Interstitial Cystitis: Examination of the Central Autonomic Network
Condition: Interstitial Cystitis/Painful Bladder Syndrome; Myofascial Pelvic Pain
MeSH terms: Cystitis; Cystitis, Interstitial; Pelvic Pain
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Metoprolol Tartrate Oral Tablet; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Other intervention name(s): Metoprolol; Placebo
Intervention MeSH terms: Metoprolol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Interstitial Cystitis; Pelvic Pain