<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/NCT03836664</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00140465</org_study_id>
    <nct_id>NCT03836664</nct_id>
  </id_info>
  <brief_title>A Randomized Study Evaluating the Efficacy and Safety of Timolol Ophthalmic Solution as an Acute Treatment of Migraine</brief_title>
  <official_title>A Randomized, Double-Blinded, Placebo-Controlled, Cross Over Study Evaluating the Efficacy and Safety of Timolol Ophthalmic Solution as an Acute Treatment of Migraine</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Kansas Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Kansas Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <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>
      The purpose of this study is to assess the efficacy (headache freedom at 2 hours) of Timolol&#xD;
      0.5% ophthalmic solution compared to placebo in acute treatment of migraine headache. And to&#xD;
      assess the safety and tolerability of Timolol 0.5% ophthalmic solution in treatment of acute&#xD;
      migraine headache.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Oral beta-blockers are a class of medications frequently used to control blood pressure,&#xD;
      angina, and heart irregularities. Certain oral beta-blockers such as propranolol and timolol&#xD;
      are used on a daily basis to prevent migraines. However, propranolol and timolol tablets have&#xD;
      not been shown to be effective as an acute treatment to stop attacks of migraine because of&#xD;
      their longer onset of action. We propose that, since beta-blocker eye drops, unlike tablets&#xD;
      are quickly absorbed through the covering of the eye and lining of the nose and can be&#xD;
      detected in the bloodstream within minutes, can be beneficial and efficacious in the&#xD;
      treatment of headache abortion.&#xD;
&#xD;
      Timolol is a non-selective beta-adrenoreceptor antagonist. Oral timolol (20-30 mg daily) has&#xD;
      been studied in 3 randomized controlled trials and have been found to reduce headache&#xD;
      frequency by more than 50% when compared to placebo. It has been approved by FDA for&#xD;
      prophylactic use in migraine patients and had level A evidence to support this indication.&#xD;
      The prophylactic benefit of beta-blockers in migraine treatment is not completely understood.&#xD;
      It may be related to the effect of beta-blockers on central autonomic vascular tone center,&#xD;
      which in turn modulate the cerebrovascular reactivity to sensory stimulation.Propranolol, a&#xD;
      beta-adrenergic blocker modulates serotonergic transmission, regulates peri aqueductal&#xD;
      pathway activation and prevents central sensitization, normalizes neuronal excitability in&#xD;
      the CNS, and blocks cortical spreading depression (CSD). Topical ocular beta blockers have&#xD;
      been reported to be successful in retinal arteriolar spasm, retinal migraines causing visual&#xD;
      field defects, migraines causing oculomotor nerve palsy, and as abortive agents in migraine&#xD;
      patients. Topical timolol maleate solution 0.5% reaches a concentration of 0.5 ng/ml in the&#xD;
      plasma within 4 hours of first dose after being used twice daily for 7 days.&#xD;
&#xD;
      Topical beta-blockers so far have been noted to be effective for acute migraine episodes only&#xD;
      in case reports. We believe that this pilot study, to evaluate the efficacy and safety of a&#xD;
      timolol eye drop for acute treatment of migraine headaches, will open doors for future trials&#xD;
      and larger studies. If successful, this will be able establish the use of beta-blocker eye&#xD;
      drops which is a simple, painless and low cost acute treatment of migraine.&#xD;
&#xD;
      The aim of this study is to determine the efficacy of timolol eye drops for the acute&#xD;
      treatment of migraine.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 27, 2017</start_date>
  <completion_date type="Actual">April 14, 2018</completion_date>
  <primary_completion_date type="Actual">April 14, 2018</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Headache Severity</measure>
    <time_frame>Headache/ pain severity at onset and at 120 minutes post intervention use</time_frame>
    <description>Measure of the change in severity using visual analogue pain scale ranging from 0-10 with zero being no pain and ten being worst pain. Scale will be completed after each migraine episode over course of participation in study, up to 8 weeks.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse Reaction From Using Timolol Eye Drops</measure>
    <time_frame>8 weeks</time_frame>
    <description>Measured by number of adverse events experienced by the participants from the intervention. Each adverse event was counted as one.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Satisfied With Intervention</measure>
    <time_frame>8 weeks</time_frame>
    <description>Measured by patient-reported satisfaction questionnaire. Satisfaction level was looked at as &quot;satisfactory and very satisfactory&quot; compared to &quot;neutral and unsatisfied&quot;.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Migraine</condition>
  <arm_group>
    <arm_group_label>Group 1: Timolol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be given 0.5% timolol ophthalmic solution to use after migraine onset. Participants will put 2 drops of solution in each eye after migraine and then again 2 hours later.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2: Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will be given matching placebo (0.9% normal saline solution) to use after migraine onset. Participants will put 2 drops of solution in each eye after migraine and then again 2 hours later.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Timolol</intervention_name>
    <description>Timolol is a clear solution supplied in a plastic ophthalmic dispenser.</description>
    <arm_group_label>Group 1: Timolol</arm_group_label>
    <other_name>0.5% timolol ophthalmic solution</other_name>
    <other_name>beta blocker eye drops</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo is normal saline solution that will be supplied in container matched to Timolol container.</description>
    <arm_group_label>Group 2: Placebo</arm_group_label>
    <other_name>inactive drug</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of migraine, with or without aura, according to ICHD-2 criteria (Appendix A)&#xD;
             for at least 1 year prior to screening; experience an average of 1 to 8 migraines per&#xD;
             month.&#xD;
&#xD;
          -  Females must be practicing an effective method of birth control before entry and&#xD;
             throughout the study, or be surgically sterile, or be postmenopausal&#xD;
&#xD;
          -  Females of child-bearing potential must have a negative urine pregnancy test&#xD;
&#xD;
          -  Subjects should be able to demonstrate the ability to properly administer study&#xD;
             medication&#xD;
&#xD;
          -  Subjects should be able and willing to read and comprehend written instructions and&#xD;
             complete the diary information required by the protocol&#xD;
&#xD;
          -  Subjects must be capable, in the opinion of the Investigator, of providing informed&#xD;
             consent or assent to participate in the study&#xD;
&#xD;
          -  Subjects (and their legally acceptable representatives, if applicable) must provide an&#xD;
             informed consent indicating that they understand the purpose of and procedures&#xD;
             required for the study and are willing to participate in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to distinguish other headaches from migraine&#xD;
&#xD;
          -  Experiences headache of any kind at a frequency greater than or equal to 15 days per&#xD;
             month&#xD;
&#xD;
          -  Current use of medication for migraine prophylaxis that has not been stable (no dose&#xD;
             adjustment) for 30 days prior to screening&#xD;
&#xD;
          -  Chronic opioid therapy for headaches (&gt; 3 consecutive days in the 30 days prior to&#xD;
             screening)&#xD;
&#xD;
          -  Hemiplegic migraine&#xD;
&#xD;
          -  History, symptoms or signs of ischemic cardiac, cerebrovascular or peripheral vascular&#xD;
             syndromes&#xD;
&#xD;
          -  History of glaucoma and/or current treatment with prescription eye drops&#xD;
&#xD;
          -  History of naso-lacrimal duct (&quot;tear duct problem&quot; to patients) obstruction or surgery&#xD;
             for such&#xD;
&#xD;
          -  Active treatment by ophthalmologist or optometrist for any severe ophthalmic disease&#xD;
             or problem&#xD;
&#xD;
          -  Any physical problems or co-ordination difficulty or eye avoidance sensitivity&#xD;
             (&quot;squeezer&quot;) that would preclude proper installation of eye drops in either or both&#xD;
             eyes&#xD;
&#xD;
          -  History of uncontrolled asthma, COPD, or reversible airway disease which in the&#xD;
             opinion of the investigator would be worsened by the use of beta blockers&#xD;
&#xD;
          -  History of clinically symptomatic bradycardia, congestive heart failure, or&#xD;
             hypotension&#xD;
&#xD;
          -  Uncontrolled Diabetes Mellitus&#xD;
&#xD;
          -  Uncontrolled Hyperthyroidism&#xD;
&#xD;
          -  History (within 2 years) of drug or alcohol abuse&#xD;
&#xD;
          -  Systemic disease, which in the opinion of the Investigator, would contraindicate&#xD;
             participation&#xD;
&#xD;
          -  History of a neurological or psychiatric condition, which in the opinion of the&#xD;
             Investigator would contraindicate participation&#xD;
&#xD;
          -  History of hypersensitivity or intolerance to beta-blockers eye drops&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Have taken any investigational medication within 12 weeks before randomization, or are&#xD;
             scheduled to receive an investigational drug&#xD;
&#xD;
          -  Subjects, who in opinion of the Investigator, should not be enrolled in the study&#xD;
             because of the precautions, warnings or contra-indications sections of the timolol&#xD;
             Package Insert&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dipika Aggarwal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Kansas Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Kansas Medical Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>February 8, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <results_first_submitted>April 10, 2019</results_first_submitted>
  <results_first_submitted_qc>July 1, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">July 2, 2019</results_first_posted>
  <last_update_submitted>July 1, 2019</last_update_submitted>
  <last_update_submitted_qc>July 1, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 2, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Headache</keyword>
  <keyword>Acute migraine headache</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Migraine Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Timolol</mesh_term>
    <mesh_term>Ophthalmic Solutions</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 6, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/64/NCT03836664/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>A total of 26 participants in the age group of 18-65 years were recruited from the general neurology clinics at the University of Kansas Medical Center. One participant did not meet inclusion criteria and was excluded from the study. Finally 25 participants were enrolled. Recruitment period ended from 4/21/17 to 2/23/18.</recruitment_details>
      <pre_assignment_details>Out of the 26 recruited participants, upon screening one participant no more met inclusion criteria due to worsening of his clinical condition. He had an increase in his migraine frequency and therefore, did not meet the inclusion criteria of 1-8 migraine episodes per month. He was considered to be a screen fail and was not enrolled in the study.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Timolol Intervention (2hours), no Washout, Placebo (2 Hours)</title>
          <description>Participants were randomized to either Timolol/placebo group or placebo/Timolol group.&#xD;
Migraine 1: Participants were given 0.5% timolol ophthalmic solution to use after migraine onset. They will put 2 drops of the solution in each eye after migraine onset and again 2 hours later if needed or headache persists.&#xD;
Timolol: Timolol is a clear solution supplied in a plastic ophthalmic dispenser&#xD;
There was no washout period.&#xD;
Migraine 2: Participants were given matching placebo (0.9% normal saline solution) to use after migraine onset. They put 2 drops of solution in each eye after migraine onset and then again 2 hours later if needed or if headache persisted.&#xD;
Placebo: Placebo is normal saline solution supplied in container matched to Timolol container.</description>
        </group>
        <group group_id="P2">
          <title>Placebo (2 Hours), no Washout, Timolol (2 Hours)</title>
          <description>Participants were randomized to either Timolol/placebo group or placebo/Timolol group.&#xD;
Migraine 1: Participants were given placebo (0.9% normal saline solution) to use after migraine onset. They put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or if headache persisted.&#xD;
Placebo: Placebo is normal saline solution supplied in container matched to Timolol container.&#xD;
There was no washout period.&#xD;
Migraine 2: Participants were given 0.5% timolol ophthalmic solution to use after migraine onset. They put 2 drops of solution in each eye after migraine onset and then again 2 hours later if needed or if headache persisted.&#xD;
Timolol: Timolol is a clear solution supplied in a plastic ophthalmic dispenser.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Didn't complete forms and lost drug</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Timolol Intervention (2 Hours), Followed by Placebo (2 Hours)</title>
          <description>Participants were randomized to either Timolol/placebo group or placebo/Timolol group.&#xD;
Migraine 1: Participants were given 0.5% timolol ophthalmic solution to use after migraine onset. They will put 2 drops of the solution in each eye after migraine onset and again 2 hours later if needed or headache persists.&#xD;
Timolol: Timolol is a clear solution supplied in a plastic ophthalmic dispenser&#xD;
There was no washout period.&#xD;
Migraine 2: Participants were given matching placebo (0.9% normal saline solution) to use after migraine onset. They put 2 drops of solution in each eye after migraine onset and then again 2 hours later if needed or if headache persisted.&#xD;
Placebo: Placebo is normal saline solution supplied in container matched to Timolol container.</description>
        </group>
        <group group_id="B2">
          <title>Placebo (2 Hours), Followed by Timolol Intervention (2 Hours)</title>
          <description>Participants were randomized to either Timolol/placebo group or placebo/Timolol group.&#xD;
Migraine 1: Participants were given matching placebo (0.9% normal saline solution) to use after migraine onset. They put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or if headache persisted.&#xD;
Placebo: Placebo is normal saline solution supplied in container matched to Timolol container.&#xD;
There was no washout period.&#xD;
Migraine 2: Participants were given 0.5% timolol ophthalmic solution to use after migraine onset. They put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or if headache persisted.&#xD;
Timolol: Timolol is a clear solution supplied in a plastic ophthalmic dispenser.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="14"/>
            <count group_id="B2" value="11"/>
            <count group_id="B3" value="25"/>
          </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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="13"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Headache Severity</title>
        <description>Measure of the change in severity using visual analogue pain scale ranging from 0-10 with zero being no pain and ten being worst pain. Scale will be completed after each migraine episode over course of participation in study, up to 8 weeks.</description>
        <time_frame>Headache/ pain severity at onset and at 120 minutes post intervention use</time_frame>
        <population>All participants</population>
        <group_list>
          <group group_id="O1">
            <title>All Participants Post Timolol</title>
            <description>Participants given 0.5% timolol ophthalmic solution to use after migraine onset. Participants put 2 drops of solution in each eye after migraine and then again 2 hours later.&#xD;
Timolol: Timolol is a clear solution supplied in a plastic ophthalmic dispenser.</description>
          </group>
          <group group_id="O2">
            <title>All Participants Post Placebo</title>
            <description>Participants given matching placebo (0.9% normal saline solution) to use after migraine onset. Participants put 2 drops of solution in each eye after migraine and then again 2 hours later.&#xD;
Placebo: Placebo is normal saline solution supplied in container matched to Timolol container.</description>
          </group>
        </group_list>
        <measure>
          <title>Headache Severity</title>
          <description>Measure of the change in severity using visual analogue pain scale ranging from 0-10 with zero being no pain and ten being worst pain. Scale will be completed after each migraine episode over course of participation in study, up to 8 weeks.</description>
          <population>All participants</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.00" lower_limit="1.04" upper_limit="2.96"/>
                    <measurement group_id="O2" value="2.00" lower_limit="0.72" upper_limit="3.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adverse Reaction From Using Timolol Eye Drops</title>
        <description>Measured by number of adverse events experienced by the participants from the intervention. Each adverse event was counted as one.</description>
        <time_frame>8 weeks</time_frame>
        <population>total number of adverse events in each group</population>
        <group_list>
          <group group_id="O1">
            <title>Total Number of Adverse Events Post Timolol Intervention</title>
            <description>Participants given 0.5% timolol ophthalmic solution to use after migraine onset. Participants put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or if headache persisted.&#xD;
Timolol: Timolol is a clear solution supplied in a plastic ophthalmic dispenser.</description>
          </group>
          <group group_id="O2">
            <title>Total Number of Adverse Events Post Placebo</title>
            <description>Participants given matching placebo (0.9% normal saline solution) to use after migraine onset. Participants put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or if headache persisted.&#xD;
Placebo: Placebo is normal saline solution supplied in container matched to Timolol container.</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Reaction From Using Timolol Eye Drops</title>
          <description>Measured by number of adverse events experienced by the participants from the intervention. Each adverse event was counted as one.</description>
          <population>total number of adverse events in each group</population>
          <units>events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Satisfied With Intervention</title>
        <description>Measured by patient-reported satisfaction questionnaire. Satisfaction level was looked at as &quot;satisfactory and very satisfactory&quot; compared to &quot;neutral and unsatisfied&quot;.</description>
        <time_frame>8 weeks</time_frame>
        <population>All participants</population>
        <group_list>
          <group group_id="O1">
            <title>Number of Participants Satisfied Post Timolol Intervention</title>
            <description>Participants given 0.5% timolol ophthalmic solution to use after migraine onset. Participants put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or if headache persisted.&#xD;
Timolol: Timolol is a clear solution supplied in a plastic ophthalmic dispenser.</description>
          </group>
          <group group_id="O2">
            <title>Number of Participants Satisfied Post Placebo</title>
            <description>Participants given matching placebo (0.9% normal saline solution) to use after migraine onset. Participants put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or if headache persisted.&#xD;
Placebo: Placebo is normal saline solution supplied in container matched to Timolol container.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Satisfied With Intervention</title>
          <description>Measured by patient-reported satisfaction questionnaire. Satisfaction level was looked at as &quot;satisfactory and very satisfactory&quot; compared to &quot;neutral and unsatisfied&quot;.</description>
          <population>All participants</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data was collected within 1 day of drug administration. All participants were advised to report any adverse event within 24 hours.</time_frame>
      <desc>Participants were advised to call with minor side effects/ adverse events within 24 hours, and go to nearest ER in case of any serious adverse event.</desc>
      <group_list>
        <group group_id="E1">
          <title>All Participants Post Timolol</title>
          <description>Participants will be given 0.5% timolol ophthalmic solution to use after migraine onset. Participants will put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or headache persists.&#xD;
Timolol: Timolol is a clear solution supplied in a plastic ophthalmic dispenser.</description>
        </group>
        <group group_id="E2">
          <title>All Participants Post Placebo</title>
          <description>Participants will be given matching placebo (0.9% normal saline solution) to use after migraine onset. Participants will put 2 drops of solution in each eye after migraine and then again 2 hours later if needed or headache persists.&#xD;
Placebo: Placebo is normal saline solution that will be supplied in container matched to Timolol container.</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="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>burning, stinging</default_vocab>
        <default_assessment>Non-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="2" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eyes burning/ stinging</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="19"/>
              </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>
    <limitations_and_caveats>Participant compliance was also found to be a big limitation with 6 participants considered as study drop outs since they did not return study drug/ forms even after repeated attempts to contact them. This led to loss of data.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr Dipika Aggarwal, Clinical Assistant Professor</name_or_title>
      <organization>University of Kansas Medical Center</organization>
      <phone>9139459926</phone>
      <email>daggarwal@kumc.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/NCT03836664
org study id: STUDY00140465
nct id: NCT03836664
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The purpose of this study is to assess the efficacy (headache freedom at 2 hours) of Timolol
      0.5% ophthalmic solution compared to placebo in acute treatment of migraine headache. And to
      assess the safety and tolerability of Timolol 0.5% ophthalmic solution in treatment of acute
      migraine headache.
Oral beta-blockers are a class of medications frequently used to control blood pressure,
      angina, and heart irregularities. Certain oral beta-blockers such as propranolol and timolol
      are used on a daily basis to prevent migraines. However, propranolol and timolol tablets have
      not been shown to be effective as an acute treatment to stop attacks of migraine because of
      their longer onset of action. We propose that, since beta-blocker eye drops, unlike tablets
      are quickly absorbed through the covering of the eye and lining of the nose and can be
      detected in the bloodstream within minutes, can be beneficial and efficacious in the
      treatment of headache abortion.

      Timolol is a non-selective beta-adrenoreceptor antagonist. Oral timolol (20-30 mg daily) has
      been studied in 3 randomized controlled trials and have been found to reduce headache
      frequency by more than 50% when compared to placebo. It has been approved by FDA for
      prophylactic use in migraine patients and had level A evidence to support this indication.
      The prophylactic benefit of beta-blockers in migraine treatment is not completely understood.
      It may be related to the effect of beta-blockers on central autonomic vascular tone center,
      which in turn modulate the cerebrovascular reactivity to sensory stimulation.Propranolol, a
      beta-adrenergic blocker modulates serotonergic transmission, regulates peri aqueductal
      pathway activation and prevents central sensitization, normalizes neuronal excitability in
      the CNS, and blocks cortical spreading depression (CSD). Topical ocular beta blockers have
      been reported to be successful in retinal arteriolar spasm, retinal migraines causing visual
      field defects, migraines causing oculomotor nerve palsy, and as abortive agents in migraine
      patients. Topical timolol maleate solution 0.5% reaches a concentration of 0.5 ng/ml in the
      plasma within 4 hours of first dose after being used twice daily for 7 days.

      Topical beta-blockers so far have been noted to be effective for acute migraine episodes only
      in case reports. We believe that this pilot study, to evaluate the efficacy and safety of a
      timolol eye drop for acute treatment of migraine headaches, will open doors for future trials
      and larger studies. If successful, this will be able establish the use of beta-blocker eye
      drops which is a simple, painless and low cost acute treatment of migraine.

      The aim of this study is to determine the efficacy of timolol eye drops for the acute
      treatment of migraine.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Headache Severity
time frame: Headache/ pain severity at onset and at 120 minutes post intervention use
description: Measure of the change in severity using visual analogue pain scale ranging from 0-10 with zero being no pain and ten being worst pain. Scale will be completed after each migraine episode over course of participation in study, up to 8 weeks.
measure: Adverse Reaction From Using Timolol Eye Drops
time frame: 8 weeks
description: Measured by number of adverse events experienced by the participants from the intervention. Each adverse event was counted as one.
measure: Number of Participants Satisfied With Intervention
time frame: 8 weeks
description: Measured by patient-reported satisfaction questionnaire. Satisfaction level was looked at as "satisfactory and very satisfactory" compared to "neutral and unsatisfied".
arm group label: Group 1: Timolol
arm group type: Experimental
description: Participants will be given 0.5% timolol ophthalmic solution to use after migraine onset. Participants will put 2 drops of solution in each eye after migraine and then again 2 hours later.
arm group label: Group 2: Placebo
arm group type: Placebo Comparator
description: Participants will be given matching placebo (0.9% normal saline solution) to use after migraine onset. Participants will put 2 drops of solution in each eye after migraine and then again 2 hours later.
intervention type: Drug
intervention name: Timolol
description: Timolol is a clear solution supplied in a plastic ophthalmic dispenser.
arm group label: Group 1: Timolol
other name: 0.5% timolol ophthalmic solution
other name: beta blocker eye drops
intervention type: Drug
intervention name: Placebo
description: Placebo is normal saline solution that will be supplied in container matched to Timolol container.
arm group label: Group 2: Placebo
other name: inactive drug
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Dipika Aggarwal, MD
role: Principal Investigator
affiliation: University of Kansas Medical Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Migraine Disorders
mesh term: Timolol
mesh term: Ophthalmic Solutions
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Participant compliance was also found to be a big limitation with 6 participants considered as study drop outs since they did not return study drug/ forms even after repeated attempts to contact them. This led to loss of data.
point of contact: 