
  • Must have a headache history of more than 6 months
  • Must be able to attend or remotely participate (by video conference or telephone) in seven dietitian counseling sessions, and adhere to diet supplied to study participants.
  • Must be a Department of Defense (DoD) healthcare beneficiary and eligible to receive care at Walter Reed National Military Medical Center (WRNMMC), Fort Belvoir Community Hospital (FBCH) or Womack Army Medical Center (WAMC).

Exclusion Criteria:

  • A person cannot be in this study if they have a history of specific food allergies, especially to fish, dairy or gluten.

Also exclusionary are:

  • Pregnancy or anticipated pregnancy
  • Aversion to eating fish
  • History of organic brain disorder other than TBI (vasculitis, encephalitis, meningitis, brain tumor)
  • Major medical illness such as malignancy, diabetes, autoimmune or immune deficiency disorders, history of stroke or myocardial infarction
  • Anticipated deployment or move to alternate location in the next 16 weeks
  • Inability to read and communicate in English
  • Regular use of fatty acid containing supplements
  • Active or recent (2 years) history of treatment for substance abuse
  • Cognitive impairment that prevents understanding of the protocol and completion of study procedures including compliance with the diet, blood draws and maintaining a daily headache diary.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: H3-L6
High Omega-3, low Omega-6 diet
Other: Diet/nutrition intervention
The intervention will be administered through food products rather than dietary supplements
Other Names:
  • High omega-3 versus high omega-6 dietary intervention
Active Comparator: L3-H6
Control diet containing average US polyunsaturated fatty acid (PUFA) content with low omega-3 and high omega-6 content
Other: Diet/nutrition intervention
The intervention will be administered through food products rather than dietary supplements
Other Names:
  • High omega-3 versus high omega-6 dietary intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary Clinical Outcome: To compare the efficacy of the high omega-3/low omega-6 (H3-L6) diet to the low omega-3/high omega-6 (L3-H6) diet in reducing headache pain and improving headache-related quality of life.
Time Frame: The HIT-6 is administered at study visits at week 0 (enrollment), 4, 10, 12, 14, 16
Up to 300 participants complete the Headache Impact Test (HIT-6)-a headache-specific quality of life measure 6 times while enrolled in the study. The primary outcome measure is the change in the HIT-6 scores at baseline and at the end of the diet intervention.
The HIT-6 is administered at study visits at week 0 (enrollment), 4, 10, 12, 14, 16
Primary Biochemical Outcome: To evaluate the effects of the H3-L6 and L3-H6 Diet on circulating fatty acids and bioactive metabolites.
Time Frame: Fasting blood draws at study visits at weeks 4, 10, 16
All study participants will have blood drawn 3 times during the 16-week study for analysis of circulating fatty acids and their bioactive metabolites. The following fatty acids will be measured in each blood sample (ng or pg per mL): 17-hydroxy-DHA (docosahexaenoic acid), 18-Hydroxy-EPA (eicosapentaenoic acid), 9-HODE (hydroxyl-octadecadienoic acid), 13-ODE (octadecadienoic acid), 5-HETE (hydroxyl-eicosatetraenoic acid), 8-HETE, 9-HETE, 11-HETE. Changes in 17-hydroxy-DHA and related fatty acids levels between blood draws at baseline and at the end of the 12-week diet intervention will be compared with changes in headache frequency and severity at the same time points.
Fasting blood draws at study visits at weeks 4, 10, 16

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To compare the efficacy of the high omega-3/low omega-6 (H3-L6) diet to the low omega-3/high omega-6 (L3-H6) diet in reducing headache pain.
Time Frame: Daily on-line diary entry during the 16-week study
Up to 300 participants complete a headache diary daily while enrolled in the 16-week study. Participants record the total number of headache hours per day. The outcome measure is the change in the mean daily headache hours at baseline and at the end of the diet intervention between the H3-L6 and L3-H6 diet intervention groups.
Daily on-line diary entry during the 16-week study
To explore the potential of the H3-L6 intervention for improving non-headache pain outcomes.
Time Frame: Study visits at week 0 and 16
Compared to the Control Diet, the H3-L6 Diet may produce significant improvement in non-headache pain. A survey of pain, the Total Body Pain Scale, will be administered at baseline and at the end of the 12-week diet intervention. The outcome measure is a reduction in non-headache pain as measured by the survey at baseline and at the end of the diet intervention.
Study visits at week 0 and 16
To explore the potential of the H3-L6 intervention for decreasing acute pain medication usage
Time Frame: Daily on-line diary entry during the 16-week study
Compared to the Control Diet, the H3-L6 Diet may produce significant improvement in: Use of acute pain medications. Participants will daily record all pain medications used in that 24-hour period. The outcome measure is the change in the acute pain medications sued at baseline and at the end of the diet intervention between the H3-L6 and L3-H6 diet intervention groups.
Daily on-line diary entry during the 16-week study
To explore the potential of the H3-L6 intervention for improving sleep quality
Time Frame: the PSQI is administered at weeks 4 and 16 of the study
Compared to the Control Diet, the H3-L6 Diet may produce significant improvement in sleep quality. A sleep quality survey, the PSQI, will be administered at baseline at and the end of the 12-week diet intervention. The outcome measure is the change in the PSQI score at baseline and at the end of the diet intervention between the H3-L6 and L3-H6 diet intervention groups.
the PSQI is administered at weeks 4 and 16 of the study
To explore the potential of the H3-L6 intervention for improving psychological distress (depression/anxiety)
Time Frame: Study visits at week 0 and 16
The PROMIS-29, a survey of psychological distress (depression/anxiety), will be administered at baseline and at the end of the 12-week diet intervention. The outcome measure is a reduction in depression and/or anxiety as measured by the PROMIS-29 at baseline and at the end of the diet intervention.
Study visits at week 0 and 16
To explore the potential of the H3-L6 intervention for improving symptoms of post-traumatic stress disorder (PTSD)
Time Frame: The PCL-C is administered at study visits at weeks 4 &16
Compared to the Control Diet, the H3-L6 Diet may produce significant improvement in symptoms of post-traumatic stress disorder (PTSD). The PCL-C, a survey of post-traumatic stress symptoms, will be administered at baseline and at the end of the 12-week diet intervention. The outcome measure is the reduction in the PCL-C score at baseline and at the end of the diet intervention between the H3-L6 and L3-H6 diet intervention groups.
The PCL-C is administered at study visits at weeks 4 &16
To explore the potential of the H3-L6 intervention for improving post-concussive symptoms.
Time Frame: NSI and GOS-E are administered at weeks 4 and 16.
Compared to the Control Diet, the H3-L6 Diet may produce significant improvement in post-concussive symptoms. The Neurobehavioral Symptom Inventory (NSI) and the Glasgow Outcome Score-Extended (GOS-E) will be administered at baseline and at the end of the 12-week diet intervention. The outcome measure is a change in the NSI and GOS-E score at baseline and at the end of the diet intervention between the H3-L6 and L3-H6 diet intervention groups.
NSI and GOS-E are administered at weeks 4 and 16.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Uniformed Services University of the Health Sciences

Collaborators

National Institutes of Health (NIH)
University of North Carolina, Chapel Hill
Walter Reed National Military Medical Center
Womack Army Medical Center
Fort Belvoir Community Hospital

Investigators

  • Principal Investigator: Kimbra Kenney, MD, Uniformed Services University of the Health Sciences
  • Study Director: Chris Ramsden, MD, National Institutes of Health (NIH)
  • Study Director: John Mann, MD, UNC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 21, 2017

Primary Completion (Anticipated)

March 31, 2022

Study Completion (Anticipated)

March 31, 2022

Study Registration Dates

First Submitted

August 21, 2017

First Submitted That Met QC Criteria

August 30, 2017

First Posted (Actual)

September 5, 2017

Study Record Updates

Last Update Posted (Actual)

October 5, 2021

Last Update Submitted That Met QC Criteria

October 4, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 416047

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Study data to be uploaded into Federation Interagency Traumatic Brain Injury Repository (FITBIR) and made accessible after study is completed

IPD Sharing Time Frame

After study is uploaded into FITBIR

IPD Sharing Access Criteria

Through FITBIR

IPD Sharing Supporting Information Type

  • Study Protocol
  • Clinical Study Report (CSR)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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