<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/NCT04460365</url>
  </required_header>
  <id_info>
    <org_study_id>1/378/1535</org_study_id>
    <nct_id>NCT04460365</nct_id>
  </id_info>
  <brief_title>European Nutrition in Glaucoma Management Trial</brief_title>
  <acronym>ENIGMA</acronym>
  <official_title>European Nutrition in Glaucoma Management Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre for Eye Research Ireland</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre for Eye Research Ireland</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>
      European Nutrition in Glaucoma Management (ENIGMA) trial will evaluate the effect of 18-month&#xD;
      supplementation with lutein, zeaxanthin and meso-zeaxanthin on macular pigment (MP) levels,&#xD;
      vision, cognition and serum biomarkers of inflammation and oxidative stress in glaucoma&#xD;
      patients.&#xD;
&#xD;
      This study comprises a randomised, placebo controlled and double masked clinical trial&#xD;
      designed to establish MP response to supplementation with lutein, zeaxanthin and&#xD;
      meso-zeaxanthin over an 18-month period. The study will also investigate the relationship&#xD;
      between macular pigment, cognitive function, oxidative stress and inflammation, and determine&#xD;
      the impact of dietary supplementation on vision, retinal structure, quality of life and&#xD;
      cognitive function among glaucoma subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a research study looking at the effects of dietary MP supplementation in glaucoma&#xD;
      patients. Glaucoma can cause irreversible visual impairment. Current treatment modalities&#xD;
      only halt disease progression and do not improve visual function. It is important to&#xD;
      understand that poor visual function can have major consequences to an individual's&#xD;
      day-to-day tasks such as increased risk of falls and automobile accidents.&#xD;
&#xD;
      Disability glare is commonly experienced by eye disease patients, including those with&#xD;
      glaucoma, and has been shown to be present even in those who are mildly affected by the&#xD;
      disease. MP is a blue-light filter that plays an important role in visual performance&#xD;
      including glare sensitivity. Moreover, MP is a potent antioxidant, and it is widely known&#xD;
      that oxidative stress is involved in the pathogenesis of glaucoma, both at the level of&#xD;
      retinal ganglion cells and trabecular meshwork.&#xD;
&#xD;
      Glaucoma and cognitive decline are both neurodegenerative processes that share several&#xD;
      antecedents. The clustering of degenerative disorders towards the end of life is thought to&#xD;
      be the result of cumulative and lifelong oxidative injury, and is consistent with the free&#xD;
      radical theory of aging. Observational studies have revealed links between the two&#xD;
      conditions. The commonalities between glaucoma and cognitive decline, including their shared&#xD;
      risk factor profile and pathophysiological pathways, suggest a role for exploring common&#xD;
      mechanisms and perhaps even a shared therapeutic approach.&#xD;
&#xD;
      The purpose of this study is to investigate the effects of dietary MP supplementation on MP&#xD;
      levels, serum biomarkers of inflammation and oxidative stress, vision, retinal structure and&#xD;
      cognition in glaucoma patients.&#xD;
&#xD;
      Study design 64 glaucoma participants Treatment arm: 10 mg Lutein, 2 mg zeaxanthin, 10 mg&#xD;
      meso-zeaxanthin - 2/3 Placebo arm: Identical capsule containing no active ingredients - 1/3&#xD;
      Duration of intervention: 18 months&#xD;
&#xD;
      At baseline, all glaucoma participants undergo detailed vision assessments including visual&#xD;
      acuity, microperimetry, measurement of macular pigment optical density (MPOD) with&#xD;
      dual-wavelength fundus autofluorescence technique, optical coherence tomography scans,&#xD;
      contrast sensitivity testing with and without glare, photostress recovery time, pupil&#xD;
      reaction assessment, lens fluorescence measurement and fill out vision-related and dietary&#xD;
      questionnaires. Patients also undergo detailed cognitive assessment including the flanker&#xD;
      task, sound-induced flash illusions task, verbal fluency (FAS and animal fluency tests), SKT&#xD;
      (short cognitive assessment) and MMSE (mini-mental state examination) tests which provide&#xD;
      measures of reaction time, short-term memory, multisensory integration and attention. A blood&#xD;
      sample is also collected for analysis of oxidative stress and inflammatory biomarkers.&#xD;
&#xD;
      After the baseline assessments, glaucoma participants are randomised (2:1) to receive a&#xD;
      dietary MP supplementation or placebo for 6 months. Each daily dose of the supplement&#xD;
      contains 10mg Lutein, 10mg meso-Zeaxanthin and 2mg Zeaxanthin in a softgel capsule. The&#xD;
      intervention consists of a daily oral consumption of one softgel capsule (recommended to be&#xD;
      consumed with food) for a period of 18 months, with patients compliance checks and re-supply&#xD;
      of supplement every 6 months. The placebo looks identical to the active supplement in its&#xD;
      preparation size, colour, smell and taste. It contains no active ingredients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2017</start_date>
  <completion_date type="Actual">September 17, 2020</completion_date>
  <primary_completion_date type="Actual">September 17, 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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in MPOD in response to treatment from baseline at 18 months</measure>
    <time_frame>18 months</time_frame>
    <description>Change in MPOD measured at each study visit from baseline to 18 months will be evaluated between active and placebo arms</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in multisensory integration from baseline following 18 months supplementation</measure>
    <time_frame>18 months</time_frame>
    <description>Multisensory integration will be assessed using a sound-induced flash illusions task (SIFI). Change in SIFI scores will be assessed between active and placebo treatment arms from baseline to 18 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in flanker task scores (reaction time and attention) from baseline following 18 months supplementation</measure>
    <time_frame>18 months</time_frame>
    <description>Change in flanker task scores will be assessed between active and placebo treatment arms from baseline to 18 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in SKT (Syndrom-Kurztest) score from baseline following 18 months supplementation</measure>
    <time_frame>18 months</time_frame>
    <description>SKT is a short cognitive battery of tests that evaluates general cognitive function. Change in SKT score will be assessed between active and placebo treatment arms from baseline to 18 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in verbal fluency (FAS score) from baseline following 18 months supplementation</measure>
    <time_frame>18 months</time_frame>
    <description>Change in verbal fluency assessed using the FAS test will be evaluated between active and placebo treatment arms from baseline to 18 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in verbal fluency (animal fluency test) from baseline following 18 months supplementation</measure>
    <time_frame>18 months</time_frame>
    <description>Change in verbal fluency assessed using the animal fluency test will be evaluated between active and placebo treatment arms from baseline to 18 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Visual Acuity in response to treatment from baseline at 18 months</measure>
    <time_frame>18 months</time_frame>
    <description>Change in Visual Acuity will be evaluated between active and placebo treatment arms from baseline to 18 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Contrast Sensitivity in response to treatment from baseline at 18 months</measure>
    <time_frame>18 months</time_frame>
    <description>Change in Contrast Sensitivity under photopic and mesopic conditions at 1.5, 3, 6, 12 and 18 cycles per degree will be evaluated between active and placebo treatment arms from baseline to 18 months, using the FACT device</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in incremental light sensitivity in response to treatment from baseline at 18 months</measure>
    <time_frame>18 months</time_frame>
    <description>Change in Microperimetry average threshold will be evaluated between active and placebo treatment arms from baseline to 18 months, using the Maia device</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Retinal Thickness parameters in response to treatment from baseline at 18 months</measure>
    <time_frame>18 months</time_frame>
    <description>Change in Retinal Thickness parameters will be evaluated between active and placebo treatment arms from baseline to 18 months, using the Spectralis OCT device</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum biomarkers of inflammation (C-reactive protein) from baseline following 18 months supplementation</measure>
    <time_frame>18 months</time_frame>
    <description>Inflammation will be assessed using the C-reactive protein biomarker measured in serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum biomarkers of oxidative stress (Oxidized LDL) from baseline following 18 months supplementation</measure>
    <time_frame>18 months</time_frame>
    <description>Oxidative stress will be assessed using the Oxidized LDL biomarker measured in serum</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">64</enrollment>
  <condition>Glaucoma, Open-Angle</condition>
  <arm_group>
    <arm_group_label>Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Softgel capsules: 10 mg Lutein, 2 mg zeaxanthin, 10 mg meso-zeaxanthin once a day with a meal for 18 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Identical capsule containing no active ingredients</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>10 mg Lutein, 2 mg zeaxanthin, 10 mg meso-zeaxanthin</intervention_name>
    <description>This is a lutein (10mg), zeaxanthin (2mg) and meso-zeaxanthin (10mg) one-a-day food supplement which combines all three macular carotenoids.&#xD;
These three nutrients are found at the back of the eye, at the macula, where they form the macular pigment (yellow colour). Meso-zeaxanthin is particularly concentrated at the centre of this pigment.&#xD;
Lutein and zeaxanthin can be found in fruits and dark green leafy vegetables and meso-zeaxanthin is present in some species of fish and seafood.</description>
    <arm_group_label>Active</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Softgel capsule containing sunflower oil (no active ingredients)</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Open-angle glaucoma patients aged 18 years or older&#xD;
&#xD;
               1. Primary open-angle glaucoma (POAG)&#xD;
&#xD;
               2. Normal-tension glaucoma (NTG)&#xD;
&#xD;
               3. Pseudoexfoliative glaucoma&#xD;
&#xD;
               4. Pigment dispersion glaucoma&#xD;
&#xD;
          -  Best corrected visual acuity of better than 6/12 in the study eye (logMAR &lt;0.3)&#xD;
&#xD;
          -  Either gender&#xD;
&#xD;
          -  Able to give informed consent, make the required study follow-up visits and adhere to&#xD;
             trial protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Underlying ocular disease such as age-related macular degeneration, diabetic&#xD;
             retinopathy or moderate to significant cataract (patients with established cataract&#xD;
             who are likely to progress)&#xD;
&#xD;
          -  Best corrected visual acuity of worse than 6/12 in the study eye (logMAR &gt; 0.3)&#xD;
&#xD;
          -  History of diabetes mellitus, any type of dementia (e.g. Alzheimer's has been shown to&#xD;
             be associated with lower macular pigment levels) or other significant systemic&#xD;
             condition that might affect capacity to complete the trial&#xD;
&#xD;
          -  MMSE score &lt; 26&#xD;
&#xD;
          -  Individuals taking dietary macular pigment supplements (containing lutein, zeaxanthin&#xD;
             and meso-zeaxanthin, such as MacuShield, Ocuvite Lutein/Complete, I-Caps etc.) in the&#xD;
             past 6 months&#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>James Loughman, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Head of the Centre for Eye Research Ireland, Professor</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centre for Eye Research Ireland</name>
      <address>
        <city>Dublin</city>
        <state>Co. Dublin</state>
        <zip>D07 H6K8</zip>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ireland</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>March 2, 2020</study_first_submitted>
  <study_first_submitted_qc>July 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>August 5, 2021</last_update_submitted>
  <last_update_submitted_qc>August 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 6, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>multisensory integration</keyword>
  <keyword>macular pigment</keyword>
  <keyword>lutein</keyword>
  <keyword>zeaxanthin</keyword>
  <keyword>meso-zeaxanthin</keyword>
  <keyword>cognitive function</keyword>
  <keyword>glaucoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glaucoma</mesh_term>
    <mesh_term>Glaucoma, Open-Angle</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/NCT04460365
org study id: 1/378/1535
nct id: NCT04460365
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
European Nutrition in Glaucoma Management (ENIGMA) trial will evaluate the effect of 18-month
      supplementation with lutein, zeaxanthin and meso-zeaxanthin on macular pigment (MP) levels,
      vision, cognition and serum biomarkers of inflammation and oxidative stress in glaucoma
      patients.

      This study comprises a randomised, placebo controlled and double masked clinical trial
      designed to establish MP response to supplementation with lutein, zeaxanthin and
      meso-zeaxanthin over an 18-month period. The study will also investigate the relationship
      between macular pigment, cognitive function, oxidative stress and inflammation, and determine
      the impact of dietary supplementation on vision, retinal structure, quality of life and
      cognitive function among glaucoma subjects.
This is a research study looking at the effects of dietary MP supplementation in glaucoma
      patients. Glaucoma can cause irreversible visual impairment. Current treatment modalities
      only halt disease progression and do not improve visual function. It is important to
      understand that poor visual function can have major consequences to an individual's
      day-to-day tasks such as increased risk of falls and automobile accidents.

      Disability glare is commonly experienced by eye disease patients, including those with
      glaucoma, and has been shown to be present even in those who are mildly affected by the
      disease. MP is a blue-light filter that plays an important role in visual performance
      including glare sensitivity. Moreover, MP is a potent antioxidant, and it is widely known
      that oxidative stress is involved in the pathogenesis of glaucoma, both at the level of
      retinal ganglion cells and trabecular meshwork.

      Glaucoma and cognitive decline are both neurodegenerative processes that share several
      antecedents. The clustering of degenerative disorders towards the end of life is thought to
      be the result of cumulative and lifelong oxidative injury, and is consistent with the free
      radical theory of aging. Observational studies have revealed links between the two
      conditions. The commonalities between glaucoma and cognitive decline, including their shared
      risk factor profile and pathophysiological pathways, suggest a role for exploring common
      mechanisms and perhaps even a shared therapeutic approach.

      The purpose of this study is to investigate the effects of dietary MP supplementation on MP
      levels, serum biomarkers of inflammation and oxidative stress, vision, retinal structure and
      cognition in glaucoma patients.

      Study design 64 glaucoma participants Treatment arm: 10 mg Lutein, 2 mg zeaxanthin, 10 mg
      meso-zeaxanthin - 2/3 Placebo arm: Identical capsule containing no active ingredients - 1/3
      Duration of intervention: 18 months

      At baseline, all glaucoma participants undergo detailed vision assessments including visual
      acuity, microperimetry, measurement of macular pigment optical density (MPOD) with
      dual-wavelength fundus autofluorescence technique, optical coherence tomography scans,
      contrast sensitivity testing with and without glare, photostress recovery time, pupil
      reaction assessment, lens fluorescence measurement and fill out vision-related and dietary
      questionnaires. Patients also undergo detailed cognitive assessment including the flanker
      task, sound-induced flash illusions task, verbal fluency (FAS and animal fluency tests), SKT
      (short cognitive assessment) and MMSE (mini-mental state examination) tests which provide
      measures of reaction time, short-term memory, multisensory integration and attention. A blood
      sample is also collected for analysis of oxidative stress and inflammatory biomarkers.

      After the baseline assessments, glaucoma participants are randomised (2:1) to receive a
      dietary MP supplementation or placebo for 6 months. Each daily dose of the supplement
      contains 10mg Lutein, 10mg meso-Zeaxanthin and 2mg Zeaxanthin in a softgel capsule. The
      intervention consists of a daily oral consumption of one softgel capsule (recommended to be
      consumed with food) for a period of 18 months, with patients compliance checks and re-supply
      of supplement every 6 months. The placebo looks identical to the active supplement in its
      preparation size, colour, smell and taste. It contains no active ingredients.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in MPOD in response to treatment from baseline at 18 months
time frame: 18 months
description: Change in MPOD measured at each study visit from baseline to 18 months will be evaluated between active and placebo arms
measure: Change in multisensory integration from baseline following 18 months supplementation
time frame: 18 months
description: Multisensory integration will be assessed using a sound-induced flash illusions task (SIFI). Change in SIFI scores will be assessed between active and placebo treatment arms from baseline to 18 months
measure: Change in flanker task scores (reaction time and attention) from baseline following 18 months supplementation
time frame: 18 months
description: Change in flanker task scores will be assessed between active and placebo treatment arms from baseline to 18 months
measure: Change in SKT (Syndrom-Kurztest) score from baseline following 18 months supplementation
time frame: 18 months
description: SKT is a short cognitive battery of tests that evaluates general cognitive function. Change in SKT score will be assessed between active and placebo treatment arms from baseline to 18 months
measure: Change in verbal fluency (FAS score) from baseline following 18 months supplementation
time frame: 18 months
description: Change in verbal fluency assessed using the FAS test will be evaluated between active and placebo treatment arms from baseline to 18 months
measure: Change in verbal fluency (animal fluency test) from baseline following 18 months supplementation
time frame: 18 months
description: Change in verbal fluency assessed using the animal fluency test will be evaluated between active and placebo treatment arms from baseline to 18 months
measure: Change in Visual Acuity in response to treatment from baseline at 18 months
time frame: 18 months
description: Change in Visual Acuity will be evaluated between active and placebo treatment arms from baseline to 18 months
measure: Change in Contrast Sensitivity in response to treatment from baseline at 18 months
time frame: 18 months
description: Change in Contrast Sensitivity under photopic and mesopic conditions at 1.5, 3, 6, 12 and 18 cycles per degree will be evaluated between active and placebo treatment arms from baseline to 18 months, using the FACT device
measure: Change in incremental light sensitivity in response to treatment from baseline at 18 months
time frame: 18 months
description: Change in Microperimetry average threshold will be evaluated between active and placebo treatment arms from baseline to 18 months, using the Maia device
measure: Change in Retinal Thickness parameters in response to treatment from baseline at 18 months
time frame: 18 months
description: Change in Retinal Thickness parameters will be evaluated between active and placebo treatment arms from baseline to 18 months, using the Spectralis OCT device
measure: Change in serum biomarkers of inflammation (C-reactive protein) from baseline following 18 months supplementation
time frame: 18 months
description: Inflammation will be assessed using the C-reactive protein biomarker measured in serum
measure: Change in serum biomarkers of oxidative stress (Oxidized LDL) from baseline following 18 months supplementation
time frame: 18 months
description: Oxidative stress will be assessed using the Oxidized LDL biomarker measured in serum
arm group label: Active
arm group type: Active Comparator
description: Softgel capsules: 10 mg Lutein, 2 mg zeaxanthin, 10 mg meso-zeaxanthin once a day with a meal for 18 months
arm group label: Placebo
arm group type: Placebo Comparator
description: Identical capsule containing no active ingredients
intervention type: Dietary Supplement
intervention name: 10 mg Lutein, 2 mg zeaxanthin, 10 mg meso-zeaxanthin
description: This is a lutein (10mg), zeaxanthin (2mg) and meso-zeaxanthin (10mg) one-a-day food supplement which combines all three macular carotenoids.
These three nutrients are found at the back of the eye, at the macula, where they form the macular pigment (yellow colour). Meso-zeaxanthin is particularly concentrated at the centre of this pigment.
Lutein and zeaxanthin can be found in fruits and dark green leafy vegetables and meso-zeaxanthin is present in some species of fish and seafood.
arm group label: Active
intervention type: Other
intervention name: Placebo
description: Softgel capsule containing sunflower oil (no active ingredients)
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: James Loughman, PhD
role: Principal Investigator
affiliation: Head of the Centre for Eye Research Ireland, Professor
facility: 
country: Ireland
responsible party type: Sponsor
mesh term: Glaucoma
mesh term: Glaucoma, Open-Angle