<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/NCT01665508</url>
  </required_header>
  <id_info>
    <org_study_id>BYS-IT-75</org_study_id>
    <nct_id>NCT01665508</nct_id>
  </id_info>
  <brief_title>Study to Evaluate Effect of Nebivolol on Angina in Women With Microvascular Disease</brief_title>
  <acronym>NIRVANA</acronym>
  <official_title>Nebivolol for the Relief of Microvascular Angina in Women</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Forest Laboratories</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Women have less significant blockages of coronary arteries, however have greater symptoms and&#xD;
      worse outcomes compared to their age-matched male counterparts. This paradox has led to the&#xD;
      recognition and importance of the microvasculature ( small vessels) as a contributor to&#xD;
      symptoms and outcomes. Nebivolol has unique antioxidant properties and dilates blood vessels&#xD;
      and it is therefore proposed that treatment with nebivolol will reduce angina (chest&#xD;
      symptoms) in women with microvascular disease as well as improve exercise capacity, reduce&#xD;
      resource utilization and improve other measures of artery function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Though women have less obstructive coronary artery disease (CAD) they continue to have a&#xD;
      greater burden of symptoms, more myocardial ischemia, and a higher rate of adverse outcomes&#xD;
      than their age-matched male counterparts. This ostensible paradox has led to the recognition&#xD;
      of a distinct pathophysiology of ischemic heart disease, in part related to microvascular&#xD;
      dysfunction, and abnormal coronary reactivity. The term primary microvascular angina, (MVA)&#xD;
      is used to describe a syndrome among patients who have symptoms suggestive of cardiac&#xD;
      ischemia, evidence of electrocardiographic abnormalities, abnormalities on stress imaging or&#xD;
      a history of ACS, but no evidence of obstructive epicardial coronary disease. In this&#xD;
      population, microvascular angina causes significant morbidity and in some may contribute to&#xD;
      increased mortality.&#xD;
&#xD;
      The treatment of microvascular disease remains empirical due to lack of data regarding&#xD;
      symptom alleviation, as well as ultimate mortality reduction. Women with ischemic heart&#xD;
      disease and microvascular angina continue to report more frequent angina and worse quality of&#xD;
      life. They frequently seek medical attention for the evaluation of cardiovascular symptoms&#xD;
      including chest pain and shortness of breath. Consequently, these women incur greater&#xD;
      healthcare costs, with more office visits, hospitalizations, and myocardial infarctions. In&#xD;
      fact, more than one half of women without obstructive coronary disease continue to have&#xD;
      ischemic symptoms that lead to further consumption of CAD resources, most often because of&#xD;
      diagnostic uncertainty.&#xD;
&#xD;
      In the absence of robust outcomes data to drive the care of these women with microvascular&#xD;
      ischemia, various approaches are taken, in addition to the fundamental management of baseline&#xD;
      risk factors. Some physicians treat these women as they would treat patients with known&#xD;
      obstructive CAD, while some, in the setting of &quot;open&quot; coronary arteries and persistent chest&#xD;
      pain, opt for reassurance. Nevertheless, given that these women with microvascular ischemia&#xD;
      continue to have higher morbidity and mortality, as well as increased resource consumption,&#xD;
      there is a widely recognized need for effective therapeutic agents to reduce symptoms,&#xD;
      improve quality of life, decrease resource consumption, and ultimately reduce mortality.&#xD;
&#xD;
      Nebivolol, due to its unique antioxidant and vasodilator properties, via its effect on NO&#xD;
      bioactivity, and subsequent effects on the endothelium may be a potentially ideal therapeutic&#xD;
      agent for the treatment of microvascular angina among women. For example, one previous study&#xD;
      showed that nebivolol improved exercise parameters, as well as endothelial function, more&#xD;
      effectively than other beta blockade with metoprolol, among patients with persistent angina&#xD;
      and non-obstructive coronary disease.&#xD;
&#xD;
      Cardiopulmonary exercise testing is an ideal diagnostic test in this study as it will provide&#xD;
      unique information on how microvascular ischemia influences functional capacity as measured&#xD;
      through sensitive gas exchange parameters. Because it is known that a distinct&#xD;
      pathophysiology contributes to microvascular angina among this subset of women, these&#xD;
      parameters provided by CPET may provide essential information regarding the mechanism of&#xD;
      symptom mitigation should nebivolol confer therapeutic value.&#xD;
&#xD;
      Furthermore, because exercise tolerance is often significantly impaired, objective measures&#xD;
      of gas exchange that reflect submaximum and maximum fitness among these women will be useful&#xD;
      both at baseline and on nebivolol.&#xD;
&#xD;
      Peripheral arterial tone and pulse wave analysis will also be performed. PAT signal&#xD;
      technology provides a widely validated measurement of endothelium-mediated changes in&#xD;
      vascular tone, using non-invasive bio-sensors on the fingertips that are elicited by creating&#xD;
      a down-stream hyperemic response. This parameter correlates well with endothelial dysfunction&#xD;
      in coronary arteries. We will perform endothelial function testing at baseline and after 3&#xD;
      months.&#xD;
&#xD;
      Metabolomics is an emerging field that offers the possibility of using the body's metabolites&#xD;
      to both phenotype a disease as well as track its response to isolated perturbations, such as&#xD;
      administration of a drug. In this study we will utilize metabolomics to define signatures of&#xD;
      microvascular ischemia as well as nebivolol-mediated changes in metabolic profiles. Baseline&#xD;
      metabolic profiling, as well as metabolic profiling after 3 months of nebivolol treatment&#xD;
      will be performed in this study.&#xD;
&#xD;
      This type of assessment is an ideal complement to the clinical parameters delineated above as&#xD;
      it combines targeted mass spectrometry to measures small molecules related to nitric oxide&#xD;
      metabolism (ie: arginine, arginosuccinate, citrulline, ornithine, cGMP, ADMA) as well as more&#xD;
      unbiased screening of metabolites that are not known to be associated with either nebivolol&#xD;
      exposure or microvascular angina.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2013</start_date>
  <completion_date type="Actual">May 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Seattle Angina Questionnaire Score</measure>
    <time_frame>3 months</time_frame>
    <description>Seattle Angina Questionnaire (SAQ):&#xD;
The SAQ is a 5 part survey that is widely used and well validated tool to assess angina stability and angina frequency among patients with coronary artery disease.&#xD;
The SAQ is a validated, self-administered 19-item questionnaire with 5 different dimensions of health status in patients with CAD including: angina frequency, angina stability, disease-specific quality of life, physical limitations and treatment satisfaction. Each SAQ domain score ranges from 0-100, with higher scores indicating a better health status.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Peak VO2 Measured by Cardiopulmonary Exercise Testing</measure>
    <time_frame>3 months</time_frame>
    <description>Assessment of exercise capacity (peak VO2) as determined by CPET</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resource Utilization Questionnaire</measure>
    <time_frame>3 months</time_frame>
    <description>Resource utilization as determined by patient phone calls, office visits, emergency room visits, and number of hospitalizations, as well an index cost for any hospitalizations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SF36</measure>
    <time_frame>baseline and 12 week follow-up</time_frame>
    <description>The SF-36v2 is a commonly used instrument to assess HRQoL8. The questionnaire evaluates 8 HRQoL domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role emotional and mental health. The physical component score is a composite of the SF-36v2 physical health domains (physical functioning, role-physical, bodily pain and general health) and the mental component score a composite of the mental health domains (vitality, social functioning, role-emotional and mental health). Each HRQoL domain score ranges from 0 to 100, with higher scores corresponding to a better health status. The SF-36v2 domain scores were calculated using the QualityMetric Health Outcomes Scoring Software version 4.5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exercise Duration</measure>
    <time_frame>3 months</time_frame>
    <description>Assessment of exercise duration as determined by CPET</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Heart Rate as Measured by Cardiopulmonary Exercise Testing</measure>
    <time_frame>3 months</time_frame>
    <description>Assessment of peak heart rate as determined by CPET</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak O2 Pulse</measure>
    <time_frame>3 months</time_frame>
    <description>peak O2 pulse as measured by cardiopulmonary exercise testing</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Microvascular Angina</condition>
  <arm_group>
    <arm_group_label>Nebivolol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nebivolol</intervention_name>
    <description>Patient to start nebivolol and have repeat testing in 3 months</description>
    <arm_group_label>Nebivolol</arm_group_label>
    <other_name>Bystolic</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  women between the ages of 40-80&#xD;
&#xD;
          -  with evidence of coronary microvascular dysfunction as determined by the presence of&#xD;
             rest and or exertional chest tightness and a history of either an elevated troponin&#xD;
             level or positive stress test ( EKG criteria or imaging) , as well as non-obstructive&#xD;
             coronary artery disease (&lt;50% epicardial obstruction) by either diagnostic&#xD;
             catheterization with coronary angiography or CT angiography.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Women who cannot tolerate a beta blocker.&#xD;
&#xD;
          -  Women receiving Hormone Replacement Therapy&#xD;
&#xD;
          -  Women of child-bearing age who are not on a birth-control method.&#xD;
&#xD;
          -  Women with inability to exercise.&#xD;
&#xD;
          -  Women with left ventricular systolic dysfunction (LVEF less than 40%)&#xD;
&#xD;
          -  Women who have a medical condition that, in the Investigator's opinion, would expose&#xD;
             them to an increased risk of a significant adverse event or interfere with assessments&#xD;
             of safety and efficacy during the course of the trial.&#xD;
&#xD;
          -  Women with any current malignancy, or any clinically significant hematological,&#xD;
             endocrine, cardiovascular, renal, hepatic, gastrointestinal or neurological disease.&#xD;
             If there is a history of such disease but the condition has been stable for at least&#xD;
             the past year and is judged by the investigator not to interfere with the patient's&#xD;
             participation in the study, the patient may be included.&#xD;
&#xD;
          -  Women who are unable to speak, read, and understand English and are judged by the&#xD;
             investigator to be unable or unlikely to follow the study protocol and complete all&#xD;
             scheduled visits.&#xD;
&#xD;
          -  Women with any contraindications to beta blocker therapy&#xD;
&#xD;
          -  Women with myocardial bridging&#xD;
&#xD;
          -  Women with Prinzmetal's angina&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nandita S Scott, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Malissa J Wood, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>August 9, 2012</study_first_submitted>
  <study_first_submitted_qc>August 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 15, 2012</study_first_posted>
  <results_first_submitted>September 12, 2016</results_first_submitted>
  <results_first_submitted_qc>March 8, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">April 20, 2017</results_first_posted>
  <last_update_submitted>March 8, 2017</last_update_submitted>
  <last_update_submitted_qc>March 8, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 20, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Nandita Scott</investigator_full_name>
    <investigator_title>Co-Director Corrigan Women's Heart Health Program</investigator_title>
  </responsible_party>
  <keyword>angina</keyword>
  <keyword>cardiopulmonary testing</keyword>
  <keyword>metabolomics</keyword>
  <keyword>nebivolol</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Angina Pectoris</mesh_term>
    <mesh_term>Microvascular Angina</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nebivolol</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Nebivolol</title>
          <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Nebivolol</title>
          <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="12"/>
          </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="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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="61.6" spread="10"/>
                  </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="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" 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="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Seattle Angina Questionnaire Score</title>
        <description>Seattle Angina Questionnaire (SAQ):&#xD;
The SAQ is a 5 part survey that is widely used and well validated tool to assess angina stability and angina frequency among patients with coronary artery disease.&#xD;
The SAQ is a validated, self-administered 19-item questionnaire with 5 different dimensions of health status in patients with CAD including: angina frequency, angina stability, disease-specific quality of life, physical limitations and treatment satisfaction. Each SAQ domain score ranges from 0-100, with higher scores indicating a better health status.</description>
        <time_frame>3 months</time_frame>
        <population>7 patients complete baseline and followup data reported below is anginal stability</population>
        <group_list>
          <group group_id="O1">
            <title>Nebivolol</title>
            <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months&#xD;
There was a significant improvement in angina stability (p=0.034) post treatment compared to baseline. The other parameter of the SAQ were not statistically different ( physical limitation, angina frequency, treatment satisfaction and quality of life)</description>
          </group>
          <group group_id="O2">
            <title>Baseline</title>
            <description>results prior to nebivolol start</description>
          </group>
        </group_list>
        <measure>
          <title>Seattle Angina Questionnaire Score</title>
          <description>Seattle Angina Questionnaire (SAQ):&#xD;
The SAQ is a 5 part survey that is widely used and well validated tool to assess angina stability and angina frequency among patients with coronary artery disease.&#xD;
The SAQ is a validated, self-administered 19-item questionnaire with 5 different dimensions of health status in patients with CAD including: angina frequency, angina stability, disease-specific quality of life, physical limitations and treatment satisfaction. Each SAQ domain score ranges from 0-100, with higher scores indicating a better health status.</description>
          <population>7 patients complete baseline and followup data reported below is anginal stability</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>anginal stability</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="83.3" spread="25.8"/>
                    <measurement group_id="O2" value="29.2" spread="18.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>phyisical limitation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="74.1" spread="18.0"/>
                    <measurement group_id="O2" value="67.6" spread="21.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>anginal frequency</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="80.0" spread="20.0"/>
                    <measurement group_id="O2" value="70.0" spread="15.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>treatment satisfaction</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81.3" spread="18.5"/>
                    <measurement group_id="O2" value="84.4" spread="13.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>qualify of life</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="62.5" spread="33.6"/>
                    <measurement group_id="O2" value="51.4" spread="23.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak VO2 Measured by Cardiopulmonary Exercise Testing</title>
        <description>Assessment of exercise capacity (peak VO2) as determined by CPET</description>
        <time_frame>3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nebivolol</title>
            <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months</description>
          </group>
          <group group_id="O2">
            <title>Baseline</title>
            <description>results off nebivolol</description>
          </group>
        </group_list>
        <measure>
          <title>Peak VO2 Measured by Cardiopulmonary Exercise Testing</title>
          <description>Assessment of exercise capacity (peak VO2) as determined by CPET</description>
          <units>ml/beat</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.1" spread="2.3"/>
                    <measurement group_id="O2" value="11.0" spread="2.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Resource Utilization Questionnaire</title>
        <description>Resource utilization as determined by patient phone calls, office visits, emergency room visits, and number of hospitalizations, as well an index cost for any hospitalizations</description>
        <time_frame>3 months</time_frame>
        <population>data was not collected</population>
        <group_list>
          <group group_id="O1">
            <title>Nebivolol</title>
            <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months&#xD;
this data was incomplete and not useful for analysis</description>
          </group>
        </group_list>
        <measure>
          <title>Resource Utilization Questionnaire</title>
          <description>Resource utilization as determined by patient phone calls, office visits, emergency room visits, and number of hospitalizations, as well an index cost for any hospitalizations</description>
          <population>data was not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>SF36</title>
        <description>The SF-36v2 is a commonly used instrument to assess HRQoL8. The questionnaire evaluates 8 HRQoL domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role emotional and mental health. The physical component score is a composite of the SF-36v2 physical health domains (physical functioning, role-physical, bodily pain and general health) and the mental component score a composite of the mental health domains (vitality, social functioning, role-emotional and mental health). Each HRQoL domain score ranges from 0 to 100, with higher scores corresponding to a better health status. The SF-36v2 domain scores were calculated using the QualityMetric Health Outcomes Scoring Software version 4.5.</description>
        <time_frame>baseline and 12 week follow-up</time_frame>
        <population>physical functioning reported below</population>
        <group_list>
          <group group_id="O1">
            <title>Nebivolol</title>
            <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months</description>
          </group>
          <group group_id="O2">
            <title>Baseline</title>
            <description>results off nebivolol</description>
          </group>
        </group_list>
        <measure>
          <title>SF36</title>
          <description>The SF-36v2 is a commonly used instrument to assess HRQoL8. The questionnaire evaluates 8 HRQoL domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role emotional and mental health. The physical component score is a composite of the SF-36v2 physical health domains (physical functioning, role-physical, bodily pain and general health) and the mental component score a composite of the mental health domains (vitality, social functioning, role-emotional and mental health). Each HRQoL domain score ranges from 0 to 100, with higher scores corresponding to a better health status. The SF-36v2 domain scores were calculated using the QualityMetric Health Outcomes Scoring Software version 4.5.</description>
          <population>physical functioning reported below</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>physical functioning</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75.0" spread="13.8"/>
                    <measurement group_id="O2" value="67.9" spread="10.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>role-physical</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85.4" spread="12.9"/>
                    <measurement group_id="O2" value="82.3" spread="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>bodily pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75.2" spread="19.9"/>
                    <measurement group_id="O2" value="78.7" spread="22.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>general health</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75" spread="12.6"/>
                    <measurement group_id="O2" value="72.8" spread="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>vitality</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="67.7" spread="14.5"/>
                    <measurement group_id="O2" value="63.5" spread="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>social functioning</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="91.7" spread="10.2"/>
                    <measurement group_id="O2" value="91.7" spread="15.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>role-emotional</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="90.3" spread="15.3"/>
                    <measurement group_id="O2" value="97.2" spread="16.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>mental health</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81.7" spread="6.1"/>
                    <measurement group_id="O2" value="81.7" spread="9.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>physical component</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.3" spread="4.9"/>
                    <measurement group_id="O2" value="48.4" spread="6.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>mental component</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="55.3" spread="5"/>
                    <measurement group_id="O2" value="56.7" spread="3.6"/>
                  </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>Continuous variables were reported as the mean ± (SD) and categorical data presented as frequency and percentage of the sample. Comparisons between baseline and post-treatment SAQ scores, SF-36v2 scores, and CPET variables were performed using a paired t-test for normally distributed variables or a Wilcoxon signed-rank test for non-normally distributed variables. Normality was defined by the Shapiro-Wilk test. For categorical variables, data were compared using a chi-squared test.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt; 0.05</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Exercise Duration</title>
        <description>Assessment of exercise duration as determined by CPET</description>
        <time_frame>3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nebivolol</title>
            <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months&#xD;
this data was incomplete and not useful for analysis</description>
          </group>
          <group group_id="O2">
            <title>Baseline</title>
            <description>results without nebivolol</description>
          </group>
        </group_list>
        <measure>
          <title>Exercise Duration</title>
          <description>Assessment of exercise duration as determined by CPET</description>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.9" spread="1.1"/>
                    <measurement group_id="O2" value="11.8" spread="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak Heart Rate as Measured by Cardiopulmonary Exercise Testing</title>
        <description>Assessment of peak heart rate as determined by CPET</description>
        <time_frame>3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nebivolol</title>
            <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months&#xD;
There was a significant improvement in angina stability (p=0.034) post treatment compared to baseline. The other parameter of the SAQ were not statistically different ( physical limitation, angina frequency, treatment satisfaction and quality of life)</description>
          </group>
          <group group_id="O2">
            <title>Baseline</title>
            <description>results prior to nebivolol start</description>
          </group>
        </group_list>
        <measure>
          <title>Peak Heart Rate as Measured by Cardiopulmonary Exercise Testing</title>
          <description>Assessment of peak heart rate as determined by CPET</description>
          <units>beats per minute</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="119" spread="11"/>
                    <measurement group_id="O2" value="145" spread="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak O2 Pulse</title>
        <description>peak O2 pulse as measured by cardiopulmonary exercise testing</description>
        <time_frame>3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nebivolol</title>
            <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months&#xD;
this data was incomplete and not useful for analysis</description>
          </group>
          <group group_id="O2">
            <title>Baseline</title>
            <description>results without nebivolol</description>
          </group>
        </group_list>
        <measure>
          <title>Peak O2 Pulse</title>
          <description>peak O2 pulse as measured by cardiopulmonary exercise testing</description>
          <units>ml/beat</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.1" spread="2.3"/>
                    <measurement group_id="O2" value="11" spread="2.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Nebivolol</title>
          <description>Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.&#xD;
Nebivolol: Patient to start nebivolol and have repeat testing in 3 months</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="12"/>
              </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>Nandita S. Scott</name_or_title>
      <organization>Massachusetts General Hospital</organization>
      <phone>6177241739</phone>
      <email>nsscott@partners.org</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/NCT01665508
org study id: BYS-IT-75
nct id: NCT01665508
lead sponsor: 
collaborator: 
has dmc: Yes
Women have less significant blockages of coronary arteries, however have greater symptoms and
      worse outcomes compared to their age-matched male counterparts. This paradox has led to the
      recognition and importance of the microvasculature ( small vessels) as a contributor to
      symptoms and outcomes. Nebivolol has unique antioxidant properties and dilates blood vessels
      and it is therefore proposed that treatment with nebivolol will reduce angina (chest
      symptoms) in women with microvascular disease as well as improve exercise capacity, reduce
      resource utilization and improve other measures of artery function.
Though women have less obstructive coronary artery disease (CAD) they continue to have a
      greater burden of symptoms, more myocardial ischemia, and a higher rate of adverse outcomes
      than their age-matched male counterparts. This ostensible paradox has led to the recognition
      of a distinct pathophysiology of ischemic heart disease, in part related to microvascular
      dysfunction, and abnormal coronary reactivity. The term primary microvascular angina, (MVA)
      is used to describe a syndrome among patients who have symptoms suggestive of cardiac
      ischemia, evidence of electrocardiographic abnormalities, abnormalities on stress imaging or
      a history of ACS, but no evidence of obstructive epicardial coronary disease. In this
      population, microvascular angina causes significant morbidity and in some may contribute to
      increased mortality.

      The treatment of microvascular disease remains empirical due to lack of data regarding
      symptom alleviation, as well as ultimate mortality reduction. Women with ischemic heart
      disease and microvascular angina continue to report more frequent angina and worse quality of
      life. They frequently seek medical attention for the evaluation of cardiovascular symptoms
      including chest pain and shortness of breath. Consequently, these women incur greater
      healthcare costs, with more office visits, hospitalizations, and myocardial infarctions. In
      fact, more than one half of women without obstructive coronary disease continue to have
      ischemic symptoms that lead to further consumption of CAD resources, most often because of
      diagnostic uncertainty.

      In the absence of robust outcomes data to drive the care of these women with microvascular
      ischemia, various approaches are taken, in addition to the fundamental management of baseline
      risk factors. Some physicians treat these women as they would treat patients with known
      obstructive CAD, while some, in the setting of "open" coronary arteries and persistent chest
      pain, opt for reassurance. Nevertheless, given that these women with microvascular ischemia
      continue to have higher morbidity and mortality, as well as increased resource consumption,
      there is a widely recognized need for effective therapeutic agents to reduce symptoms,
      improve quality of life, decrease resource consumption, and ultimately reduce mortality.

      Nebivolol, due to its unique antioxidant and vasodilator properties, via its effect on NO
      bioactivity, and subsequent effects on the endothelium may be a potentially ideal therapeutic
      agent for the treatment of microvascular angina among women. For example, one previous study
      showed that nebivolol improved exercise parameters, as well as endothelial function, more
      effectively than other beta blockade with metoprolol, among patients with persistent angina
      and non-obstructive coronary disease.

      Cardiopulmonary exercise testing is an ideal diagnostic test in this study as it will provide
      unique information on how microvascular ischemia influences functional capacity as measured
      through sensitive gas exchange parameters. Because it is known that a distinct
      pathophysiology contributes to microvascular angina among this subset of women, these
      parameters provided by CPET may provide essential information regarding the mechanism of
      symptom mitigation should nebivolol confer therapeutic value.

      Furthermore, because exercise tolerance is often significantly impaired, objective measures
      of gas exchange that reflect submaximum and maximum fitness among these women will be useful
      both at baseline and on nebivolol.

      Peripheral arterial tone and pulse wave analysis will also be performed. PAT signal
      technology provides a widely validated measurement of endothelium-mediated changes in
      vascular tone, using non-invasive bio-sensors on the fingertips that are elicited by creating
      a down-stream hyperemic response. This parameter correlates well with endothelial dysfunction
      in coronary arteries. We will perform endothelial function testing at baseline and after 3
      months.

      Metabolomics is an emerging field that offers the possibility of using the body's metabolites
      to both phenotype a disease as well as track its response to isolated perturbations, such as
      administration of a drug. In this study we will utilize metabolomics to define signatures of
      microvascular ischemia as well as nebivolol-mediated changes in metabolic profiles. Baseline
      metabolic profiling, as well as metabolic profiling after 3 months of nebivolol treatment
      will be performed in this study.

      This type of assessment is an ideal complement to the clinical parameters delineated above as
      it combines targeted mass spectrometry to measures small molecules related to nitric oxide
      metabolism (ie: arginine, arginosuccinate, citrulline, ornithine, cGMP, ADMA) as well as more
      unbiased screening of metabolites that are not known to be associated with either nebivolol
      exposure or microvascular angina.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Seattle Angina Questionnaire Score
time frame: 3 months
description: Seattle Angina Questionnaire (SAQ):
The SAQ is a 5 part survey that is widely used and well validated tool to assess angina stability and angina frequency among patients with coronary artery disease.
The SAQ is a validated, self-administered 19-item questionnaire with 5 different dimensions of health status in patients with CAD including: angina frequency, angina stability, disease-specific quality of life, physical limitations and treatment satisfaction. Each SAQ domain score ranges from 0-100, with higher scores indicating a better health status.
measure: Peak VO2 Measured by Cardiopulmonary Exercise Testing
time frame: 3 months
description: Assessment of exercise capacity (peak VO2) as determined by CPET
measure: Resource Utilization Questionnaire
time frame: 3 months
description: Resource utilization as determined by patient phone calls, office visits, emergency room visits, and number of hospitalizations, as well an index cost for any hospitalizations
measure: SF36
time frame: baseline and 12 week follow-up
description: The SF-36v2 is a commonly used instrument to assess HRQoL8. The questionnaire evaluates 8 HRQoL domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role emotional and mental health. The physical component score is a composite of the SF-36v2 physical health domains (physical functioning, role-physical, bodily pain and general health) and the mental component score a composite of the mental health domains (vitality, social functioning, role-emotional and mental health). Each HRQoL domain score ranges from 0 to 100, with higher scores corresponding to a better health status. The SF-36v2 domain scores were calculated using the QualityMetric Health Outcomes Scoring Software version 4.5.
measure: Exercise Duration
time frame: 3 months
description: Assessment of exercise duration as determined by CPET
measure: Peak Heart Rate as Measured by Cardiopulmonary Exercise Testing
time frame: 3 months
description: Assessment of peak heart rate as determined by CPET
measure: Peak O2 Pulse
time frame: 3 months
description: peak O2 pulse as measured by cardiopulmonary exercise testing
arm group label: Nebivolol
arm group type: Experimental
description: Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.
intervention type: Drug
intervention name: Nebivolol
description: Patient to start nebivolol and have repeat testing in 3 months
arm group label: Nebivolol
other name: Bystolic
criteria: 
gender: Female
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Nandita S Scott, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Malissa J Wood, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Nandita Scott
investigator title: Co-Director Corrigan Women's Heart Health Program
mesh term: Angina Pectoris
mesh term: Microvascular Angina
mesh term: Nebivolol
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 