<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03272399</url>
  </required_header>
  <id_info>
    <org_study_id>416047</org_study_id>
    <nct_id>NCT03272399</nct_id>
  </id_info>
  <brief_title>Nutrition for Post-Traumatic Headache</brief_title>
  <official_title>Targeted Alteration in Omega-3 and Omega-6 Fatty Acids for Post-traumatic Headache (Nutrition for PTH)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Uniformed Services University of the Health Sciences</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Walter Reed National Military Medical Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fort Belvoir Community Hospital</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>Womack Army Medical Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Uniformed Services University of the Health Sciences</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this multi-site study is to evaluate the efficacy of a high omega-3/low&#xD;
      omega-6 dietary intervention (the H3-L6 Diet) vs. a Control Diet in reducing headache pain&#xD;
      and improving function in soldiers, veterans and military healthcare beneficiaries with&#xD;
      post-traumatic headache (PTH). In addition, the study will examine the effects of the diet&#xD;
      interventions on anti-nociceptive and pro-nociceptive lipid mediators derived from omega-3&#xD;
      and omega-6 fatty acids.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Migraine-like PTH is an ideal patient population to test the effects of the H3-L6&#xD;
      intervention for several reasons. First, although PTH is considered a secondary headache&#xD;
      syndrome, the fact that migraine-like PTH has a phenotype indistinguishable from primary&#xD;
      migraine disorders and shares common pain-related comorbidities (e.g. anxiety, depression)&#xD;
      suggests that shared biochemical mechanisms may underlie both conditions. Second, many PTH&#xD;
      patients experience poor or incomplete therapeutic responses to available treatments, often&#xD;
      while suffering from drug-related adverse effects. The prospect of improved headache outcomes&#xD;
      with concurrent reduction in medication use (as seen in the Chronic Daily Headache Trial) may&#xD;
      be particularly beneficial in PTH, since certain headache medications (e.g. opiates, muscle&#xD;
      relaxants, sleep aids) have cognitive side effects, which may worsen residual cognitive&#xD;
      impairment from Traumatic Brain Injury (TBI).&#xD;
&#xD;
      While PTH is an important cause of disability after TBI, problems with memory, executive&#xD;
      function, depression, anxiety, irritability, fatigue, post-traumatic stress, and other&#xD;
      neurobehavioral disorders are also common after TBI and contribute to disability. The H3-L6&#xD;
      (High Omega-3 Low Omega-6) intervention increased circulating concentrations of several key&#xD;
      bioactive mediators which could hypothetically also have favorable effects on these&#xD;
      TBI-associated non-headache impairments associated with TBI combat injuries. Omega-3 fatty&#xD;
      acids have been widely studied in pre-clinical models and human TBI and demonstrate promising&#xD;
      evidence of both neuroprotective and neurorestorative efficacy.&#xD;
&#xD;
      Potential mechanisms include antioxidant, anti-inflammatory, and pro-neurogenic effects. In&#xD;
      our pilot study, the H3-L6 intervention significantly increased circulating levels of&#xD;
      docosahexaenoic acid-eicosapentaenoic acid (DHA-EPA) , a potent stimulator of neurite growth&#xD;
      and synaptogenesis in hippocampus and other central nervous system (CNS) tissues.&#xD;
      Corresponding increases in the synaptamide biosynthesis in central nervous system tissues&#xD;
      could hypothetically assist cognitive and functional neurorecovery associated with traumatic&#xD;
      brain injury. Further, the reduction of proinflammatory metabolites of omega-6 fatty acids&#xD;
      may provide additional benefits beyond what can be achieved through omega-3 supplementation&#xD;
      alone.&#xD;
&#xD;
      Study Type: Interventional, Phase 2, double blind Study Design: Allocation: Randomized,&#xD;
      parallel group Masking: Double Blind (Participant, Investigator, Outcomes Assessor) Primary&#xD;
      Purpose: Treatment&#xD;
&#xD;
      Primary Outcome Measures:&#xD;
&#xD;
      Hypothesis and Objective: The investigators will obtain support for the following hypotheses&#xD;
      through three specific aims:&#xD;
&#xD;
      Specific Aim 1: To compare the efficacy of the H3-L6 Diet to the Control Diet, in reducing&#xD;
      headache pain and improving headache-related quality of life.&#xD;
&#xD;
      Hypothesis 1: Compared to the Control Diet, the H3-L6 Diet will produce significant&#xD;
      improvement in:&#xD;
&#xD;
      (1a) the Headache Impact Test-a headache-specific quality of life measure-Primary Clinical&#xD;
      Outcome);&#xD;
&#xD;
      (1b) mean total Headache Hours per day; and&#xD;
&#xD;
      (1c) mean Severe Headache Hours per day.&#xD;
&#xD;
      Secondary Outcomes Measures:&#xD;
&#xD;
      Specific Aim 2: To evaluate whether the H3-L6 Diet can increase circulating anti-nociceptive&#xD;
      omega-3 metabolites, and reduce pro-nociceptive omega-6 metabolites, in patients with&#xD;
      Posttraumatic Headaches.&#xD;
&#xD;
      Hypothesis 2: Compared to the Control Diet, the H3-L6 Diet will produce significant increases&#xD;
      in anti-nociceptive omega-3 metabolites including 17-hydroxy DHA (Primary Biochemical Aim),&#xD;
      and reductions in pro-nociceptive omega-6 metabolites.&#xD;
&#xD;
      Other Outcomes Measures Specific Aim 3: To explore the potential of the H3-L6 intervention&#xD;
      for improving non-headache TBI outcomes.&#xD;
&#xD;
      Hypothesis 3: Compared to the Control Diet, the H3-L6 Diet will produce significant&#xD;
      improvement in:&#xD;
&#xD;
      (3a) non-headache pain; (3b) depression/anxiety; (3c) symptoms of post-traumatic stress&#xD;
      disorder; (3d) cognitive function; (3e) sleep quality; and (3f) will significantly reduce the&#xD;
      use of acute pain medications. Enrollment: Up to 300 total participants enrolled among the 3&#xD;
      military sites for 120 12-week diet completers&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 21, 2017</start_date>
  <completion_date type="Anticipated">March 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <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.</measure>
    <time_frame>The HIT-6 is administered at study visits at week 0 (enrollment), 4, 10, 12, 14, 16</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Primary Biochemical Outcome: To evaluate the effects of the H3-L6 and L3-H6 Diet on circulating fatty acids and bioactive metabolites.</measure>
    <time_frame>Fasting blood draws at study visits at weeks 4, 10, 16</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <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.</measure>
    <time_frame>Daily on-line diary entry during the 16-week study</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To explore the potential of the H3-L6 intervention for improving non-headache pain outcomes.</measure>
    <time_frame>Study visits at week 0 and 16</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To explore the potential of the H3-L6 intervention for decreasing acute pain medication usage</measure>
    <time_frame>Daily on-line diary entry during the 16-week study</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To explore the potential of the H3-L6 intervention for improving sleep quality</measure>
    <time_frame>the PSQI is administered at weeks 4 and 16 of the study</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To explore the potential of the H3-L6 intervention for improving psychological distress (depression/anxiety)</measure>
    <time_frame>Study visits at week 0 and 16</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To explore the potential of the H3-L6 intervention for improving symptoms of post-traumatic stress disorder (PTSD)</measure>
    <time_frame>The PCL-C is administered at study visits at weeks 4 &amp;16</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To explore the potential of the H3-L6 intervention for improving post-concussive symptoms.</measure>
    <time_frame>NSI and GOS-E are administered at weeks 4 and 16.</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Post-Traumatic Headache Chronic Without Intractable Headache</condition>
  <arm_group>
    <arm_group_label>H3-L6</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>High Omega-3, low Omega-6 diet</description>
  </arm_group>
  <arm_group>
    <arm_group_label>L3-H6</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Control diet containing average US polyunsaturated fatty acid (PUFA) content with low omega-3 and high omega-6 content</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Diet/nutrition intervention</intervention_name>
    <description>The intervention will be administered through food products rather than dietary supplements</description>
    <arm_group_label>H3-L6</arm_group_label>
    <arm_group_label>L3-H6</arm_group_label>
    <other_name>High omega-3 versus high omega-6 dietary intervention</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  In order to be included in the study, you must be a person of either gender who is at&#xD;
             least 18 years of age, meets criteria of having had a traumatic brain injury, a&#xD;
             physiological disruption of brain function, as manifested by at least one of the&#xD;
             following:&#xD;
&#xD;
               1. . Any period of loss of consciousness&#xD;
&#xD;
               2. . Any loss of memory for events immediately before or after the accident&#xD;
&#xD;
               3. . Any alteration of mental state at the time of the accident (e.g., feeling&#xD;
                  dazed, disoriented, and confused)&#xD;
&#xD;
               4. . Focal neurologic deficits that may or may not be permanent.&#xD;
&#xD;
                    -  Traumatically induced includes the head being struck, the head striking an&#xD;
                       object, or the brain undergoing an acceleration/deceleration movement (i.e.&#xD;
                       whiplash) without direct external trauma to the head.&#xD;
&#xD;
          -  Meets Internation Classification of Headache Disorders-version III (ICHD-III) criteria&#xD;
             for persistent post-traumatic headache which is defined as a headache of at least 3&#xD;
             months duration caused by a traumatic injury to the head.&#xD;
&#xD;
          -  Meets ICHD-III criteria for episodic/chronic migraine, with or without aura (excepting&#xD;
             exclusion for organic disease):&#xD;
&#xD;
               1. . Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)&#xD;
&#xD;
               2. . Headache has at least 2 of the following characteristics:&#xD;
&#xD;
                    1. unilateral location&#xD;
&#xD;
                    2. pulsating quality&#xD;
&#xD;
                    3. moderate or severe pain intensity&#xD;
&#xD;
                    4. aggravation by or causing avoidance of routine physical activity (eg,&#xD;
                       walking or climbing stairs)&#xD;
&#xD;
               3. . During headache at least 1 of the following:&#xD;
&#xD;
                    1. nausea and/or vomiting&#xD;
&#xD;
                    2. photophobia and phonophobia&#xD;
&#xD;
          -  A potential candidate for this study must be under the care of a physician for&#xD;
             headaches and have an incomplete response to standard headache treatments.&#xD;
&#xD;
          -  Must have headache frequency of more than 8 days per month.&#xD;
&#xD;
          -  Must have a headache history of more than 6 months&#xD;
&#xD;
          -  Must be able to attend or remotely participate (by video conference or telephone) in&#xD;
             seven dietitian counseling sessions, and adhere to diet supplied to study&#xD;
             participants.&#xD;
&#xD;
          -  Must be a Department of Defense (DoD) healthcare beneficiary and eligible to receive&#xD;
             care at Walter Reed National Military Medical Center (WRNMMC), Fort Belvoir Community&#xD;
             Hospital (FBCH) or Womack Army Medical Center (WAMC).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A person cannot be in this study if they have a history of specific food allergies,&#xD;
             especially to fish, dairy or gluten.&#xD;
&#xD;
        Also exclusionary are:&#xD;
&#xD;
          -  Pregnancy or anticipated pregnancy&#xD;
&#xD;
          -  Aversion to eating fish&#xD;
&#xD;
          -  History of organic brain disorder other than TBI (vasculitis, encephalitis,&#xD;
             meningitis, brain tumor)&#xD;
&#xD;
          -  Major medical illness such as malignancy, diabetes, autoimmune or immune deficiency&#xD;
             disorders, history of stroke or myocardial infarction&#xD;
&#xD;
          -  Anticipated deployment or move to alternate location in the next 16 weeks&#xD;
&#xD;
          -  Inability to read and communicate in English&#xD;
&#xD;
          -  Regular use of fatty acid containing supplements&#xD;
&#xD;
          -  Active or recent (2 years) history of treatment for substance abuse&#xD;
&#xD;
          -  Cognitive impairment that prevents understanding of the protocol and completion of&#xD;
             study procedures including compliance with the diet, blood draws and maintaining a&#xD;
             daily headache diary.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kimbra Kenney, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Uniformed Services University of the Health Sciences</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Chris Ramsden, MD</last_name>
    <role>Study Director</role>
    <affiliation>National Institutes of Health (NIH)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>John Mann, MD</last_name>
    <role>Study Director</role>
    <affiliation>UNC</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kimbra Kenney, MD</last_name>
    <phone>301 400 0492</phone>
    <email>kimbra.kenney@usuhs.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Carol Moore, MS</last_name>
    <email>carol.moore.ctr@usuhs.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Walter Reed National Military Medical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20889</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cora Davis</last_name>
      <phone>301-319-3780</phone>
      <email>cora.davis.ctr@usuhs.edu</email>
    </contact>
    <contact_backup>
      <last_name>Kimbra Kenney, MD</last_name>
      <phone>301 400 0942</phone>
      <email>kimbra.kenney@usuhs.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Womack Army Medical Center (WAMC)</name>
      <address>
        <city>Fort Bragg</city>
        <state>North Carolina</state>
        <zip>28310</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jacques Arrieux</last_name>
      <phone>910-908-2268</phone>
      <email>jacques.p.arrieux.ctr@mail.mil</email>
    </contact>
    <contact_backup>
      <last_name>Katie Russell</last_name>
      <phone>910 908 2274</phone>
      <email>katie.n.russell.ctr@mail.mil</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Fort Belvoir Community Hospital</name>
      <address>
        <city>Fort Belvoir</city>
        <state>Virginia</state>
        <zip>22060</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rebecca Sandlain</last_name>
      <email>rebecca.l.sandlain.ctr@mail.mil</email>
    </contact>
    <contact_backup>
      <last_name>Melissa Guerra, MD</last_name>
      <email>melissa.f.guerra.civ@mail.mil</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.medlineplus.gov/traumaticbraininjury.html</url>
    <description>Medline Plus related topic: Traumatic Brain Injury</description>
  </link>
  <link>
    <url>http://www.medlineplus.gov/headache.html</url>
    <description>Medline Plus related topic: Post-traumatic headache</description>
  </link>
  <link>
    <url>http://www.medlineplus.gov/migraine.html</url>
    <description>Medline Plus related topic: Migraine</description>
  </link>
  <reference>
    <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>
    <PMID>23886520</PMID>
  </reference>
  <reference>
    <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>
    <PMID>25790451</PMID>
  </reference>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>August 21, 2017</study_first_submitted>
  <study_first_submitted_qc>August 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 5, 2017</study_first_posted>
  <last_update_submitted>October 4, 2021</last_update_submitted>
  <last_update_submitted_qc>October 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Uniformed Services University of the Health Sciences</investigator_affiliation>
    <investigator_full_name>Kimbra Kenney</investigator_full_name>
    <investigator_title>Associate Professor, Neurology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Post-Traumatic Headache</mesh_term>
    <mesh_term>Headache Disorders</mesh_term>
    <mesh_term>Headache</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Study data to be uploaded into Federation Interagency Traumatic Brain Injury Repository (FITBIR) and made accessible after study is completed</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>After study is uploaded into FITBIR</ipd_time_frame>
    <ipd_access_criteria>Through FITBIR</ipd_access_criteria>
  </patient_data>
  <pending_results>
    <submitted>March 12, 2023</submitted>
    <returned>April 5, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03272399
org study id: 416047
nct id: NCT03272399
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
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.
time frame: The HIT-6 is administered at study visits at week 0 (enrollment), 4, 10, 12, 14, 16
description: 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.
measure: 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
description: 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.
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.
time frame: Daily on-line diary entry during the 16-week study
description: 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.
measure: To explore the potential of the H3-L6 intervention for improving non-headache pain outcomes.
time frame: Study visits at week 0 and 16
description: 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.
measure: 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
description: 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.
measure: 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
description: 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.
measure: To explore the potential of the H3-L6 intervention for improving psychological distress (depression/anxiety)
time frame: Study visits at week 0 and 16
description: 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.
measure: 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
description: 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.
measure: 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.
description: 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.
arm group label: H3-L6
arm group type: Experimental
description: High Omega-3, low Omega-6 diet
arm group label: L3-H6
arm group type: Active Comparator
description: Control diet containing average US polyunsaturated fatty acid (PUFA) content with low omega-3 and high omega-6 content
intervention type: Other
intervention name: Diet/nutrition intervention
description: The intervention will be administered through food products rather than dietary supplements
arm group label: H3-L6
arm group label: L3-H6
other name: High omega-3 versus high omega-6 dietary intervention
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kimbra Kenney, MD
role: Principal Investigator
affiliation: Uniformed Services University of the Health Sciences
last name: Chris Ramsden, MD
role: Study Director
affiliation: National Institutes of Health (NIH)
last name: John Mann, MD
role: Study Director
affiliation: UNC
last name: Kimbra Kenney, MD
phone: 301 400 0492
email: kimbra.kenney@usuhs.edu
last name: Carol Moore, MS
email: carol.moore.ctr@usuhs.edu
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
url: http://www.medlineplus.gov/traumaticbraininjury.html
description: Medline Plus related topic: Traumatic Brain Injury
url: http://www.medlineplus.gov/headache.html
description: Medline Plus related topic: Post-traumatic headache
url: http://www.medlineplus.gov/migraine.html
description: Medline Plus related topic: Migraine
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.
PMID: 23886520
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.
PMID: 25790451
responsible party type: Principal Investigator
investigator affiliation: Uniformed Services University of the Health Sciences
investigator full name: Kimbra Kenney
investigator title: Associate Professor, Neurology
mesh term: Post-Traumatic Headache
mesh term: Headache Disorders
mesh term: Headache
sharing ipd: Yes
ipd description: Study data to be uploaded into Federation Interagency Traumatic Brain Injury Repository (FITBIR) and made accessible after study is completed
ipd info type: Study Protocol
ipd info type: Clinical Study Report (CSR)
ipd time frame: After study is uploaded into FITBIR
ipd access criteria: Through FITBIR
submitted: March 12, 2023
returned: April 5, 2023