<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/NCT01707381</url>
  </required_header>
  <id_info>
    <org_study_id>803</org_study_id>
    <nct_id>NCT01707381</nct_id>
  </id_info>
  <brief_title>BOL-303259-X With Timolol 0.5% in Subjects With Open-Angle Glaucoma or Ocular Hypertension</brief_title>
  <acronym>Constellation</acronym>
  <official_title>A Randomized, Single-Center, Open-Label, Crossover Study Comparing the Efficacy of BOL-303259-X Ophthalmic Solution With Timolol Maleate Ophthalmic Solution 0.5% in Subjects With Open-Angle Glaucoma or Ocular Hypertension.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bausch &amp; Lomb Incorporated</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bausch &amp; Lomb Incorporated</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical investigation is being performed to compare the effect of BOL-303259-X dosed&#xD;
      once daily (QD) with timolol maleate 0.5% dosed twice daily (BID) in reducing intraocular&#xD;
      pressure (IOP) measured over a 24-hour period in subjects with open-angle glaucoma (OAG) or&#xD;
      ocular hypertension (OHT).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">February 2014</completion_date>
  <primary_completion_date type="Actual">December 2013</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>24 Hour IOP</measure>
    <time_frame>after 4 weeks of treatment</time_frame>
    <description>Supine intraocular pressure (IOP) measured in the study eye following 4 weeks of treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>24-hour Ocular Perfusion Pressure</measure>
    <time_frame>after 4 weeks of treatment</time_frame>
    <description>Sitting Ocular Perfusion Pressure = 95/140 x mean arterial blood pressure - IOP; Supine Ocular Perfusion Pressure = 115/130 x mean arterial blood pressure - IOP; the nocturnal time frame encompassed measures taken at 10pm, 12am, 2am and 4 am; whereas the diurnal time frame encompassed measures taken at 6am, 8am, 10am, 12pm, 2pm, 4pm, 6pm, and 8pm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IOP Area Under the Curve Over 24 Hours</measure>
    <time_frame>after 4 weeks of treatment</time_frame>
    <description>The Area Under the Curve(AUC) is the weighted average of IOP over all 24-hour IOP assessment times (2pm, 4pm, 6pm, 8pm, 10pm, 12am, 2am, 4am, 6am, 8am, 10am, 12pm). The AUC was calculated using the trapezoidal rule.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Ocular Hypertension</condition>
  <condition>Open Angle Glaucoma</condition>
  <arm_group>
    <arm_group_label>Timolol Maleate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Timolol maleate ophthalmic solution 0.5% administered 1 drop BID once in morning and once in the evening for 4 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>BOL-303259-X</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>BOL-303259-X topical ophthalmic solution administered 1 drop QD in the evening for 4 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BOL-303259-X</intervention_name>
    <description>Topical ophthalmic solution</description>
    <arm_group_label>BOL-303259-X</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Timolol maleate</intervention_name>
    <description>Topical ophthalmic solution</description>
    <arm_group_label>Timolol Maleate</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must have a diagnosis of OAG or OHT in 1 or both eyes.&#xD;
&#xD;
          -  Subjects who are treatment-naïve must meet the following IOP requirements at Visit 1&#xD;
             (Screening), and pretreated subjects must meet the following IOP requirements at Visit&#xD;
             2 (Washout): Intraocular pressure ≥ 22 mmHg in at least 1 eye and ≤ 36 mmHg in both&#xD;
             eyes.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects who have been exposed to BOL-303259-X within 3 months prior to Visit 1&#xD;
             (Screening).&#xD;
&#xD;
          -  Subjects with a history or presence of chronic generalized systemic disease that the&#xD;
             Investigator feels might increase the risk to the subject or confound the results of&#xD;
             the study.&#xD;
&#xD;
          -  Subjects with an irregular daily sleep schedule.&#xD;
&#xD;
          -  Subjects who are unable to wear sleep monitoring device for 7 days prior to laboratory&#xD;
             study.&#xD;
&#xD;
          -  Subjects with an anticipated need to initiate or modify medication (systemic or&#xD;
             topical) that is known to affect IOP.&#xD;
&#xD;
          -  Subjects for whom concomitant use of medications may interact with the safety or&#xD;
             efficacy of a nitric oxide.&#xD;
&#xD;
          -  Subjects with known hypersensitivity or contraindications to latanoprost or any of the&#xD;
             ingredients in the study drugs.&#xD;
&#xD;
          -  Subjects who are expected to require treatment with ocular or systemic&#xD;
             corticosteroids.&#xD;
&#xD;
          -  Subjects who are in need of any other topical or systemic treatment of OAG or OHT.&#xD;
&#xD;
          -  Subjects who are unable to discontinue contact lens use during and for 24 hours before&#xD;
             the laboratory study.&#xD;
&#xD;
          -  Subjects with a central corneal thickness greater than 600 μm in either eye.&#xD;
&#xD;
          -  Subjects with any condition that prevents reliable applanationtonometry in either eye.&#xD;
&#xD;
          -  Subjects with advanced glaucoma and subjects with a cup/disc ratio greater than 0.8 or&#xD;
             a history of split fixation, or a field loss threatening fixation in either eye.&#xD;
&#xD;
          -  Subjects with previous or active corneal disease.&#xD;
&#xD;
          -  Subjects with a history of severe dry eye.&#xD;
&#xD;
          -  Subjects with active optic disc hemorrhage.&#xD;
&#xD;
          -  Subjects with a history of central/branch retinal vein or artery occlusion.&#xD;
&#xD;
          -  Subjects with a history of macular edema.&#xD;
&#xD;
          -  Subjects with very narrow angles and subjects with angle closure, congenital, and&#xD;
             secondary glaucoma, and subjects with history of angle closure in either eye.&#xD;
&#xD;
          -  Subjects with a diagnosis of a clinically significant or progressive retinal disease&#xD;
             in either eye.&#xD;
&#xD;
          -  Subjects with any intraocular infection or inflammation within 3 months prior to Visit&#xD;
             1 (Screening).&#xD;
&#xD;
          -  Subjects with a history of ocular laser surgery within the 3 months prior to Visit 1&#xD;
             (Screening).&#xD;
&#xD;
          -  Subjects with a history of incisional ocular surgery or severe trauma within 3 months&#xD;
             prior to Visit 1 (Screening).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Quintus Ngumah, OD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Bausch &amp; Lomb Incorporated</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California San Diego</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Liu JHK, Slight JR, Vittitow JL, Scassellati Sforzolini B, Weinreb RN. Efficacy of Latanoprostene Bunod 0.024% Compared With Timolol 0.5% in Lowering Intraocular Pressure Over 24 Hours. Am J Ophthalmol. 2016 Sep;169:249-257. doi: 10.1016/j.ajo.2016.04.019. Epub 2016 Jul 22.</citation>
    <PMID>27457257</PMID>
  </results_reference>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>October 12, 2012</study_first_submitted>
  <study_first_submitted_qc>October 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 16, 2012</study_first_posted>
  <results_first_submitted>June 11, 2018</results_first_submitted>
  <results_first_submitted_qc>August 3, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">September 4, 2018</results_first_posted>
  <last_update_submitted>August 3, 2018</last_update_submitted>
  <last_update_submitted_qc>August 3, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 4, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>
    <mesh_term>Ocular Hypertension</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Timolol</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Timolol Maleate Cross Over to BOL-303259X</title>
          <description>Participants first recieved timolol maleate ophthalmic solution 0.5% administered 1 drop BID once in morning and once in the evening for 4 weeks. Thereafter they received BOL-303259X once in the evening for 4 weeks.</description>
        </group>
        <group group_id="P2">
          <title>BOL-303259-X Crossover to Timolol Maleate</title>
          <description>Participants first received BOL-303259-X topical ophthalmic solution administered 1 drop QD in the evening for 4 weeks. Thereafter, they received timolol maleate ophthalmic solution 0.5% administered 1 drop BID once in morning and once in the evening for 4 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Period 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>ITT Population: All randomized subjects who received at least one dose of study drug, had a baseline and at least one postbaseline intraocular assessment.</population>
      <group_list>
        <group group_id="B1">
          <title>All Study Participants</title>
          <description>Participants who were randomized to receive either latanoprostene ophthalmic solution 0.024% or timolol maleate 0.5%</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="21"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61.0" spread="11.13"/>
                  </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>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Treatment-Naive</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>24 Hour IOP</title>
        <description>Supine intraocular pressure (IOP) measured in the study eye following 4 weeks of treatment</description>
        <time_frame>after 4 weeks of treatment</time_frame>
        <population>Intent to Treat (ITT) Population:All randomized subjects who received at least one dose of study drug, had a baseline and at least one postbaseline intraocular assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Timolol Maleate</title>
            <description>Timolol maleate ophthalmic solution 0.5% administered 1 drop BID once in morning and once in the evening for 4 weeks.&#xD;
Timolol maleate: Topical ophthalmic solution</description>
          </group>
          <group group_id="O2">
            <title>BOL-303259-X</title>
            <description>BOL-303259-X topical ophthalmic solution administered 1 drop QD in the evening for 4 weeks.&#xD;
BOL-303259-X: Topical ophthalmic solution</description>
          </group>
        </group_list>
        <measure>
          <title>24 Hour IOP</title>
          <description>Supine intraocular pressure (IOP) measured in the study eye following 4 weeks of treatment</description>
          <population>Intent to Treat (ITT) Population:All randomized subjects who received at least one dose of study drug, had a baseline and at least one postbaseline intraocular assessment.</population>
          <units>mm Hg</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.55" spread="2.46"/>
                    <measurement group_id="O2" value="21.77" spread="2.37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANCOVA</method>
            <param_type>Treatment difference</param_type>
            <param_value>-1.773</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.380</ci_lower_limit>
            <ci_upper_limit>-1.166</ci_upper_limit>
            <estimate_desc>Treatment Difference = BOL-303259-X 0.024% - Timolol maleate 0.5%.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>24-hour Ocular Perfusion Pressure</title>
        <description>Sitting Ocular Perfusion Pressure = 95/140 x mean arterial blood pressure - IOP; Supine Ocular Perfusion Pressure = 115/130 x mean arterial blood pressure - IOP; the nocturnal time frame encompassed measures taken at 10pm, 12am, 2am and 4 am; whereas the diurnal time frame encompassed measures taken at 6am, 8am, 10am, 12pm, 2pm, 4pm, 6pm, and 8pm.</description>
        <time_frame>after 4 weeks of treatment</time_frame>
        <population>Intent to Treat (ITT): All randomized subjects who received at least one dose of study drug, had a baseline, and at least one post baseline intraocular assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Timolol Maleate</title>
            <description>Timolol maleate ophthalmic solution 0.5% administered 1 drop BID once in morning and once in the evening for 4 weeks.&#xD;
Timolol maleate: Topical ophthalmic solution</description>
          </group>
          <group group_id="O2">
            <title>BOL-303259-X</title>
            <description>BOL-303259-X topical ophthalmic solution administered 1 drop QD in the evening for 4 weeks.&#xD;
BOL-303259-X: Topical ophthalmic solution</description>
          </group>
        </group_list>
        <measure>
          <title>24-hour Ocular Perfusion Pressure</title>
          <description>Sitting Ocular Perfusion Pressure = 95/140 x mean arterial blood pressure - IOP; Supine Ocular Perfusion Pressure = 115/130 x mean arterial blood pressure - IOP; the nocturnal time frame encompassed measures taken at 10pm, 12am, 2am and 4 am; whereas the diurnal time frame encompassed measures taken at 6am, 8am, 10am, 12pm, 2pm, 4pm, 6pm, and 8pm.</description>
          <population>Intent to Treat (ITT): All randomized subjects who received at least one dose of study drug, had a baseline, and at least one post baseline intraocular assessment.</population>
          <units>mm Hg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>OPP (nocturnal)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48.4" spread="9.4"/>
                    <measurement group_id="O2" value="52.5" spread="9.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>OPP (Diurnal supine)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.8" spread="7.5"/>
                    <measurement group_id="O2" value="55.9" spread="7.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>OPP (Diurnal sitting)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.2" spread="5.7"/>
                    <measurement group_id="O2" value="45.2" spread="6.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Statistical analysis of nocturnal (supine) OPP was performed among baseline, the BOL-303259-X treatment and timolol treatment using ANOVA. the criteria for statistical significance was P&lt;0.05. Post hoc Bonferroni T-tests were then utilized to compare BOL and timolol groups.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <method>ANOVA</method>
            <param_type>Bonferroni t-test used for paired compar</param_type>
            <param_value>0.010</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
            <estimate_desc>the bonferroni result applies to nocturnal supine OPP data comparing BOL group to timolol group</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>IOP Area Under the Curve Over 24 Hours</title>
        <description>The Area Under the Curve(AUC) is the weighted average of IOP over all 24-hour IOP assessment times (2pm, 4pm, 6pm, 8pm, 10pm, 12am, 2am, 4am, 6am, 8am, 10am, 12pm). The AUC was calculated using the trapezoidal rule.</description>
        <time_frame>after 4 weeks of treatment</time_frame>
        <population>ITT population</population>
        <group_list>
          <group group_id="O1">
            <title>Timolol Maleate</title>
            <description>Timolol maleate ophthalmic solution 0.5% administered 1 drop BID once in morning and once in the evening for 4 weeks.&#xD;
Timolol maleate: Topical ophthalmic solution</description>
          </group>
          <group group_id="O2">
            <title>BOL-303259-X</title>
            <description>BOL-303259-X topical ophthalmic solution administered 1 drop QD in the evening for 4 weeks.&#xD;
BOL-303259-X: Topical ophthalmic solution</description>
          </group>
        </group_list>
        <measure>
          <title>IOP Area Under the Curve Over 24 Hours</title>
          <description>The Area Under the Curve(AUC) is the weighted average of IOP over all 24-hour IOP assessment times (2pm, 4pm, 6pm, 8pm, 10pm, 12am, 2am, 4am, 6am, 8am, 10am, 12pm). The AUC was calculated using the trapezoidal rule.</description>
          <population>ITT population</population>
          <units>mm Hg</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.54" spread="2.44"/>
                    <measurement group_id="O2" value="21.77" spread="2.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.004</p_value>
            <method>ANOVA</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-1.770</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.915</ci_lower_limit>
            <ci_upper_limit>-0.625</ci_upper_limit>
            <estimate_desc>Treatment Difference = BOL-303259-X 0.024% - Timolol maleate 0.5%.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Four weeks for each intervention</time_frame>
      <desc>Safety population included all participants who received at least one dose of intervention</desc>
      <group_list>
        <group group_id="E1">
          <title>Timolol Maleate</title>
          <description>Timolol maleate ophthalmic solution 0.5% administered 1 drop BID once in morning and once in the evening for 4 weeks.&#xD;
Timolol maleate: Topical ophthalmic solution</description>
        </group>
        <group group_id="E2">
          <title>BOL-303259-X</title>
          <description>BOL-303259-X topical ophthalmic solution administered 1 drop QD in the evening for 4 weeks.&#xD;
BOL-303259-X: Topical ophthalmic solution</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="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (13.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Punctate keratitis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Instillation site erythema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Instillation site irritations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood pressure decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Heart rate decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Heleen DeCory, Ph.D.</name_or_title>
      <organization>Bausch + Lomb</organization>
      <phone>(585) 338-8161</phone>
      <email>Heleen.DeCory@bausch.com</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/NCT01707381
org study id: 803
nct id: NCT01707381
lead sponsor: 
has dmc: No
This clinical investigation is being performed to compare the effect of BOL-303259-X dosed
      once daily (QD) with timolol maleate 0.5% dosed twice daily (BID) in reducing intraocular
      pressure (IOP) measured over a 24-hour period in subjects with open-angle glaucoma (OAG) or
      ocular hypertension (OHT).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 24 Hour IOP
time frame: after 4 weeks of treatment
description: Supine intraocular pressure (IOP) measured in the study eye following 4 weeks of treatment
measure: 24-hour Ocular Perfusion Pressure
time frame: after 4 weeks of treatment
description: Sitting Ocular Perfusion Pressure = 95/140 x mean arterial blood pressure - IOP; Supine Ocular Perfusion Pressure = 115/130 x mean arterial blood pressure - IOP; the nocturnal time frame encompassed measures taken at 10pm, 12am, 2am and 4 am; whereas the diurnal time frame encompassed measures taken at 6am, 8am, 10am, 12pm, 2pm, 4pm, 6pm, and 8pm.
measure: IOP Area Under the Curve Over 24 Hours
time frame: after 4 weeks of treatment
description: The Area Under the Curve(AUC) is the weighted average of IOP over all 24-hour IOP assessment times (2pm, 4pm, 6pm, 8pm, 10pm, 12am, 2am, 4am, 6am, 8am, 10am, 12pm). The AUC was calculated using the trapezoidal rule.
arm group label: Timolol Maleate
arm group type: Active Comparator
description: Timolol maleate ophthalmic solution 0.5% administered 1 drop BID once in morning and once in the evening for 4 weeks.
arm group label: BOL-303259-X
arm group type: Experimental
description: BOL-303259-X topical ophthalmic solution administered 1 drop QD in the evening for 4 weeks.
intervention type: Drug
intervention name: BOL-303259-X
description: Topical ophthalmic solution
arm group label: BOL-303259-X
intervention type: Drug
intervention name: Timolol maleate
description: Topical ophthalmic solution
arm group label: Timolol Maleate
criteria: 
gender: All
minimum age: 40 Years
maximum age: 90 Years
healthy volunteers: No
last name: Quintus Ngumah, OD, PhD
role: Study Director
affiliation: Bausch & Lomb Incorporated
facility: 
country: United States
citation: Liu JHK, Slight JR, Vittitow JL, Scassellati Sforzolini B, Weinreb RN. Efficacy of Latanoprostene Bunod 0.024% Compared With Timolol 0.5% in Lowering Intraocular Pressure Over 24 Hours. Am J Ophthalmol. 2016 Sep;169:249-257. doi: 10.1016/j.ajo.2016.04.019. Epub 2016 Jul 22.
PMID: 27457257
responsible party type: Sponsor
mesh term: Glaucoma
mesh term: Glaucoma, Open-Angle
mesh term: Ocular Hypertension
mesh term: Hypertension
mesh term: Timolol
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 