<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/NCT03008382</url>
  </required_header>
  <id_info>
    <org_study_id>PRO25031</org_study_id>
    <nct_id>NCT03008382</nct_id>
  </id_info>
  <brief_title>Interstitial Cystitis: Examination of the Central Autonomic Network</brief_title>
  <acronym>ICECAN</acronym>
  <official_title>Interstitial Cystitis: Examination of the Central Autonomic Network</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical College of Wisconsin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>NorthShore University HealthSystem</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Case Western Reserve University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Medical College of Wisconsin</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) afflicts 3 to 8 million women in the US.&#xD;
      Symptoms of IC/BPS reduce quality of life, suppressing both social well-being and physical&#xD;
      function. The chronic pain, voiding dysfunction, sleep deprivation and associated co-morbid&#xD;
      conditions interfere with relationships and employment with significant direct (doctor&#xD;
      visits, medication, surgery) and indirect (loss of productivity) economic impact, currently&#xD;
      exceeding $100 million per year.This proposal aims to move the science of chronic pelvic pain&#xD;
      (CPP) from simple associations towards an investigation of cause and effect relationships.&#xD;
      The investigators will determine whether the striking changes in autonomic nervous system&#xD;
      responsiveness (ANS-R) contribute meaningfully to the pathogenesis of IC/BPS.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This multi-site trial will recruit 3 groups of female subjects ages 18-80 years, evenly&#xD;
      distributed across decades (10 or 20 per decade as appropriate): Interstitial&#xD;
      Cystitis/Bladder Pain Syndrome (IC/BPS), Myofascial Pelvic Pain (MPP) and Healthy Controls&#xD;
      (HC).&#xD;
&#xD;
      This proposal aims to move the science of chronic pelvic pain (CPP) from simple associations&#xD;
      towards an investigation of cause and effect relationships. We will determine whether the&#xD;
      striking changes in ANS-R contribute meaningfully to the pathogenesis of Interstitial&#xD;
      Cystitis/Bladder Pain Syndrome IC/BPS through 3 aims:&#xD;
&#xD;
        1. Careful longitudinal repeated measures in individual subjects to determine if ANS-R&#xD;
           changes precede clinical changes;&#xD;
&#xD;
        2. Assessing the impact of an intervention designed to change ANS-R on the clinical course&#xD;
           of IC/BPS;&#xD;
&#xD;
        3. Evaluating changes in brain connectivity between the prefrontal cortex (PFC) and the&#xD;
           periaqueductal gray (PAG) associated with changes in ANS-R and improved disease status.&#xD;
&#xD;
      Subjects will be pre-screened in person or on the phone. An in-person pre-screen takes place&#xD;
      in the MCW Neurology Research Rooms at Froedtert Hospital. If the subject is able to&#xD;
      participate, subject will sign the informed consent form before completing a baseline&#xD;
      evaluation. The baseline evaluation occurs either following consent or at another date&#xD;
      convenient for them. Subjects must complete all baseline activities within 2 weeks, or before&#xD;
      their Week 4/Visit 2. The baseline evaluation is comprised of a general examination, a set of&#xD;
      questionnaires, background history documenting date of diagnosis, medications tried, duration&#xD;
      of each treatment and dosing, surgeries and therapeutic and exploratory procedures performed.&#xD;
      A pelvic examination will be performed with CPP subjects patients only. Active Change in&#xD;
      Posture (ACP) is administered to the subject. Subjects will complete the uroflow (urine)&#xD;
      measurement and Valsalva maneuver in the MCW Neurology Research Rooms with a member of the&#xD;
      research team present.&#xD;
&#xD;
      Observational Substudy:&#xD;
&#xD;
      This substudy is identical to the above with the exception of not taking a beta-blocker or&#xD;
      placebo and is only 12 weeks long instead of 24. This is strictly an observational study to&#xD;
      monitor subjects who have been diagnosed with IC or MPP. If the screening information shows&#xD;
      that the subject meets the requirements, then they will be able to start. If the screening&#xD;
      information shows that they cannot be in the research, the research doctor will discuss other&#xD;
      options with them and/or refer them back to their regular doctor.&#xD;
&#xD;
      If the subject is able to participate, they will complete 3 regular on-site long-visits at&#xD;
      weeks 0, 4, and 12. The first long-visit (baseline evaluation) may occur either today&#xD;
      following consent or at another date convenient for them. The baseline evaluation comprises a&#xD;
      general and pelvic examination (no speculum), psychological questionnaires and a background&#xD;
      history questionnaire.&#xD;
&#xD;
      Weekly Home Checks will occur for 24 weeks (or 12 weeks if in observational sub-study)&#xD;
      following consent. Once each a week, subjects will complete a 24-hour heart rate (HR)&#xD;
      recording and the ACP recording using the eMotion Faros 360° portable EKG device. A member of&#xD;
      the research team will contact the subject each week while they complete the weekly&#xD;
      questionnaires and ACP recording. This will ensure compliance and will give the subject the&#xD;
      opportunity to ask any questions.The researcher will remain on the phone or via Skype to&#xD;
      monitor the subject while the ACP recording is completed from home just prior to the&#xD;
      subject's bedtime. The HR recording will be uploaded to MCW's secure server at the subject's&#xD;
      next hospital visit. Throughout the study, subjects flare activity will be monitored via&#xD;
      phone calls and recording flares in the EMA application on the smartphone. This will be a&#xD;
      Daily Flare Question in the EMA which is a set alarmed time to sound as a reminder for the&#xD;
      duration of the subject's participation.&#xD;
&#xD;
      The following weeks after each site visit and the night before visit 5, subjects will repeat&#xD;
      complete the 24-hr HR recording to ensure comparability of the HRV recording at home to the&#xD;
      one performed at the matching on-site visit., Subjects will also complete the 24-h voiding&#xD;
      diary, a set of questions using the ICECAN mobile App installed on a pre-loaded smartphone&#xD;
      and questionnaires. Deidentified 24-hour HRV and ACP recordings will be sent to Ohio State&#xD;
      University for analysis.&#xD;
&#xD;
      Follow-up Visits: Weeks 4, 12, 16, 24, Visits 2-5 (weeks 4 and 12 (Visits 2 and 3) for the&#xD;
      observational substudy) Subjects will arrive to MCW Neurology Research Rooms to repeat the&#xD;
      following: review of comorbidities, tender points exam, questionnaires, ACP and DNIC tests.&#xD;
      Subjects will complete the Valsalva maneuver in the MCW Neurology Research Rooms with a&#xD;
      member of the research team present. Chronic Pelvic Pain patients subjects will complete a&#xD;
      repeat pelvic examination at Weeks 12 and 24.&#xD;
&#xD;
      MPP and IC/BPS patients subjects will be randomized to receive 8 weeks of either placebo (a&#xD;
      pill with no active agent), or metoprolol (a pill that reduces the impact of the brain's&#xD;
      &quot;fight or flight&quot; circuits). Metoprolol is in the class of &quot;beta-blockers&quot; commonly used for&#xD;
      mild blood pressure control, and also commonly used for migraine. Subjects will be&#xD;
      administered 8 weeks of metoprolol or placebo starting at their Week 4 Visit. Subjects will&#xD;
      complete a 4-week washout period (Week 12-16) and will be administered 8 weeks of crossover&#xD;
      (Weeks 16-24).&#xD;
&#xD;
      Blood will be drawn (~ 50 mL, a little more than 3 tablespoons) at each in-person visit at&#xD;
      weeks 0, 4, 12, 16, and 24 for chronic pelvic pain subjects (healthy control only at Baseline&#xD;
      and Final visits; 2 draws total). A portion of the blood plasma/serum will be sent to the&#xD;
      University of Pittsburgh for additional related analysis. The sample will be labeled by a&#xD;
      number and will not contain any information that can be used to directly identify subject.&#xD;
      This portion of the study is critical to gather new information about pelvic pain, which is&#xD;
      very poorly understood and we highly encourage subjects to participate in this portion of the&#xD;
      study; however, it is optional.&#xD;
&#xD;
      Healthy Controls:&#xD;
&#xD;
      60 healthy control subjects will also complete this study in 24 weeks that include 4 long&#xD;
      site visits and 6 weekly home check visits. During this first long visit they will complete a&#xD;
      general exam and physician evaluation, DNIC, ACP, Valsalva maneuver, and questionnaires.&#xD;
      Subjects will complete a 24-hour HR recording from home once a week for 6 weeks total.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 1, 2017</start_date>
  <completion_date type="Actual">March 16, 2022</completion_date>
  <primary_completion_date type="Actual">March 16, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Correlation between the change in Autonomic Nervous System Responsiveness (ANS-R) and the change in the connectivity between prefrontal cortex (PFC) and periaqueductal gray (PAG)</measure>
    <time_frame>24 Weeks</time_frame>
    <description>A linear model with connectivity at 24 weeks as outcome, connectivity at baseline as a covariate and change in ANS-R, demographics such as age and group and the interactions of group with other covariate.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">80</enrollment>
  <condition>Interstitial Cystitis/Painful Bladder Syndrome</condition>
  <condition>Myofascial Pelvic Pain</condition>
  <arm_group>
    <arm_group_label>Double-Blind Randomized Drug</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Participants with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and/or Myofascial Pelvic Pain (MPP) will be randomized to take 8 weeks of Metoprolol Tartrate Oral Tablet or Placebo Oral Tablet, followed by a 4-Week washout period, and then 8 weeks of Placebo or Metoprolol.&#xD;
This intervention aims at finding if subjects with IC/BPS have higher baseline HR compared to HCs. After 4 weeks baseline, subjects will receive a bottle with capsules containing 25 mg of metoprolol tartrate or placebo distributed in a double-blind manner by each site's investigational pharmacy. Subjects will start at 25 mg once daily and increase to the goal dose of 25 mg 2/day after one week, if HR has not decreased below 55 bpm at rest. Subjects will report daily rest HR for the first week. The subjects will then washout for 4 weeks and enter crossover in similar manner.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Double-Blind Randomized Placebo</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Participants with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and/or Myofascial Pelvic Pain (MPP) will be randomized to take 8 weeks of Metoprolol Tartrate Oral Tablet or Placebo Oral Tablet, followed by a 4-Week washout period, and then 8 weeks of Placebo or Metoprolol.&#xD;
This intervention aims at finding if subjects with IC/BPS have higher baseline HR compared to HCs. After 4 weeks baseline, subjects will receive a bottle with capsules containing 25 mg of metoprolol tartrate or placebo distributed in a double-blind manner by each site's investigational pharmacy. Subjects will start at 25 mg once daily and increase to the goal dose of 25 mg 2/day after one week, if HR has not decreased below 55 bpm at rest. Subjects will report daily rest HR for the first week. The subjects will then washout for 4 weeks and enter crossover in similar manner.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metoprolol Tartrate Oral Tablet</intervention_name>
    <description>Metoprolol is a beta-blocker commonly used for mild blood pressure control, and also commonly used for migraine. Subjects with IC/BPS or MPP will start metoprolol at 25 mg once daily and increase to the goal dose of 25 mg 2/day after one week and continue for 8 weeks total.</description>
    <arm_group_label>Double-Blind Randomized Drug</arm_group_label>
    <other_name>Metoprolol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Subjects with IC/BPS or MPP will start placebo distributed in a double-blind manner. Subjects will take placebo once daily and increase to the goal dose of 25 mg 2/day after one week and continue for 8 weeks total.</description>
    <arm_group_label>Double-Blind Randomized Placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Women aged between 18 and 80 years old&#xD;
&#xD;
          -  Healthy controls; Patients diagnosed with Interstitial cystitis/Painful bladder&#xD;
             syndrome (IC/BPS) or Myofascial pelvic pain (MPP)&#xD;
&#xD;
          -  IC/BPS - ≥3 months chronic pelvic pain, pressure or discomfort perceived to be related&#xD;
             to the urinary bladder accompanied by at least one other urinary symptom like&#xD;
             persistent urge to void or frequency. Confusable diseases as the cause of the symptoms&#xD;
             must be excluded, particularly recurrent UTI&#xD;
&#xD;
          -  MPP - ≥3 months of non-cyclic continuous pelvic pain unrelated to bladder state and a&#xD;
             minimum of 2 of 5 examined pelvic floor TPs scoring at least 4 out of 10 on a numeric&#xD;
             rating scale using 2 kg pressure applied with the index finger&#xD;
&#xD;
          -  Provision of informed consent prior to any study specific procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known nervous system conditions including but not limited to diabetic neuropathy,&#xD;
             Parkinson's disease, Alzheimer's disease, multiple sclerosis, strokes, seizures, etc.&#xD;
&#xD;
          -  Baseline heart rate &lt; 50 bpm; blood pressure ≥ 140/80 mmHg at rest or uncontrolled&#xD;
             hypertension; or hypertension requiring more than two drugs for control&#xD;
&#xD;
          -  Pregnant, attempting to become pregnant , or breast-feeding&#xD;
&#xD;
          -  Unevaluated hematuria or infection at the time of enrollment&#xD;
&#xD;
          -  Pelvic or bladder neoplasm or infection&#xD;
&#xD;
          -  Severe asthma, inflammatory arthritis, connective tissue or auto-immune disorders&#xD;
&#xD;
          -  Evidence of unstable medical disorder such as kidney (rising creatinine or end-stage&#xD;
             renal failure) or liver impairment (rising AST or ALT, or end-stage with&#xD;
             coagulopathy); poorly controlled significant cardiovascular (CHF), respiratory,&#xD;
             endocrine (diabetes - A1c &gt; 9 - or untreated thyroid dysfunction) or uncontrolled&#xD;
             psychiatric illness (such as untreated depression, psychosis, etc.)&#xD;
&#xD;
          -  Treatment with a drug or medical device within the previous 30 days that has not&#xD;
             received regulatory approval&#xD;
&#xD;
          -  Use of hormones (except insulin, thyroid replacement or oral contraceptives). Hormone&#xD;
             replacement therapy is acceptable&#xD;
&#xD;
          -  Current, ongoing drug or alcohol abuse&#xD;
&#xD;
          -  Current use of 150 mg or more of narcotics or morphine equivalent (or inconsistent&#xD;
             dosages or frequency - varying by &gt; 50 mg morphine equivalent per day)&#xD;
&#xD;
          -  Previous augmentation cystoplasty, cystectomy, cytolysis, or neurectomy. Pelvic&#xD;
             surgery in the last 6 months.&#xD;
&#xD;
          -  Any major surgical intervention with general anesthesia in the last 90 days. Current&#xD;
             use of anticholinergic medications.&#xD;
&#xD;
          -  Current use of beta-blocker(s).&#xD;
&#xD;
          -  Unwillingness to take a beta blocker and placebo, or planned use of beta-blocker(s)&#xD;
             other than study medication.&#xD;
&#xD;
          -  Previous allergic or serious reaction to beta-blockers. Initiation of neural&#xD;
             stimulator in the last 30 days.&#xD;
&#xD;
          -  Any on-going or pending medical, health or disability related litigation, or current&#xD;
             pursuit of disability.&#xD;
&#xD;
          -  Any condition that in the judgment of the investigator and the internal advisory panel&#xD;
             would interfere with the patient's ability to provide informed consent, comply with&#xD;
             study instructions, place the patient at increased risk, or which would clearly&#xD;
             confound the interpretation of the study results (specific reason will be documented).&#xD;
&#xD;
          -  Current participation in another clinical trial that interferes with ICECAN policies&#xD;
             and procedures .&#xD;
&#xD;
          -  Investigators, study staff and their immediate families.&#xD;
&#xD;
          -  Inability to speak, read, and understand English.&#xD;
&#xD;
          -  Allergy to adhesives.&#xD;
&#xD;
          -  Initiation of any new treatment class in the last 30 days, or intent to initiate a new&#xD;
             class of treatment in the study. Treatment classes include:&#xD;
&#xD;
               1. Pelvic injection&#xD;
&#xD;
               2. Pelvic floor therapy&#xD;
&#xD;
               3. Agents with specific FDA approval for IC/BPS or MPP (e.g., Elmiron)&#xD;
&#xD;
               4. Anticonvulsants&#xD;
&#xD;
               5. Tricyclic agents&#xD;
&#xD;
               6. Intravesical therapy or Botox&#xD;
&#xD;
               7. Bladder hydrodistention&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas Chelimsky, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical College of Wisconsin</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NorthShore University HealthSystem</name>
      <address>
        <city>Evanston</city>
        <state>Illinois</state>
        <zip>60201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <disposition_first_submitted>February 9, 2023</disposition_first_submitted>
  <disposition_first_submitted_qc>February 9, 2023</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">February 13, 2023</disposition_first_posted>
  <last_update_submitted>February 9, 2023</last_update_submitted>
  <last_update_submitted_qc>February 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
    <investigator_full_name>Thomas Chelimsky</investigator_full_name>
    <investigator_title>Medical Doctor and Professor of Neurology</investigator_title>
  </responsible_party>
  <keyword>Interstitial Cystitis</keyword>
  <keyword>Pelvic Pain</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cystitis</mesh_term>
    <mesh_term>Cystitis, Interstitial</mesh_term>
    <mesh_term>Pelvic Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metoprolol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All participant data will be de-identified before sharing.&#xD;
Blood and Urine: A portion of the blood plasma/serum and urine will be sent to the University of Pittsburgh for additional related analysis.&#xD;
Heart Rate Variability (HRV): 24-hour HRV and Active Change of Posture recordings will be sent to Ohio State University for analysis.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>The participant's collected data is de-identified immediately. The blood and urine are stored in a freezer until there are enough samples to send out for analysis.&#xD;
Heart rate recordings are uploaded to a secure MCW storage site and shared for analysis throughout the participant's participation.</ipd_time_frame>
    <ipd_access_criteria>Participant data will be shared through a secured web dropbox called BOX. BOX access is paid for and controlled by the Medical College of Wisconsin (MCW). The folders containing participant data are password protected and only those who are adding to the folders or performing analysis on collected data are given access through MCW.&#xD;
MCW's other two recruiting sites, NorthShore University HealthSystem and Case Western Reserve University, are able to add participant data to their own site folders, and each site only has access to their participants' data.&#xD;
Ohio State University has access to the folder containing participants' heart rate recording to perform analysis.&#xD;
Blood and Urine samples are deidentified and stored at MCW until a shipment is prepared. They are then sent to the University of Pittsburgh for further analysis.</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 8, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/82/NCT03008382/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT03008382
org study id: PRO25031
nct id: NCT03008382
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) afflicts 3 to 8 million women in the US.
      Symptoms of IC/BPS reduce quality of life, suppressing both social well-being and physical
      function. The chronic pain, voiding dysfunction, sleep deprivation and associated co-morbid
      conditions interfere with relationships and employment with significant direct (doctor
      visits, medication, surgery) and indirect (loss of productivity) economic impact, currently
      exceeding $100 million per year.This proposal aims to move the science of chronic pelvic pain
      (CPP) from simple associations towards an investigation of cause and effect relationships.
      The investigators will determine whether the striking changes in autonomic nervous system
      responsiveness (ANS-R) contribute meaningfully to the pathogenesis of IC/BPS.
This multi-site trial will recruit 3 groups of female subjects ages 18-80 years, evenly
      distributed across decades (10 or 20 per decade as appropriate): Interstitial
      Cystitis/Bladder Pain Syndrome (IC/BPS), Myofascial Pelvic Pain (MPP) and Healthy Controls
      (HC).

      This proposal aims to move the science of chronic pelvic pain (CPP) from simple associations
      towards an investigation of cause and effect relationships. We will determine whether the
      striking changes in ANS-R contribute meaningfully to the pathogenesis of Interstitial
      Cystitis/Bladder Pain Syndrome IC/BPS through 3 aims:

        1. Careful longitudinal repeated measures in individual subjects to determine if ANS-R
           changes precede clinical changes;

        2. Assessing the impact of an intervention designed to change ANS-R on the clinical course
           of IC/BPS;

        3. Evaluating changes in brain connectivity between the prefrontal cortex (PFC) and the
           periaqueductal gray (PAG) associated with changes in ANS-R and improved disease status.

      Subjects will be pre-screened in person or on the phone. An in-person pre-screen takes place
      in the MCW Neurology Research Rooms at Froedtert Hospital. If the subject is able to
      participate, subject will sign the informed consent form before completing a baseline
      evaluation. The baseline evaluation occurs either following consent or at another date
      convenient for them. Subjects must complete all baseline activities within 2 weeks, or before
      their Week 4/Visit 2. The baseline evaluation is comprised of a general examination, a set of
      questionnaires, background history documenting date of diagnosis, medications tried, duration
      of each treatment and dosing, surgeries and therapeutic and exploratory procedures performed.
      A pelvic examination will be performed with CPP subjects patients only. Active Change in
      Posture (ACP) is administered to the subject. Subjects will complete the uroflow (urine)
      measurement and Valsalva maneuver in the MCW Neurology Research Rooms with a member of the
      research team present.

      Observational Substudy:

      This substudy is identical to the above with the exception of not taking a beta-blocker or
      placebo and is only 12 weeks long instead of 24. This is strictly an observational study to
      monitor subjects who have been diagnosed with IC or MPP. If the screening information shows
      that the subject meets the requirements, then they will be able to start. If the screening
      information shows that they cannot be in the research, the research doctor will discuss other
      options with them and/or refer them back to their regular doctor.

      If the subject is able to participate, they will complete 3 regular on-site long-visits at
      weeks 0, 4, and 12. The first long-visit (baseline evaluation) may occur either today
      following consent or at another date convenient for them. The baseline evaluation comprises a
      general and pelvic examination (no speculum), psychological questionnaires and a background
      history questionnaire.

      Weekly Home Checks will occur for 24 weeks (or 12 weeks if in observational sub-study)
      following consent. Once each a week, subjects will complete a 24-hour heart rate (HR)
      recording and the ACP recording using the eMotion Faros 360° portable EKG device. A member of
      the research team will contact the subject each week while they complete the weekly
      questionnaires and ACP recording. This will ensure compliance and will give the subject the
      opportunity to ask any questions.The researcher will remain on the phone or via Skype to
      monitor the subject while the ACP recording is completed from home just prior to the
      subject's bedtime. The HR recording will be uploaded to MCW's secure server at the subject's
      next hospital visit. Throughout the study, subjects flare activity will be monitored via
      phone calls and recording flares in the EMA application on the smartphone. This will be a
      Daily Flare Question in the EMA which is a set alarmed time to sound as a reminder for the
      duration of the subject's participation.

      The following weeks after each site visit and the night before visit 5, subjects will repeat
      complete the 24-hr HR recording to ensure comparability of the HRV recording at home to the
      one performed at the matching on-site visit., Subjects will also complete the 24-h voiding
      diary, a set of questions using the ICECAN mobile App installed on a pre-loaded smartphone
      and questionnaires. Deidentified 24-hour HRV and ACP recordings will be sent to Ohio State
      University for analysis.

      Follow-up Visits: Weeks 4, 12, 16, 24, Visits 2-5 (weeks 4 and 12 (Visits 2 and 3) for the
      observational substudy) Subjects will arrive to MCW Neurology Research Rooms to repeat the
      following: review of comorbidities, tender points exam, questionnaires, ACP and DNIC tests.
      Subjects will complete the Valsalva maneuver in the MCW Neurology Research Rooms with a
      member of the research team present. Chronic Pelvic Pain patients subjects will complete a
      repeat pelvic examination at Weeks 12 and 24.

      MPP and IC/BPS patients subjects will be randomized to receive 8 weeks of either placebo (a
      pill with no active agent), or metoprolol (a pill that reduces the impact of the brain's
      "fight or flight" circuits). Metoprolol is in the class of "beta-blockers" commonly used for
      mild blood pressure control, and also commonly used for migraine. Subjects will be
      administered 8 weeks of metoprolol or placebo starting at their Week 4 Visit. Subjects will
      complete a 4-week washout period (Week 12-16) and will be administered 8 weeks of crossover
      (Weeks 16-24).

      Blood will be drawn (~ 50 mL, a little more than 3 tablespoons) at each in-person visit at
      weeks 0, 4, 12, 16, and 24 for chronic pelvic pain subjects (healthy control only at Baseline
      and Final visits; 2 draws total). A portion of the blood plasma/serum will be sent to the
      University of Pittsburgh for additional related analysis. The sample will be labeled by a
      number and will not contain any information that can be used to directly identify subject.
      This portion of the study is critical to gather new information about pelvic pain, which is
      very poorly understood and we highly encourage subjects to participate in this portion of the
      study; however, it is optional.

      Healthy Controls:

      60 healthy control subjects will also complete this study in 24 weeks that include 4 long
      site visits and 6 weekly home check visits. During this first long visit they will complete a
      general exam and physician evaluation, DNIC, ACP, Valsalva maneuver, and questionnaires.
      Subjects will complete a 24-hour HR recording from home once a week for 6 weeks total.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Correlation between the change in Autonomic Nervous System Responsiveness (ANS-R) and the change in the connectivity between prefrontal cortex (PFC) and periaqueductal gray (PAG)
time frame: 24 Weeks
description: A linear model with connectivity at 24 weeks as outcome, connectivity at baseline as a covariate and change in ANS-R, demographics such as age and group and the interactions of group with other covariate.
arm group label: Double-Blind Randomized Drug
arm group type: Other
description: Participants with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and/or Myofascial Pelvic Pain (MPP) will be randomized to take 8 weeks of Metoprolol Tartrate Oral Tablet or Placebo Oral Tablet, followed by a 4-Week washout period, and then 8 weeks of Placebo or Metoprolol.
This intervention aims at finding if subjects with IC/BPS have higher baseline HR compared to HCs. After 4 weeks baseline, subjects will receive a bottle with capsules containing 25 mg of metoprolol tartrate or placebo distributed in a double-blind manner by each site's investigational pharmacy. Subjects will start at 25 mg once daily and increase to the goal dose of 25 mg 2/day after one week, if HR has not decreased below 55 bpm at rest. Subjects will report daily rest HR for the first week. The subjects will then washout for 4 weeks and enter crossover in similar manner.
arm group label: Double-Blind Randomized Placebo
arm group type: Other
description: Participants with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and/or Myofascial Pelvic Pain (MPP) will be randomized to take 8 weeks of Metoprolol Tartrate Oral Tablet or Placebo Oral Tablet, followed by a 4-Week washout period, and then 8 weeks of Placebo or Metoprolol.
This intervention aims at finding if subjects with IC/BPS have higher baseline HR compared to HCs. After 4 weeks baseline, subjects will receive a bottle with capsules containing 25 mg of metoprolol tartrate or placebo distributed in a double-blind manner by each site's investigational pharmacy. Subjects will start at 25 mg once daily and increase to the goal dose of 25 mg 2/day after one week, if HR has not decreased below 55 bpm at rest. Subjects will report daily rest HR for the first week. The subjects will then washout for 4 weeks and enter crossover in similar manner.
intervention type: Drug
intervention name: Metoprolol Tartrate Oral Tablet
description: Metoprolol is a beta-blocker commonly used for mild blood pressure control, and also commonly used for migraine. Subjects with IC/BPS or MPP will start metoprolol at 25 mg once daily and increase to the goal dose of 25 mg 2/day after one week and continue for 8 weeks total.
arm group label: Double-Blind Randomized Drug
other name: Metoprolol
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Subjects with IC/BPS or MPP will start placebo distributed in a double-blind manner. Subjects will take placebo once daily and increase to the goal dose of 25 mg 2/day after one week and continue for 8 weeks total.
arm group label: Double-Blind Randomized Placebo
other name: Placebo
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Thomas Chelimsky, MD
role: Principal Investigator
affiliation: Medical College of Wisconsin
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Medical College of Wisconsin
investigator full name: Thomas Chelimsky
investigator title: Medical Doctor and Professor of Neurology
mesh term: Cystitis
mesh term: Cystitis, Interstitial
mesh term: Pelvic Pain
mesh term: Metoprolol
sharing ipd: Yes
ipd description: All participant data will be de-identified before sharing.
Blood and Urine: A portion of the blood plasma/serum and urine will be sent to the University of Pittsburgh for additional related analysis.
Heart Rate Variability (HRV): 24-hour HRV and Active Change of Posture recordings will be sent to Ohio State University for analysis.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Analytic Code
ipd time frame: The participant's collected data is de-identified immediately. The blood and urine are stored in a freezer until there are enough samples to send out for analysis.
Heart rate recordings are uploaded to a secure MCW storage site and shared for analysis throughout the participant's participation.
ipd access criteria: Participant data will be shared through a secured web dropbox called BOX. BOX access is paid for and controlled by the Medical College of Wisconsin (MCW). The folders containing participant data are password protected and only those who are adding to the folders or performing analysis on collected data are given access through MCW.
MCW's other two recruiting sites, NorthShore University HealthSystem and Case Western Reserve University, are able to add participant data to their own site folders, and each site only has access to their participants' data.
Ohio State University has access to the folder containing participants' heart rate recording to perform analysis.
Blood and Urine samples are deidentified and stored at MCW until a shipment is prepared. They are then sent to the University of Pittsburgh for further analysis.
provided document: 