<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/NCT04505566</url>
  </required_header>
  <id_info>
    <org_study_id>201433</org_study_id>
    <secondary_id>1R01EY031315-01A1</secondary_id>
    <nct_id>NCT04505566</nct_id>
  </id_info>
  <brief_title>INflammatory MediatorS in the PathophysIology of Diabetic REtinopathy Study</brief_title>
  <acronym>INSPIRE</acronym>
  <official_title>INflammatory MediatorS in the PathophysIology of Diabetic REtinopathy (INSPIRE) Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stephen J. Kim, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Allergan</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Eye Institute (NEI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The central hypothesis is that inflammation mediators are biomarkers of both systemic&#xD;
      diabetes and Diabetic Retinopathy (DR) progression in the aqueous and that sustained topical&#xD;
      ketorolac application reduces/suppresses those inflammatory mediators thereby reducing the&#xD;
      progression of Diabetic Retinopathy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study goals include confirming inflammation mediators are biomarkers of both systemic&#xD;
      diabetes and DR progression in the aqueous. Like the vitreous humor, the aqueous reflects&#xD;
      localized ocular inflammation, however, is technically easier to collect with less risk. The&#xD;
      investigators will also determine the long-term effects of sustained ketorolac application on&#xD;
      intraocular cytokine levels, DR progression, and diabetic macular edema (DME) incidence. The&#xD;
      proposal is the first to use a cornea-permeable Nonsteroidal anti-inflammatory drug (NSAID)&#xD;
      for the treatment of DR.&#xD;
&#xD;
      It is believed local inflammation control in the eye will transform future treatment options&#xD;
      for diabetic patients facing blindness. Tracking and inhibiting local inflammatory mediators&#xD;
      through all DR stages has the capacity to reduce or prevent disability in millions of&#xD;
      patients per year.&#xD;
&#xD;
      164 adult type II diabetic mellitus (T2DM) patients, aged 18 years or greater will be&#xD;
      enrolled to measure aqueous PGE2 and inflammatory cytokines. Because the pathophysiology of&#xD;
      type I disease and the population it effects are different, type I diabetic patients will be&#xD;
      excluded. Diabetic retinopathy is broadly categorized as nonproliferative (NPDR) and&#xD;
      proliferative (PDR). The international Clinical Disease Severity Scale is a standard&#xD;
      classification system consisting of two categories and five stages: the nonproliferative&#xD;
      category, stage 1-4 and proliferative category, stage 5. Stage 1 is characterized as &quot;no&#xD;
      apparent retinopathy.&quot; The nonproliferative stage is further grouped into stage 2 (mild),&#xD;
      stage 3 (moderate), and stage 4 (severe). Stage 5 is final stage, PDR.&#xD;
&#xD;
      Of the 164 patients enrolled for aqueous PGE2 and inflammatory cytokine measurements, the&#xD;
      diabetic participants corresponding to stages 1, 3, and 5 will be classified as patients with&#xD;
      no DR (23 patients), with PDR (23 patients), and with moderate NPDR (118 patients). The 118&#xD;
      participants with moderate NPDR will be randomized for Aim 2 described below.&#xD;
&#xD;
      In addition, 100 age-matched patients without diabetes who are undergoing unilateral&#xD;
      vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular&#xD;
      hole will be enrolled as controls.&#xD;
&#xD;
      Aim 1 of this project is to measure aqueous PGE2 and inflammatory cytokines during DR&#xD;
      progression.&#xD;
&#xD;
      Aim 2 of this project is two-fold:&#xD;
&#xD;
        1. Investigate the long-term effects of daily topical application of ketorolac on PGE2 and&#xD;
           cytokine levels.&#xD;
&#xD;
        2. Determine how topical application of ketorolac influences DR progression and development&#xD;
           of DME.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 9, 2020</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2025</primary_completion_date>
  <phase>Phase 1</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>
    <intervention_model_description>This is a 2 aim, randomized and double-masked Phase I study on topical Ketorolac for the prevention of diabetic retinopathy.&#xD;
164 adult type II diabetic patients, aged 18 years or greater will be enrolled in addition to 100 age-matched patients without diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular hole will also be enrolled.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>At the baseline visit, only patients from the moderate NPDR group will be randomized into one of 2 groups, using a red cap database for randomization in a block manner to ensure near equal randomization in both groups.&#xD;
A report is generated every 4 months for assessment of the number of patients in each randomized category.&#xD;
Patients in this group will have both eyes randomized to either Acuvail or placebo-control (preservative-free artificial tear) in double-masked fashion.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>PGE2 level during Diabetic Retinopathy progression</measure>
    <time_frame>1 year</time_frame>
    <description>Aqueous samples will be analyzed using liquid chromatography electrospray ionization tandem mass spectrometry to measure all PGE2 levels. PGE2 will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Vascular Endothelial Growth Factor (VEGF) level during Diabetic Retinopathy progression</measure>
    <time_frame>1 year</time_frame>
    <description>Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure VEGF levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Interleukin 6 (IL-6) level during Diabetic Retinopathy progression</measure>
    <time_frame>1 year</time_frame>
    <description>Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure IL-6 levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Interleukin 8 (IL-8) level during Diabetic Retinopathy progression</measure>
    <time_frame>1 year</time_frame>
    <description>Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure IL-8 levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression of Diabetic Retinopathy (DR)</measure>
    <time_frame>3 years</time_frame>
    <description>To determine progression of DR, we will analyze data from the 118 diabetic patients randomized to either Ketorolac or placebo. Diabetic retinopathy progresses in discrete steps defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale (15-step scale: minimum value of 10 and maximum value of 65, with higher scores meaning a worse outcome). With each advancing level, the risk of developing DME and/or PDR increases. A 2-stage or more worsening on the ETDRS severity scale is associated with an increased risk of vision loss.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Severity of Diabetic Retinopathy (DR)</measure>
    <time_frame>3 years</time_frame>
    <description>A blinded sub-investigator will grade DR by utilizing the 15-step severity scale established by the ETDRS. A 2-step or more increase or decrease in severity scale, observed on 2 consecutive follow-up appointments, will define a change in DR (progression or improvement).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Diabetic Macular Edema</measure>
    <time_frame>3 years</time_frame>
    <description>To determine incidence of Diabetic Macular Edema, we will analyze data from the 118 diabetic patients. An increase in macular thickness (determined by OCT as ≥ 40%) will determine development of DME.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression of Diabetic Macular Edema</measure>
    <time_frame>3 years</time_frame>
    <description>To determine progression of Diabetic Macular Edema, we will analyze data from the 118 diabetic patients. An increase in macular thickness (determined by OCT as ≥ 40%) will determine progression of DME.</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">264</enrollment>
  <condition>Diabetic Retinopathy</condition>
  <arm_group>
    <arm_group_label>Adult Type II Diabetics - Moderate NPDR - Ketorolac</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>59 Adult type II diabetic patients with baseline moderate non-proliferative diabetic retinopathy and HbA1c ≥ 8 randomized to Ketorolac treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Adult Type II Diabetics - Moderate NPDR - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>59 Adult type II diabetic patients with baseline moderate non-proliferative diabetic retinopathy randomized to placebo treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Adult Type II Diabetics - No Diabetic Retinopathy (DR)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>23 Adult type II diabetic patients with no diabetic retinopathy as a control group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Adult Type 2 Diabetics-Proliferative Diabetic Retinopathy(PDR)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>23 Adult type II diabetic patients with proliferative diabetic retinopathy as a control group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Age-matched Non-diabetics</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>We will also enroll 100 age-matched patients without diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular hole. Removed aqueous fluid that is typically discarded will instead be collected and stored at -80° C. Aqueous fluid will be tested for inflammatory markers as detailed below to provide a reference level for cross-comparison analysis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketorolac 0.45% ophthalmic solution</intervention_name>
    <description>Ketorolac 0.45% ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.</description>
    <arm_group_label>Adult Type II Diabetics - Moderate NPDR - Ketorolac</arm_group_label>
    <other_name>Acuvail</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo - Preservative-free artificial tears</intervention_name>
    <description>Preservative free artificial tears ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.</description>
    <arm_group_label>Adult Type II Diabetics - Moderate NPDR - Placebo</arm_group_label>
    <other_name>Refresh</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Aqueous PGE2 and inflammatory cytokines measurements</intervention_name>
    <description>After topical anesthetic, antibiotic and 5% povidone-iodine application, a 30 gauge needle on a 1 ml tuberculin syringe will be inserted into the anterior chamber and used to collect 0.1 ml of aqueous fluid from each eye. Aqueous PGE2 and Inflammatory cytokines will be measured</description>
    <arm_group_label>Adult Type 2 Diabetics-Proliferative Diabetic Retinopathy(PDR)</arm_group_label>
    <arm_group_label>Adult Type II Diabetics - Moderate NPDR - Ketorolac</arm_group_label>
    <arm_group_label>Adult Type II Diabetics - Moderate NPDR - Placebo</arm_group_label>
    <arm_group_label>Adult Type II Diabetics - No Diabetic Retinopathy (DR)</arm_group_label>
    <arm_group_label>Age-matched Non-diabetics</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aim 1 Diabetic Arm Inclusion Criteria: Adult patients age 18 years or greater with&#xD;
             type II diabetes.&#xD;
&#xD;
          -  Aim 1 Nondiabetic Control Arm Inclusion Criteria: age-matched patients without&#xD;
             diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory&#xD;
             conditions such as epiretinal membrane or macular hole.&#xD;
&#xD;
          -  Aim 2 Inclusion Criteria: Adult patients age 18 years or older with type II diabetes,&#xD;
             with baseline moderate NPDR and HbA1c ≥ 8.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Aim 1 Diabetic Arm Exclusion Criteria: Patients with a history of previous vitrectomy&#xD;
             in either eye; prior intravitreal injection within 3 months; co-existent macular,&#xD;
             retinovascular, or inflammatory disease; history of ocular trauma; aphakia; presence&#xD;
             of an anterior chamber intraocular lens; current use of prescription systemic NSAIDs&#xD;
             or regular use of nonprescription NSAIDs including aspirin (defined as 4 days or more&#xD;
             a week for at least 2 weeks a month); blood pressure &gt; 180/110 mmHg; risk for corneal&#xD;
             melting; and inability to comply with follow-up.&#xD;
&#xD;
          -  Aim 1 Nondiabetic Control Arm Exclusion Criteria: Patients who are unable to comply&#xD;
             with testing and follow-up.&#xD;
&#xD;
          -  Aim 2 Exclusion Criteria: Patients with a history of previous vitrectomy in either&#xD;
             eye; prior intravitreal injection within 3 months; co-existent macular,&#xD;
             retinovascular, or inflammatory disease; history of ocular trauma; aphakia; presence&#xD;
             of an anterior chamber intraocular lens; current use of prescription systemic NSAIDs&#xD;
             or regular use of nonprescription NSAIDs including aspirin (defined as 4 days or more&#xD;
             a week for at least 2 weeks a month); blood pressure &gt; 180/110 mmHg; risk for corneal&#xD;
             melting; and inability to comply with follow-up.&#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>Stephen J Kim, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Crystal Nicholson</last_name>
    <phone>615-936-0971</phone>
    <email>crystal.nicholson@vumc.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Saige Wilkins</last_name>
    <phone>615-936-1474</phone>
    <email>saige.wilkins@vumc.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 31, 2020</study_first_submitted>
  <study_first_submitted_qc>August 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2020</study_first_posted>
  <last_update_submitted>February 27, 2023</last_update_submitted>
  <last_update_submitted_qc>February 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Stephen J. Kim, MD</investigator_full_name>
    <investigator_title>Professor of Ophthalmology</investigator_title>
  </responsible_party>
  <keyword>Topical Ketorolac</keyword>
  <keyword>Acuvail</keyword>
  <keyword>Prevention of Diabetic Retinopathy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Retinal Diseases</mesh_term>
    <mesh_term>Diabetic Retinopathy</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketorolac</mesh_term>
    <mesh_term>Ophthalmic Solutions</mesh_term>
    <mesh_term>Lubricant Eye Drops</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is not a plan to make IPD available.</ipd_description>
  </patient_data>
  <!-- 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/NCT04505566
org study id: 201433
secondary id: 1R01EY031315-01A1
nct id: NCT04505566
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The central hypothesis is that inflammation mediators are biomarkers of both systemic
      diabetes and Diabetic Retinopathy (DR) progression in the aqueous and that sustained topical
      ketorolac application reduces/suppresses those inflammatory mediators thereby reducing the
      progression of Diabetic Retinopathy.
Study goals include confirming inflammation mediators are biomarkers of both systemic
      diabetes and DR progression in the aqueous. Like the vitreous humor, the aqueous reflects
      localized ocular inflammation, however, is technically easier to collect with less risk. The
      investigators will also determine the long-term effects of sustained ketorolac application on
      intraocular cytokine levels, DR progression, and diabetic macular edema (DME) incidence. The
      proposal is the first to use a cornea-permeable Nonsteroidal anti-inflammatory drug (NSAID)
      for the treatment of DR.

      It is believed local inflammation control in the eye will transform future treatment options
      for diabetic patients facing blindness. Tracking and inhibiting local inflammatory mediators
      through all DR stages has the capacity to reduce or prevent disability in millions of
      patients per year.

      164 adult type II diabetic mellitus (T2DM) patients, aged 18 years or greater will be
      enrolled to measure aqueous PGE2 and inflammatory cytokines. Because the pathophysiology of
      type I disease and the population it effects are different, type I diabetic patients will be
      excluded. Diabetic retinopathy is broadly categorized as nonproliferative (NPDR) and
      proliferative (PDR). The international Clinical Disease Severity Scale is a standard
      classification system consisting of two categories and five stages: the nonproliferative
      category, stage 1-4 and proliferative category, stage 5. Stage 1 is characterized as "no
      apparent retinopathy." The nonproliferative stage is further grouped into stage 2 (mild),
      stage 3 (moderate), and stage 4 (severe). Stage 5 is final stage, PDR.

      Of the 164 patients enrolled for aqueous PGE2 and inflammatory cytokine measurements, the
      diabetic participants corresponding to stages 1, 3, and 5 will be classified as patients with
      no DR (23 patients), with PDR (23 patients), and with moderate NPDR (118 patients). The 118
      participants with moderate NPDR will be randomized for Aim 2 described below.

      In addition, 100 age-matched patients without diabetes who are undergoing unilateral
      vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular
      hole will be enrolled as controls.

      Aim 1 of this project is to measure aqueous PGE2 and inflammatory cytokines during DR
      progression.

      Aim 2 of this project is two-fold:

        1. Investigate the long-term effects of daily topical application of ketorolac on PGE2 and
           cytokine levels.

        2. Determine how topical application of ketorolac influences DR progression and development
           of DME.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a 2 aim, randomized and double-masked Phase I study on topical Ketorolac for the prevention of diabetic retinopathy.
164 adult type II diabetic patients, aged 18 years or greater will be enrolled in addition to 100 age-matched patients without diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular hole will also be enrolled.
primary purpose: Prevention
masking: Double (Participant, Investigator)
masking description: At the baseline visit, only patients from the moderate NPDR group will be randomized into one of 2 groups, using a red cap database for randomization in a block manner to ensure near equal randomization in both groups.
A report is generated every 4 months for assessment of the number of patients in each randomized category.
Patients in this group will have both eyes randomized to either Acuvail or placebo-control (preservative-free artificial tear) in double-masked fashion.
measure: PGE2 level during Diabetic Retinopathy progression
time frame: 1 year
description: Aqueous samples will be analyzed using liquid chromatography electrospray ionization tandem mass spectrometry to measure all PGE2 levels. PGE2 will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis.
measure: Vascular Endothelial Growth Factor (VEGF) level during Diabetic Retinopathy progression
time frame: 1 year
description: Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure VEGF levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis.
measure: Interleukin 6 (IL-6) level during Diabetic Retinopathy progression
time frame: 1 year
description: Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure IL-6 levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis.
measure: Interleukin 8 (IL-8) level during Diabetic Retinopathy progression
time frame: 1 year
description: Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure IL-8 levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis.
measure: Progression of Diabetic Retinopathy (DR)
time frame: 3 years
description: To determine progression of DR, we will analyze data from the 118 diabetic patients randomized to either Ketorolac or placebo. Diabetic retinopathy progresses in discrete steps defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale (15-step scale: minimum value of 10 and maximum value of 65, with higher scores meaning a worse outcome). With each advancing level, the risk of developing DME and/or PDR increases. A 2-stage or more worsening on the ETDRS severity scale is associated with an increased risk of vision loss.
measure: Severity of Diabetic Retinopathy (DR)
time frame: 3 years
description: A blinded sub-investigator will grade DR by utilizing the 15-step severity scale established by the ETDRS. A 2-step or more increase or decrease in severity scale, observed on 2 consecutive follow-up appointments, will define a change in DR (progression or improvement).
measure: Incidence of Diabetic Macular Edema
time frame: 3 years
description: To determine incidence of Diabetic Macular Edema, we will analyze data from the 118 diabetic patients. An increase in macular thickness (determined by OCT as ≥ 40%) will determine development of DME.
measure: Progression of Diabetic Macular Edema
time frame: 3 years
description: To determine progression of Diabetic Macular Edema, we will analyze data from the 118 diabetic patients. An increase in macular thickness (determined by OCT as ≥ 40%) will determine progression of DME.
arm group label: Adult Type II Diabetics - Moderate NPDR - Ketorolac
arm group type: Experimental
description: 59 Adult type II diabetic patients with baseline moderate non-proliferative diabetic retinopathy and HbA1c ≥ 8 randomized to Ketorolac treatment.
arm group label: Adult Type II Diabetics - Moderate NPDR - Placebo
arm group type: Placebo Comparator
description: 59 Adult type II diabetic patients with baseline moderate non-proliferative diabetic retinopathy randomized to placebo treatment.
arm group label: Adult Type II Diabetics - No Diabetic Retinopathy (DR)
arm group type: Other
description: 23 Adult type II diabetic patients with no diabetic retinopathy as a control group.
arm group label: Adult Type 2 Diabetics-Proliferative Diabetic Retinopathy(PDR)
arm group type: Other
description: 23 Adult type II diabetic patients with proliferative diabetic retinopathy as a control group.
arm group label: Age-matched Non-diabetics
arm group type: Other
description: We will also enroll 100 age-matched patients without diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular hole. Removed aqueous fluid that is typically discarded will instead be collected and stored at -80° C. Aqueous fluid will be tested for inflammatory markers as detailed below to provide a reference level for cross-comparison analysis.
intervention type: Drug
intervention name: Ketorolac 0.45% ophthalmic solution
description: Ketorolac 0.45% ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.
arm group label: Adult Type II Diabetics - Moderate NPDR - Ketorolac
other name: Acuvail
intervention type: Drug
intervention name: Placebo - Preservative-free artificial tears
description: Preservative free artificial tears ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.
arm group label: Adult Type II Diabetics - Moderate NPDR - Placebo
other name: Refresh
intervention type: Other
intervention name: Aqueous PGE2 and inflammatory cytokines measurements
description: After topical anesthetic, antibiotic and 5% povidone-iodine application, a 30 gauge needle on a 1 ml tuberculin syringe will be inserted into the anterior chamber and used to collect 0.1 ml of aqueous fluid from each eye. Aqueous PGE2 and Inflammatory cytokines will be measured
arm group label: Adult Type 2 Diabetics-Proliferative Diabetic Retinopathy(PDR)
arm group label: Adult Type II Diabetics - Moderate NPDR - Ketorolac
arm group label: Adult Type II Diabetics - Moderate NPDR - Placebo
arm group label: Adult Type II Diabetics - No Diabetic Retinopathy (DR)
arm group label: Age-matched Non-diabetics
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Stephen J Kim, MD
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
last name: Crystal Nicholson
phone: 615-936-0971
email: crystal.nicholson@vumc.org
last name: Saige Wilkins
phone: 615-936-1474
email: saige.wilkins@vumc.org
facility: 
status: Recruiting
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Stephen J. Kim, MD
investigator title: Professor of Ophthalmology
mesh term: Retinal Diseases
mesh term: Diabetic Retinopathy
mesh term: Ketorolac
mesh term: Ophthalmic Solutions
mesh term: Lubricant Eye Drops
sharing ipd: No
ipd description: There is not a plan to make IPD available.