Clinical trial NCT03272399: Nutrition for Post-Traumatic Headache
Official title: Targeted Alteration in Omega-3 and Omega-6 Fatty Acids for Post-traumatic Headache (Nutrition for PTH)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Post-Traumatic Headache Chronic Without Intractable Headache
Lead sponsor: Uniformed Services University of the Health Sciences
Sponsor class: FED
Collaborators: name: Walter Reed National Military Medical Center
name: Fort Belvoir Community Hospital
name: Womack Army Medical Center
name: University of North Carolina, Chapel Hill
name: National Institutes of Health (NIH)
First posted: 2017-09-05
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: The HIT-6 is administered at study visits at week 0 (enrollment), 4, 10, 12, 14, 16
measure: Primary Biochemical Outcome: To evaluate the effects of the H3-L6 and L3-H6 Diet on circulating fatty acids and bioactive metabolites.
timeFrame: Fasting blood draws at study visits at weeks 4, 10, 16
Secondary outcomes:
measure: 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.
timeFrame: Daily on-line diary entry during the 16-week study
measure: To explore the potential of the H3-L6 intervention for improving non-headache pain outcomes.
timeFrame: Study visits at week 0 and 16
measure: To explore the potential of the H3-L6 intervention for decreasing acute pain medication usage
timeFrame: Daily on-line diary entry during the 16-week study
measure: To explore the potential of the H3-L6 intervention for improving sleep quality
timeFrame: the PSQI is administered at weeks 4 and 16 of the study
measure: To explore the potential of the H3-L6 intervention for improving psychological distress (depression/anxiety)
timeFrame: Study visits at week 0 and 16
measure: To explore the potential of the H3-L6 intervention for improving symptoms of post-traumatic stress disorder (PTSD)
timeFrame: The PCL-C is administered at study visits at weeks 4 &16
measure: To explore the potential of the H3-L6 intervention for improving post-concussive symptoms.
timeFrame: NSI and GOS-E are administered at weeks 4 and 16.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Fort Bragg
country: United States
facility: Womack Army Medical Center (WAMC)
state: North Carolina
city: Fort Belvoir
country: United States
facility: Fort Belvoir Community Hospital
state: Virginia
Study officials:
affiliation: Uniformed Services University of the Health Sciences
name: Kimbra Kenney, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institutes of Health (NIH)
name: Chris Ramsden, MD
role: STUDY_DIRECTOR
affiliation: UNC
name: John Mann, MD
role: STUDY_DIRECTOR
References:
citation: Ramsden CE, Faurot KR, Zamora D, Suchindran CM, MacIntosh BA, Gaylord S, Ringel A, Hibbeln JR, Feldstein AE, Mori TA, Barden A, Lynch C, Coble R, Mas E, Palsson O, Barrow DA, Mann DJ. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain. 2013 Nov;154(11):2441-2451. doi: 10.1016/j.pain.2013.07.028. Epub 2013 Jul 22.
citation: Ramsden CE, Faurot KR, Zamora D, Palsson OS, MacIntosh BA, Gaylord S, Taha AY, Rapoport SI, Hibbeln JR, Davis JM, Mann JD. Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized trial. Pain. 2015 Apr;156(4):587-596. doi: 10.1097/01.j.pain.0000460348.84965.47.
citation: Faurot KR, Cole WR, MacIntosh BA, Dunlap M, Moore CB, Roberson B, Guerra M, Domenichiello AF, Palsson O, Rivera W, Nothwehr A, Arrieux J, Russell K, Jones C, Werner JK, Clark R, Diaz-Arrastia R, Suchindran C, Mann JD, Ramsden CE, Kenney K. Targeted dietary interventions to reduce pain in persistent post-traumatic headache among service members: Protocol for a randomized, controlled parallel-group trial. Contemp Clin Trials. 2022 Aug;119:106851. doi: 10.1016/j.cct.2022.106851. Epub 2022 Jul 13.