<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/NCT03032302</url>
  </required_header>
  <id_info>
    <org_study_id>STH19529</org_study_id>
    <nct_id>NCT03032302</nct_id>
  </id_info>
  <brief_title>Micronutrient Supplement Effects on Cognitive Outcomes in Post-Acute TBI</brief_title>
  <official_title>Micronutrient Intervention Effects on Cognitive Outcomes in Post-Acute Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sheffield Hallam University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sheffield Teaching Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Rotherham Doncaster and South Humber NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sheffield Hallam University</source>
  <oversight_info>
    <has_dmc>No</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>
      Traumatic brain injury (TBI) refers to neuronal damage occurring as the result of an external&#xD;
      force being applied to brain tissue. In the United Kingdom annual figures (2013-2014) show&#xD;
      449,000 hospital admittances with a diagnosis of head injury with males up to five times more&#xD;
      likely to sustain a head injury than females. Traumatic brain injury (TBI) causes life-long&#xD;
      disability, with no significant reduction in life expectancy, affecting a diverse range of&#xD;
      cognitive and social functions including memory, task planning and execution, impulse&#xD;
      control, social interactions, personality changes and depression. Following traumatic brain&#xD;
      injury acquired deficits can lead to problems with resumption of aspects of daily life,&#xD;
      particularly in terms of returning to work and interpersonal relationships.&#xD;
&#xD;
      The initial injury triggers a secondary cascade of metabolic, neurochemical and cellular&#xD;
      changes within the brain, primarily aimed at limiting damage and stimulating repair.&#xD;
      Paradoxically prolonged secondary cascade mechanisms, including haemorrhage, oedema,&#xD;
      neuroinflammation and axonal injury, results in exacerbation of deficits observed. The&#xD;
      heterogeneous on-going nature of the secondary cascade presents clinicians with opportunities&#xD;
      to intervene in an attempt to limit neuronal damage. A large body of nutritional research has&#xD;
      been focused on addressing the hypermetabolic and catabolic states created by secondary&#xD;
      cascade processes in the acute stage. Addressing these demands has played a significant role&#xD;
      in reducing mortality and infection rates following head injury, however there has not been&#xD;
      the same depth of research investigating the post-acute period (once individuals are&#xD;
      discharged from hospital).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Micronutrients (including vitamins, minerals and certain polyunsaturated fatty acids) are&#xD;
      required by the brain for normal functioning and, with few exceptions, can only be obtained&#xD;
      through dietary sources. Research into degenerative diseases of aging have linked&#xD;
      mitochondrial aging and DNA damage caused by micronutrient deficiency to greater incidence of&#xD;
      cognitive decline and stroke, among other diseases, in the general population, particularly&#xD;
      in those consuming food rich in fats and carbohydrates but poor in micronutrient content.&#xD;
      Other research focusing on cognition, behaviour and mood state has associated micronutrient&#xD;
      deficiencies with a wide range of neurological conditions including Alzheimer's Disease,&#xD;
      Parkinson's Disease, multiple sclerosis, autism spectrum disorders, depression, fatigue and&#xD;
      schizophrenia. There have however been very few studies using micronutrient interventions in&#xD;
      post-acute human TBI. In a study with thirty retired American Football players an&#xD;
      intervention including supplementation with a broad-spectrum multivitamin, omega-3 fish oils&#xD;
      and a number of other substances resulted in significant percentile score improvements in&#xD;
      almost half of the participants (n=100) across a broad range of cognitive measures. Findings&#xD;
      demonstrated that micronutrient intervention can result in significant measurable&#xD;
      improvements in those with TBI many years following the initial insult. A normative study&#xD;
      will be conducted with three groups assigned to Vit D, Vit C and multivitamin arms (N = 60)&#xD;
      tested at baseline on cognitive function and post-intervention. The TBI study will recruit&#xD;
      three groups of individuals with post-acute traumatic brain injuries and measure whether&#xD;
      there is improved cognitive outcomes (measured by test-retest on a cognitive battery)&#xD;
      associated with the supplements shown to be most effective in the pilot study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2017</start_date>
  <completion_date type="Actual">April 18, 2020</completion_date>
  <primary_completion_date type="Actual">April 18, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Performance on cognitive test measures (a battery of standardized tests; memory, executive function, social cognition, general intelligence, learning and processing speed)</measure>
    <time_frame>Three time points: baseline (T1), 8 weeks (T2) and 22 weeks (T3)</time_frame>
    <description>Analysis of change in cognitive test battery results between each time point (T2 minus T1. T3 minus T2. T3 minus T1)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Average dietary intake of micronutrients and fatty acids</measure>
    <time_frame>Data collected at four time points (3 day diaries) during participant's involvement in the study via participants filling in paper food diary</time_frame>
    <description>Analysis of dietary intake via Nutritics software (https://www.nutritics.com/p/references), average intake value for each micronutrient supplied by software output. This will be compared to recommended daily amounts to evaluate levels of sufficiency/insufficiency in each participant.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Multivitamin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Swisse Womens 50+ Ultivite Multivitamin. Once daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Omega-3 Fatty Acids</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Holland and Barrett Triple Strength Omega-3 Fish Oils. Once Daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Treatment as usual (cognitive rehabilitation, occupational therapy, physiotherapy; as required)</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Swisse Womens 50+ Ultivite Multivitamin</intervention_name>
    <description>Single tablet taken once daily</description>
    <arm_group_label>Multivitamin</arm_group_label>
    <arm_group_label>Omega-3 Fatty Acids</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Holland and Barrett Triple Strength Omega-3 Fish Oil</intervention_name>
    <description>Single capsule taken once daily</description>
    <arm_group_label>Multivitamin</arm_group_label>
    <arm_group_label>Omega-3 Fatty Acids</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  First and only traumatic brain injury.&#xD;
&#xD;
          -  Complex mild to moderate injury.&#xD;
&#xD;
          -  3-24 months post-injury&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to give informed consent.&#xD;
&#xD;
          -  Already taking micronutrient/fatty acid supplements.&#xD;
&#xD;
          -  Hemianopia&#xD;
&#xD;
          -  Hemiplegia.&#xD;
&#xD;
          -  Pregnant or breastfeeding.&#xD;
&#xD;
          -  Diagnosed with clinically low blood pressure, diabetes, or disease of&#xD;
             neurodegeneration.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lynne A Barker, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Sheffield Hallam University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sheffield Hallam University</name>
      <address>
        <city>Sheffield</city>
        <state>South Yorkshire</state>
        <zip>S10 2BQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>https://digital.nhs.uk/data-and-information/data-tools-and-services/data-services/hospital-episode-statistics</url>
    <description>Hospital Episode Statistics 2017-18</description>
  </link>
  <link>
    <url>https://www.nutritics.com/p/references</url>
    <description>Nutritics</description>
  </link>
  <reference>
    <citation>Lippert-Gruner M, Kuchta J, Hellmich M, Klug N. Neurobehavioural deficits after severe traumatic brain injury (TBI). Brain Inj. 2006 Jun;20(6):569-74. doi: 10.1080/02699050600664467.</citation>
    <PMID>16754282</PMID>
  </reference>
  <reference>
    <citation>Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA. 2010 May 19;303(19):1938-45. doi: 10.1001/jama.2010.599.</citation>
    <PMID>20483970</PMID>
  </reference>
  <reference>
    <citation>Borzotta AP, Pennings J, Papasadero B, Paxton J, Mardesic S, Borzotta R, Parrott A, Bledsoe F. Enteral versus parenteral nutrition after severe closed head injury. J Trauma. 1994 Sep;37(3):459-68. doi: 10.1097/00005373-199409000-00022.</citation>
    <PMID>8083910</PMID>
  </reference>
  <reference>
    <citation>Cook AM, Peppard A, Magnuson B. Nutrition considerations in traumatic brain injury. Nutr Clin Pract. 2008 Dec-2009 Jan;23(6):608-20. doi: 10.1177/0884533608326060.</citation>
    <PMID>19033220</PMID>
  </reference>
  <reference>
    <citation>Ames BN. Optimal micronutrients delay mitochondrial decay and age-associated diseases. Mech Ageing Dev. 2010 Jul-Aug;131(7-8):473-9. doi: 10.1016/j.mad.2010.04.005. Epub 2010 Apr 24.</citation>
    <PMID>20420847</PMID>
  </reference>
  <reference>
    <citation>Balion C, Griffith LE, Strifler L, Henderson M, Patterson C, Heckman G, Llewellyn DJ, Raina P. Vitamin D, cognition, and dementia: a systematic review and meta-analysis. Neurology. 2012 Sep 25;79(13):1397-405. doi: 10.1212/WNL.0b013e31826c197f.</citation>
    <PMID>23008220</PMID>
  </reference>
  <reference>
    <citation>Bitarafan S, Harirchian MH, Nafissi S, Sahraian MA, Togha M, Siassi F, Saedisomeolia A, Alipour E, Mohammadpour N, Chamary M, Honarvar NM, Saboor-Yaraghi AA. Dietary intake of nutrients and its correlation with fatigue in multiple sclerosis patients. Iran J Neurol. 2014;13(1):28-32.</citation>
    <PMID>24800044</PMID>
  </reference>
  <reference>
    <citation>Nimitphong H, Holick MF. Vitamin D, neurocognitive functioning and immunocompetence. Curr Opin Clin Nutr Metab Care. 2011 Jan;14(1):7-14. doi: 10.1097/MCO.0b013e3283414c38.</citation>
    <PMID>21102318</PMID>
  </reference>
  <reference>
    <citation>Oudshoorn C, Mattace-Raso FU, van der Velde N, Colin EM, van der Cammen TJ. Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 2008;25(6):539-43. doi: 10.1159/000134382. Epub 2008 May 26.</citation>
    <PMID>18503256</PMID>
  </reference>
  <reference>
    <citation>Amen DG, Wu JC, Taylor D, Willeumier K. Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation. J Psychoactive Drugs. 2011 Jan-Mar;43(1):1-5. doi: 10.1080/02791072.2011.566489.</citation>
    <PMID>21615001</PMID>
  </reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>January 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 26, 2017</study_first_posted>
  <last_update_submitted>October 20, 2020</last_update_submitted>
  <last_update_submitted_qc>October 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>TBI</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
  </condition_browse>
  <!-- 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/NCT03032302
org study id: STH19529
nct id: NCT03032302
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Traumatic brain injury (TBI) refers to neuronal damage occurring as the result of an external
      force being applied to brain tissue. In the United Kingdom annual figures (2013-2014) show
      449,000 hospital admittances with a diagnosis of head injury with males up to five times more
      likely to sustain a head injury than females. Traumatic brain injury (TBI) causes life-long
      disability, with no significant reduction in life expectancy, affecting a diverse range of
      cognitive and social functions including memory, task planning and execution, impulse
      control, social interactions, personality changes and depression. Following traumatic brain
      injury acquired deficits can lead to problems with resumption of aspects of daily life,
      particularly in terms of returning to work and interpersonal relationships.

      The initial injury triggers a secondary cascade of metabolic, neurochemical and cellular
      changes within the brain, primarily aimed at limiting damage and stimulating repair.
      Paradoxically prolonged secondary cascade mechanisms, including haemorrhage, oedema,
      neuroinflammation and axonal injury, results in exacerbation of deficits observed. The
      heterogeneous on-going nature of the secondary cascade presents clinicians with opportunities
      to intervene in an attempt to limit neuronal damage. A large body of nutritional research has
      been focused on addressing the hypermetabolic and catabolic states created by secondary
      cascade processes in the acute stage. Addressing these demands has played a significant role
      in reducing mortality and infection rates following head injury, however there has not been
      the same depth of research investigating the post-acute period (once individuals are
      discharged from hospital).
Micronutrients (including vitamins, minerals and certain polyunsaturated fatty acids) are
      required by the brain for normal functioning and, with few exceptions, can only be obtained
      through dietary sources. Research into degenerative diseases of aging have linked
      mitochondrial aging and DNA damage caused by micronutrient deficiency to greater incidence of
      cognitive decline and stroke, among other diseases, in the general population, particularly
      in those consuming food rich in fats and carbohydrates but poor in micronutrient content.
      Other research focusing on cognition, behaviour and mood state has associated micronutrient
      deficiencies with a wide range of neurological conditions including Alzheimer's Disease,
      Parkinson's Disease, multiple sclerosis, autism spectrum disorders, depression, fatigue and
      schizophrenia. There have however been very few studies using micronutrient interventions in
      post-acute human TBI. In a study with thirty retired American Football players an
      intervention including supplementation with a broad-spectrum multivitamin, omega-3 fish oils
      and a number of other substances resulted in significant percentile score improvements in
      almost half of the participants (n=100) across a broad range of cognitive measures. Findings
      demonstrated that micronutrient intervention can result in significant measurable
      improvements in those with TBI many years following the initial insult. A normative study
      will be conducted with three groups assigned to Vit D, Vit C and multivitamin arms (N = 60)
      tested at baseline on cognitive function and post-intervention. The TBI study will recruit
      three groups of individuals with post-acute traumatic brain injuries and measure whether
      there is improved cognitive outcomes (measured by test-retest on a cognitive battery)
      associated with the supplements shown to be most effective in the pilot study.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Supportive Care
masking: Double (Participant, Investigator)
measure: Performance on cognitive test measures (a battery of standardized tests; memory, executive function, social cognition, general intelligence, learning and processing speed)
time frame: Three time points: baseline (T1), 8 weeks (T2) and 22 weeks (T3)
description: Analysis of change in cognitive test battery results between each time point (T2 minus T1. T3 minus T2. T3 minus T1)
measure: Average dietary intake of micronutrients and fatty acids
time frame: Data collected at four time points (3 day diaries) during participant's involvement in the study via participants filling in paper food diary
description: Analysis of dietary intake via Nutritics software (https://www.nutritics.com/p/references), average intake value for each micronutrient supplied by software output. This will be compared to recommended daily amounts to evaluate levels of sufficiency/insufficiency in each participant.
arm group label: Multivitamin
arm group type: Experimental
description: Swisse Womens 50+ Ultivite Multivitamin. Once daily.
arm group label: Omega-3 Fatty Acids
arm group type: Experimental
description: Holland and Barrett Triple Strength Omega-3 Fish Oils. Once Daily
arm group label: Control
arm group type: No Intervention
description: Treatment as usual (cognitive rehabilitation, occupational therapy, physiotherapy; as required)
intervention type: Dietary Supplement
intervention name: Swisse Womens 50+ Ultivite Multivitamin
description: Single tablet taken once daily
arm group label: Multivitamin
arm group label: Omega-3 Fatty Acids
intervention type: Dietary Supplement
intervention name: Holland and Barrett Triple Strength Omega-3 Fish Oil
description: Single capsule taken once daily
arm group label: Multivitamin
arm group label: Omega-3 Fatty Acids
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Lynne A Barker, PhD
role: Study Director
affiliation: Sheffield Hallam University
facility: 
country: United Kingdom
url: https://digital.nhs.uk/data-and-information/data-tools-and-services/data-services/hospital-episode-statistics
description: Hospital Episode Statistics 2017-18
url: https://www.nutritics.com/p/references
description: Nutritics
citation: Lippert-Gruner M, Kuchta J, Hellmich M, Klug N. Neurobehavioural deficits after severe traumatic brain injury (TBI). Brain Inj. 2006 Jun;20(6):569-74. doi: 10.1080/02699050600664467.
PMID: 16754282
citation: Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA. 2010 May 19;303(19):1938-45. doi: 10.1001/jama.2010.599.
PMID: 20483970
citation: Borzotta AP, Pennings J, Papasadero B, Paxton J, Mardesic S, Borzotta R, Parrott A, Bledsoe F. Enteral versus parenteral nutrition after severe closed head injury. J Trauma. 1994 Sep;37(3):459-68. doi: 10.1097/00005373-199409000-00022.
PMID: 8083910
citation: Cook AM, Peppard A, Magnuson B. Nutrition considerations in traumatic brain injury. Nutr Clin Pract. 2008 Dec-2009 Jan;23(6):608-20. doi: 10.1177/0884533608326060.
PMID: 19033220
citation: Ames BN. Optimal micronutrients delay mitochondrial decay and age-associated diseases. Mech Ageing Dev. 2010 Jul-Aug;131(7-8):473-9. doi: 10.1016/j.mad.2010.04.005. Epub 2010 Apr 24.
PMID: 20420847
citation: Balion C, Griffith LE, Strifler L, Henderson M, Patterson C, Heckman G, Llewellyn DJ, Raina P. Vitamin D, cognition, and dementia: a systematic review and meta-analysis. Neurology. 2012 Sep 25;79(13):1397-405. doi: 10.1212/WNL.0b013e31826c197f.
PMID: 23008220
citation: Bitarafan S, Harirchian MH, Nafissi S, Sahraian MA, Togha M, Siassi F, Saedisomeolia A, Alipour E, Mohammadpour N, Chamary M, Honarvar NM, Saboor-Yaraghi AA. Dietary intake of nutrients and its correlation with fatigue in multiple sclerosis patients. Iran J Neurol. 2014;13(1):28-32.
PMID: 24800044
citation: Nimitphong H, Holick MF. Vitamin D, neurocognitive functioning and immunocompetence. Curr Opin Clin Nutr Metab Care. 2011 Jan;14(1):7-14. doi: 10.1097/MCO.0b013e3283414c38.
PMID: 21102318
citation: Oudshoorn C, Mattace-Raso FU, van der Velde N, Colin EM, van der Cammen TJ. Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 2008;25(6):539-43. doi: 10.1159/000134382. Epub 2008 May 26.
PMID: 18503256
citation: Amen DG, Wu JC, Taylor D, Willeumier K. Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation. J Psychoactive Drugs. 2011 Jan-Mar;43(1):1-5. doi: 10.1080/02791072.2011.566489.
PMID: 21615001
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic