<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/NCT01677507</url>
  </required_header>
  <id_info>
    <org_study_id>HUM00052276</org_study_id>
    <secondary_id>R01EY022124</secondary_id>
    <nct_id>NCT01677507</nct_id>
  </id_info>
  <brief_title>Glaucoma Biomarkers</brief_title>
  <official_title>Aqueous Humor Dynamic Components That Determine Intraocular Pressure Variance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Nebraska</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Eye Institute (NEI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Michigan</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Glaucoma is a major cause of blindness. The inability to predict a patient's IOP response to&#xD;
      medications is a critical barrier for the clinician to consistently provide highly effective&#xD;
      IOP-based treatments. Current trial-and error approaches to glaucoma management are&#xD;
      inefficient and have not addressed this barrier as there are no predictive factors for drug&#xD;
      response. Our long-term goal is to improve outcomes by identifying biomarkers and&#xD;
      environmental factors that profile a patient at risk for glaucoma by age-of-onset, rate of&#xD;
      disease progression, &quot;poor response&quot; to treatment, and large IOP fluctuation. Our purpose of&#xD;
      this research project is to address this critical barrier by focusing on physiological&#xD;
      factors that predict IOP response to drugs.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">August 30, 2016</completion_date>
  <primary_completion_date type="Actual">August 30, 2016</primary_completion_date>
  <phase>Phase 4</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Variation in Eye Pressure Between Individuals.</measure>
    <time_frame>Measurement after 1 week of drug treatment</time_frame>
    <description>Eye pressure is a steady state quantitative trait that is measured in mm Hg. Eye pressure is determined by the following physiological factors (units of measure): eye fluid or aqueous humor production (microliters/minute), aqueous humor outflow (microliters/minute), outflow resistance (microliters/minute/mm Hg) and venous pressure (mm Hg) of the eye. All of these physiological factors will be determined under baseline condition and under glaucoma drug treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Variation in Aqueous Flow Between Individuals.</measure>
    <time_frame>1 week after treatment</time_frame>
    <description>Aqueous flow production (microliters/minute) will be determined under baseline condition and under glaucoma drug treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Variation in Episcleral Venous Pressure.</measure>
    <time_frame>1 week treatment</time_frame>
    <description>Episcleral venous pressure (mm Hg) of the eye will be determined under baseline condition and under glaucoma drug treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">135</enrollment>
  <condition>Glaucoma</condition>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>timolol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>To compare the variation in response to timolol between individuals</description>
  </arm_group>
  <arm_group>
    <arm_group_label>latanoprost</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>To compare the variation in response to latanoprost between individuals</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Variation in eye pressure response to timolol and latanoprost treatment</intervention_name>
    <description>Arm 1 is to test for variation in eye pressure response to timolol. Arm 2 is to test for variation in eye pressure response to latanoprost.</description>
    <arm_group_label>latanoprost</arm_group_label>
    <arm_group_label>timolol</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Either gender.&#xD;
&#xD;
          -  Any self-declared ethnoracial category.&#xD;
&#xD;
          -  Greater than or equal to 40 years.&#xD;
&#xD;
          -  Healthy eyes with the crystalline lens, without glaucoma (cup:disc ratio &lt; 0.8 both&#xD;
             eyes; asymmetry of cup:disc ratio between eyes &lt; 0.2).&#xD;
&#xD;
          -  Open angles.&#xD;
&#xD;
          -  Ability to cooperate for aqueous humor dynamic studies.&#xD;
&#xD;
          -  Nonprescription and prescription topical ophthalmic products and systemic medications&#xD;
             other than those mentioned in the exclusion criteria will be allowed during the study.&#xD;
&#xD;
          -  Contact lenses removed prior to topical fluorescein instillation, and not used until&#xD;
             the end of each fluorophotometry session.&#xD;
&#xD;
          -  Able to participate on site over the multi-visit study period.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Women who are pregnant due to IOP changes.&#xD;
&#xD;
          -  Any form of glaucoma, including extremely narrow angle with complete or partial&#xD;
             closure.&#xD;
&#xD;
          -  Current use of any glaucoma medication, either topically or orally.&#xD;
&#xD;
          -  Chronic or recurrent inflammatory eye disease.&#xD;
&#xD;
          -  Ocular trauma within the past 6 months.&#xD;
&#xD;
          -  Ocular infection or ocular inflammation in the past 3 months.&#xD;
&#xD;
          -  Clinically significant retinal disease.&#xD;
&#xD;
          -  Any abnormality preventing reliable fluorophotometry of either eye, such as corneal&#xD;
             scarring or severe dry eye that results in punctate fluorescein staining of the&#xD;
             cornea.&#xD;
&#xD;
          -  Intraocular surgery within 6 months.&#xD;
&#xD;
          -  Serious hypersensitivity to any components of the study medications or risk from&#xD;
             treatment with glaucoma medications, such as severe asthma or emphysema.&#xD;
&#xD;
          -  Subjects must be on a stable regimen for at least 30 days prior to the Visit 1&#xD;
             regarding a chronic systemic medication that may affect IOP (i.e., sympathomimetic&#xD;
             agents, beta-blockers, alpha-adrenergic agonists, alpha-adrenergic blockers, calcium&#xD;
             channel blockers, angiotensin converting enzyme inhibitors, etc.). Any change of such&#xD;
             medication during the study period will result in exclusion.&#xD;
&#xD;
          -  Use of any glucocorticoid by any route. Subject must be washed out of the&#xD;
             glucocorticoid for at least 2 weeks before study entry.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sayoko E Moroi, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska Medical Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 7, 2012</study_first_submitted>
  <study_first_submitted_qc>August 29, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2012</study_first_posted>
  <results_first_submitted>August 14, 2017</results_first_submitted>
  <results_first_submitted_qc>August 14, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">September 13, 2017</results_first_posted>
  <last_update_submitted>August 14, 2017</last_update_submitted>
  <last_update_submitted_qc>August 14, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Michigan</investigator_affiliation>
    <investigator_full_name>Sayoko E. Moroi</investigator_full_name>
    <investigator_title>PI</investigator_title>
  </responsible_party>
  <keyword>glaucoma</keyword>
  <keyword>aqueous humor dynamics</keyword>
  <keyword>intraocular pressure</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glaucoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Timolol</mesh_term>
    <mesh_term>Latanoprost</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>135 consented. Prior to baseline measures: 4 were excluded for ineligibility; 6 withdrew consent fully prior to baseline measurements.&#xD;
After baseline measures: an additional 2 were excluded based on physician decision, and 2 withdrew for participant decision.&#xD;
Thus, 121 participants are included for period 1.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Timolol Followed by Latanoprost</title>
          <description>To compare the variation in response to timolol between individuals&#xD;
Variation in eye pressure response to timolol and latanoprost treatment: Arm 1 initial period is to test for variation in eye pressure response to timolol 0.5%, then washout.&#xD;
Period 2 is to test for variation in eye pressure response to latanoprost 0.005%.</description>
        </group>
        <group group_id="P2">
          <title>Latanoprost Followed by Timolol</title>
          <description>To compare the variation in response to latanoprost between individuals&#xD;
Variation in eye pressure response to timolol and latanoprost treatment:&#xD;
Arm 1 initial period is to test for variation in eye pressure response to latanoprost 0.005%, then washout.&#xD;
Period 2 is to test for variation in eye pressure response to timolol 0.5%.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Initial Assignment</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="63"/>
                <participants group_id="P2" count="58"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="63"/>
                <participants group_id="P2" count="56"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Second Assigment</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="63"/>
                <participants group_id="P2" count="56"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="60"/>
                <participants group_id="P2" count="51"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>In addition to the 119 participants who were randomized to actual treatment, the baseline population includes the 9 who came for full baseline measurements before they were excluded or chose to withdraw.</population>
      <group_list>
        <group group_id="B1">
          <title>Baseline of Entire Population</title>
          <description>Both arms are included because the study design was a cross over intent to treat with glaucoma medications. All participants were treated with both medications.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="125"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="125"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55.1" spread="8.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="125"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="94"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="125"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="107"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Hispanic</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>American Indian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="125"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="125"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Intraocular pressure</title>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Right eye</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="125"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14.4" spread="3.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left eye</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="125"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13.9" spread="3.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Aqueous humor flow</title>
          <population>There was missing aqueous flow data on 2 participants.</population>
          <units>microliters/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Right eye</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="123"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.1" spread="1.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left eye</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="123"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2.9" spread="0.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Episcleral venous pressure</title>
          <population>One site used a different method to measure episcleral venous pressure (n=29)</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Right eye</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="96"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8.3" spread="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left eye</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="125"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7.9" spread="1.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Variation in Eye Pressure Between Individuals.</title>
        <description>Eye pressure is a steady state quantitative trait that is measured in mm Hg. Eye pressure is determined by the following physiological factors (units of measure): eye fluid or aqueous humor production (microliters/minute), aqueous humor outflow (microliters/minute), outflow resistance (microliters/minute/mm Hg) and venous pressure (mm Hg) of the eye. All of these physiological factors will be determined under baseline condition and under glaucoma drug treatment.</description>
        <time_frame>Measurement after 1 week of drug treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Timolol</title>
            <description>To characterize the response to timolol in all participants.</description>
          </group>
          <group group_id="O2">
            <title>Latanoprost</title>
            <description>To characterize the response to latanoprost in all participants.</description>
          </group>
        </group_list>
        <measure>
          <title>Variation in Eye Pressure Between Individuals.</title>
          <description>Eye pressure is a steady state quantitative trait that is measured in mm Hg. Eye pressure is determined by the following physiological factors (units of measure): eye fluid or aqueous humor production (microliters/minute), aqueous humor outflow (microliters/minute), outflow resistance (microliters/minute/mm Hg) and venous pressure (mm Hg) of the eye. All of these physiological factors will be determined under baseline condition and under glaucoma drug treatment.</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="114"/>
                <count group_id="O2" value="116"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>RIght Eyes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.5" spread="3.2"/>
                    <measurement group_id="O2" value="11.3" spread="3.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left Eyes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.0" spread="3.0"/>
                    <measurement group_id="O2" value="11.0" spread="2.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Right Eye treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Actually these are 2 sided paired t-tests.</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>2.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.4</ci_lower_limit>
            <ci_upper_limit>3.3</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Left Eye treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test, 2 sided</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>2.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.5</ci_lower_limit>
            <ci_upper_limit>3.2</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Right Eye treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test, 2 sided</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>3.0</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.5</ci_lower_limit>
            <ci_upper_limit>3.4</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Left Eye, treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test, 2 sided</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>2.9</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.5</ci_lower_limit>
            <ci_upper_limit>3.3</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Variation in Aqueous Flow Between Individuals.</title>
        <description>Aqueous flow production (microliters/minute) will be determined under baseline condition and under glaucoma drug treatment.</description>
        <time_frame>1 week after treatment</time_frame>
        <population>These measurements can be difficult for participants to tolerate, so sometimes values are missing.</population>
        <group_list>
          <group group_id="O1">
            <title>Timolol</title>
            <description>All participants while on timolol and during a post-timolol washout</description>
          </group>
          <group group_id="O2">
            <title>Latanoprost</title>
            <description>All participants while on latanoprost and during a post-latanoprost washout</description>
          </group>
        </group_list>
        <measure>
          <title>Variation in Aqueous Flow Between Individuals.</title>
          <description>Aqueous flow production (microliters/minute) will be determined under baseline condition and under glaucoma drug treatment.</description>
          <population>These measurements can be difficult for participants to tolerate, so sometimes values are missing.</population>
          <units>microliters/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="112"/>
                <count group_id="O2" value="114"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Right eye</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="112"/>
                    <count group_id="O2" value="113"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.9" spread="0.6"/>
                    <measurement group_id="O2" value="2.8" spread="0.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left eye</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="111"/>
                    <count group_id="O2" value="114"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.0" spread="0.6"/>
                    <measurement group_id="O2" value="3.0" spread="1.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Right Eye treated to untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t test, 2 sided</method_desc>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>1.1</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.9</ci_lower_limit>
            <ci_upper_limit>1.3</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Left Eye, treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t test, 2 sided</method_desc>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>0.9</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.7</ci_lower_limit>
            <ci_upper_limit>1.1</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Right Eye, treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.94</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.01</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.2</ci_lower_limit>
            <ci_upper_limit>0.2</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Left Eye, treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.54</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test, 2 sided</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.05</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.1</ci_lower_limit>
            <ci_upper_limit>0.2</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Variation in Episcleral Venous Pressure.</title>
        <description>Episcleral venous pressure (mm Hg) of the eye will be determined under baseline condition and under glaucoma drug treatment.</description>
        <time_frame>1 week treatment</time_frame>
        <population>These measures can be difficult to obtain, so sometimes participants do not tolerate it and some values are missing.</population>
        <group_list>
          <group group_id="O1">
            <title>Timolol</title>
            <description>To characterize the response to timolol in all participants.</description>
          </group>
          <group group_id="O2">
            <title>Latanoprost</title>
            <description>To characterize the response to latanoprost in all participants.</description>
          </group>
        </group_list>
        <measure>
          <title>Variation in Episcleral Venous Pressure.</title>
          <description>Episcleral venous pressure (mm Hg) of the eye will be determined under baseline condition and under glaucoma drug treatment.</description>
          <population>These measures can be difficult to obtain, so sometimes participants do not tolerate it and some values are missing.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="110"/>
                <count group_id="O2" value="107"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Right eye</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.6" spread="1.5"/>
                    <measurement group_id="O2" value="7.7" spread="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left eye</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.3" spread="1.5"/>
                    <measurement group_id="O2" value="7.4" spread="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Right Eye, treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test, 2 sided</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.4</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.01</ci_lower_limit>
            <ci_upper_limit>0.7</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Left eye, treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.15</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test, 2 sided</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.1</ci_lower_limit>
            <ci_upper_limit>0.6</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Right Eye, treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.52</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test, 2 sided</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.1</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.3</ci_lower_limit>
            <ci_upper_limit>0.6</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Left Eye, treated vs. untreated</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.88</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test, 2 sided</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.03</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.4</ci_lower_limit>
            <ci_upper_limit>0.4</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>16 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Timolol</title>
          <description>All participants while on timolol and during a post-timolol washout</description>
        </group>
        <group group_id="E2">
          <title>Latanoprost</title>
          <description>All participants while on latanoprost and during a post-latanoprost washout</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="119"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="121"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="119"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="121"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="119"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="121"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Sayoko Moroi</name_or_title>
      <organization>University of Michigan</organization>
      <phone>734-763-3732</phone>
      <email>smoroi@med.umich.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01677507
org study id: HUM00052276
secondary id: R01EY022124
nct id: NCT01677507
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Glaucoma is a major cause of blindness. The inability to predict a patient's IOP response to
      medications is a critical barrier for the clinician to consistently provide highly effective
      IOP-based treatments. Current trial-and error approaches to glaucoma management are
      inefficient and have not addressed this barrier as there are no predictive factors for drug
      response. Our long-term goal is to improve outcomes by identifying biomarkers and
      environmental factors that profile a patient at risk for glaucoma by age-of-onset, rate of
      disease progression, "poor response" to treatment, and large IOP fluctuation. Our purpose of
      this research project is to address this critical barrier by focusing on physiological
      factors that predict IOP response to drugs.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Variation in Eye Pressure Between Individuals.
time frame: Measurement after 1 week of drug treatment
description: Eye pressure is a steady state quantitative trait that is measured in mm Hg. Eye pressure is determined by the following physiological factors (units of measure): eye fluid or aqueous humor production (microliters/minute), aqueous humor outflow (microliters/minute), outflow resistance (microliters/minute/mm Hg) and venous pressure (mm Hg) of the eye. All of these physiological factors will be determined under baseline condition and under glaucoma drug treatment.
measure: Variation in Aqueous Flow Between Individuals.
time frame: 1 week after treatment
description: Aqueous flow production (microliters/minute) will be determined under baseline condition and under glaucoma drug treatment.
measure: Variation in Episcleral Venous Pressure.
time frame: 1 week treatment
description: Episcleral venous pressure (mm Hg) of the eye will be determined under baseline condition and under glaucoma drug treatment.
arm group label: timolol
arm group type: Experimental
description: To compare the variation in response to timolol between individuals
arm group label: latanoprost
arm group type: Active Comparator
description: To compare the variation in response to latanoprost between individuals
intervention type: Drug
intervention name: Variation in eye pressure response to timolol and latanoprost treatment
description: Arm 1 is to test for variation in eye pressure response to timolol. Arm 2 is to test for variation in eye pressure response to latanoprost.
arm group label: latanoprost
arm group label: timolol
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Sayoko E Moroi, MD, PhD
role: Principal Investigator
affiliation: University of Michigan
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Michigan
investigator full name: Sayoko E. Moroi
investigator title: PI
mesh term: Glaucoma
mesh term: Timolol
mesh term: Latanoprost
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 