Interstitial Cystitis: Examination of the Central Autonomic Network

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) and Descending Noxious Inhibitory Control (DNIC, or "cold-water" test) are
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.

Weekly Home Checks will occur for 24 weeks 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 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.

Inclusion Criteria:

- Women aged between 18 and 80 years old

- Healthy controls; Patients diagnosed with Interstitial cystitis/Painful bladder
syndrome (IC/BPS) or Myofascial pelvic pain (MPP)

- IC/BPS - ≥3 months chronic pelvic pain, pressure or discomfort perceived to be related
to the urinary bladder accompanied by at least one other urinary symptom like
persistent urge to void or frequency. Confusable diseases as the cause of the symptoms
must be excluded, particularly recurrent UTI

- MPP - ≥3 months of non-cyclic continuous pelvic pain unrelated to bladder state and a
minimum of 2 of 5 examined pelvic floor TPs scoring at least 4 out of 10 on a numeric
rating scale using 2 kg pressure applied with the index finger

- Provision of informed consent prior to any study specific procedures

Exclusion Criteria:

- Known nervous system conditions including but not limited to diabetic neuropathy,
Parkinson's disease, Alzheimer's disease, multiple sclerosis, strokes, seizures, etc.

- Baseline heart rate < 50 bpm; blood pressure ≥ 140/80 mmHg at rest or uncontrolled
hypertension; or hypertension requiring more than two drugs for control

- Pregnant, attempting to become pregnant , or breast-feeding

- Unevaluated hematuria or infection at the time of enrollment

- Pelvic or bladder neoplasm or infection

- Severe asthma, inflammatory arthritis, connective tissue or auto-immune disorders

- Evidence of unstable medical disorder such as kidney (rising creatinine or end-stage
renal failure) or liver impairment (rising AST or ALT, or end-stage with
coagulopathy); poorly controlled significant cardiovascular (CHF), respiratory,
endocrine (diabetes - A1c > 9 - or untreated thyroid dysfunction) or uncontrolled
psychiatric illness (such as untreated depression, psychosis, etc.)

- Treatment with a drug or medical device within the previous 30 days that has not
received regulatory approval

- Use of hormones (except insulin, thyroid replacement or oral contraceptives). Hormone
replacement therapy is acceptable

- Current, ongoing drug or alcohol abuse

- Current use of 150 mg or more of narcotics or morphine equivalent (or inconsistent
dosages or frequency - varying by > 50 mg morphine equivalent per day)

- Previous augmentation cystoplasty, cystectomy, cytolysis, or neurectomy. Pelvic
surgery in the last 6 months.

- Any major surgical intervention with general anesthesia in the last 90 days. Current
use of anticholinergic medications.

- Current use of beta-blocker(s).

- Unwillingness to take a beta blocker and placebo, or planned use of beta-blocker(s)
other than study medication.

- Previous allergic or serious reaction to beta-blockers. Initiation of neural
stimulator in the last 30 days.

- Any on-going or pending medical, health or disability related litigation, or current
pursuit of disability.

- Any condition that in the judgment of the investigator and the internal advisory panel
would interfere with the patient's ability to provide informed consent, comply with
study instructions, place the patient at increased risk, or which would clearly
confound the interpretation of the study results (specific reason will be documented).

- Current participation in another clinical trial that interferes with ICECAN policies
and procedures .

- Investigators, study staff and their immediate families.

- Inability to speak, read, and understand English.

- Allergy to adhesives.

- Initiation of any new treatment class in the last 30 days, or intent to initiate a new
class of treatment in the study. Treatment classes include:

1. Pelvic injection

2. Pelvic floor therapy

3. Agents with specific FDA approval for IC/BPS or MPP (e.g., Elmiron)

4. Anticonvulsants

5. Tricyclic agents

6. Intravesical therapy or Botox

7. Bladder hydrodistention