Conditions: Interstitial Cystitis/Painful Bladder Syndrome Myofascial Pelvic Pain
Keywords: Interstitial Cystitis Pelvic Pain
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 72
Healthy volunteers: yes

Brief summary:
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 CPP.

Detailed description:
This multi-site trial will recruit 2 groups of female subjects ages 18-80 years, evenly distributed across decades (10 or 20 per decade as appropriate): Chronic pelvic pain (CPP) and Healthy Controls (HC). The chronic pelvic pain group will be split into 2 sub groups where some participants will receive metopropol then placebo while the other participants in this interventional group will receive placebo then metoprolol.

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 CPP 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 CPP;
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.

CPP aparticipants 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.

Arms:
arm 1: Participants with chronic pelvic pain will be randomized to either take 8 weeks of Metoprolol Tartrate Oral Tablet, followed by a 4-Week washout period, and then 8 weeks of Placebo OR to take 8 weeks of Placebo Oral Tablet, followed by a 4-Week washout period, and then 8 weeks of Metoprolol Tartrate Oral Tablet. This intervention aims at determining whether Metoprolol reduces pain in subjects in both groups compared to placebo. Some participants were not randomized and were instead enrolled into the observational sub-study. arm 2: Healthy female subjects ages 18-80 with various demographic background who do not have any exclusionary diagnostic or symptomatic criteria will be recruited. Subjects will never receive any randomization or drug treatment during the entire duration of the study

Interventions: intervention 1: Metoprolol Tartrate Oral Tablet intervention 2: Placebo Oral Tablet intervention 3: No intervention- observational sub-study
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: Participants did not receive placebo or metoprolol during the entire duration of the study.

Protocol document:
Prot_SAP_001.pdf: 
1 
 
INSTITUTIONAL REVIEW BOARD  
SUMMARY 
 Version 14.3 – 21-JAN2022 
 
 
PRINCIPAL INVESTIGATOR:  Ann Helms, M.D. 
STUDY TITLE:  Interstitial Cystitis – Examination of the Central Autonomic Network (ICECAN) 
NCT03008382 
 
A. 
PURPOSE OF THE STUDY 
To determine whether abnormal Autonomic Nervous System (ANS) activity in 
subjects with Interstitial Cystitis / Bladder Pain Syndrome (IC/BPS) causes or 
results from their Chronic Pelvic Pain (CPP) state, and to elucidate underlying 
brain mechanisms. 
 
B. 
HYPOTHESIS / SPECIFIC AIMS 
Our previous grant cycle (ICEPAC) found that high frequency heart rate 
variability (hfHRV), a measure of parasympathetic function, and baroreflex 
sensitivity (BRS), a marker of ANS flexibility, were decreased in subjects with 
IC/BPS in comparison to healthy control subjects, and most significantly, in 
comparison to subjects with another type of CPP called myofascial pelvic pain 
(MPP). These findings underscored the importance of carefully phenotyping 
subjects for the presence of each CPP type. We therefore believe ANS activity 
may control endogenous pain modulation and modulate the IC/BPS disease state.  
The proposed longitudinal set of studies is designed to address this question, 
deepen our pathophysiologic understanding of CPP in general, and lead to new 
treatment insights tailored to this population. 
The findings from the last cycle, coupled with literature referenced in the 
background below, particularly related to periaqueductal gray (PAG) – prefrontal 
cortex (PFC) connections in irritable bowel syndrome (IBS) compared to 
ulcerative colitis (UC), and in subjects with CPP due to endometriosis, led us to 
hypothesize that the ventromedial (vm) PFC normally biases the 
ventrolateral PAG to inhibit ascending nociceptive pathways and urgency 
information from the bladder.  We believe loss of this vmPFC bias is both 
necessary and sufficient to incite an IC flare in a subject with IC/BPS and 
that abnormal ANS activity reflects this reset switch in the vlPAG. 
Specific Aim 1 – Do changes in HRV precede or follow changes in IC/BPS disease activity? In a cohort of 
CPP subjects, determine if hfHRV and BRS (1a) change before or after changes in CPP disease activity 
monitored weekly; (1b) at baseline predict clinical status  at 4, 12, 16 and 24 weeks after enrollment, 
irrespective of treatment; Hypothesis and Data Interpretation: If HRV abnormalities set the stage for IC/BPS, 
HRV index changes will precede changes in the clinical and  state in IC/BPS more so than in MPP. In contrast, 
improvement in HRV/BRS following symptom change will suggest the opposite, and no change in HRV/BRS 
associated with clinical change or will imply an unrelated “bystander” effect. 
Specific Aim 2 – Does modulating HRV influence CPP disease activity? Determine the effect of directly 
modulating hfHRV using beta-blocker or placebo, in a 24-week crossover design study. Hypothesis and Data 
Interpretation: If improving hfHRV truly engenders a positive outcome and is not just a consequence of better 
health, increased HRV will decrease disease activity and improve pain modulatory state in IC/BPS more so 
than in MPP. No effect will suggest that HRV changes result from, rather than produce clinical benefit.  
Specific Aim 3 – What fundamental reprogramming underlies changes in HRV and in clinical state?  
Mechanistic: Determine if HRV changes parallel improved connectivity between the vmPFC and the PAG or 
Abbreviations 
ACP: active change in 
posture 
ANS: Autonomic Nervous 
System 
ANS-R: ANS Responsiveness 
BP: blood pressure 
BRS: baroreflex sensitivity 
CPM: central pain 
modulation 
CPP: chronic pelvic pain 
DTI: diffusor tensor imaging 
EPI: echoplanar imaging 
fc: functional connectivity 
fMRI: functional magnetic 
resonance imaging 
IC/BPS: interstitial cystitis/ 
bladder pain syndrome 
IBS: irritable bowel 
syndrome 
HC: healthy control 
HR: heart rate 
HRV: heart rate variability 
(hf: high frequency; (v)lf: 
(very) low frequency) 
MI: myocardial infarction 
MPP: myofascial pelvic pain 
PAG: periaqueductal gray  
PFC: prefrontal cortex (vm: 
ventromedial; dl: 
dorsolateral) 
TP: total power (referring to 
all frequencies of HRV) 
VBM: voxel-based 
morphometry 


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increased PAG size with connectivity and morphometry data. Independent variables of increased PAG 
size and vmPFC-PAG connectivity will be regressed against HRV change, clinical improvement, and pain 
modulatory state.   
Hypothesis and Data Interpretation: If higher HRV derives from improved PFC-PAG connections, hfHRV 
rise should parallel tightened PFC-PAG connectivity and hypertrophy of the PAG. The absence of a 
relationship will suggest that improved clinical status will be the sole determinant of these brain changes.  
 
C. 
BACKGROUND, SIGNIFICANCE, AND RATIONALE  
The European Association of Urology defines chronic pelvic pain (CPP) as pain unrelated to a structural 
process, perceived in structures related to the pelvis recurrent for at least 6 months and often associated with 
negative cognitive, behavioral, sexual, and emotional consequences [1].  A 1996 study [2] estimated that 9 
million women in the US between ages 18 and 50, some 15% of the female population at the time, suffered 
from CPP.  A 1994 Gallup poll estimated direct costs of CPP at nearly $1.4 billion in 2013 dollars, with 15% of 
women reporting lost work revenue and 45% decreased work productivity [3]. 
Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) afflicts 3 to 8 million women in the US [4]. Symptoms 
of IC/BPS reduce quality of life, suppressing both social well-being and physical function[5].  The chronic pain, 
voiding dysfunction, sleep deprivation and associated co-morbid conditions interfere with relationships and 
employment [6, 7] with significant direct (doctor visits, medication, surgery) and indirect (loss of productivity) 
economic impact, currently exceeding $100 million per year [8]. 
Despite 25 years of NIH funded investigation of CPP focused on the end-organ, no new therapies have 
emerged, and the pathophysiology remains obscure. Recent studies emphasize a key role for central processing 
networks [9]. In our first cycle of funding, we moved from the more common focus on central pain processing 
to study autonomic outflow.  We hypothesized that IC/BPS would feature abnormalities in autonomic function 
not seen in other CPP disorders such as MPP (myofascial pelvic pain) so that these changes could not simply be 
construed as due to CPP, since they occur in IC/BPS but not in other types of CPP.  This hypothesis found 
support in the results of the prior cycle (see Section C, progress report).  These findings underscore the critical 
importance of a careful phenotype in CPP subjects, because the comparison of CPP subtypes would clearly 
have been impossible without it.  Since such phenotyping rarely occurs in routine clinical or scientific practice, 
we emphasize its significance as a novel part of our approach to CPP, and as a major theme in the current 
proposal. 
Significantly, our ICEPAC studies showed decreased ANS responsiveness (ANS-R) in subjects with 
IC/BPS; both in vagal tone, measured by high-frequency heart rate variability (hfHRV), and in sympathetic 
reactivity, measured by baroreflex sensitivity (BRS), both at rest and during orthostatic challenge. While 
decreased vagal tone occurs in other chronic pain disorders like fibromyalgia [10, 11], chronic neck and 
shoulder pain [12], chronic back pain [13] and irritable bowel syndrome [14], what is noteworthy is that two 
CPP disorders, IC/BPS and MPP differed in their overall ANS-R. Until now, low vagal tone was viewed as a 
general “marker” of chronic pain. Our findings suggest a new, disease-specific interpretation, perhaps 
reflecting ANS-R as a marker of specific cortical-brainstem networks that influence central modulation of pain 
experiences. 
This proposal aims to move the science of 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 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. 
 
In the first aim, we will also study ANS-R to a noxious stimulus, reported as deficient in subjects with 
IC/BPS [15]. In that report, the authors did not phenotypically separate IC/BPS from MPP by evaluating pelvic 
tender points; therefore some of these subjects may have also had MPP [15]. Despite this limitation, their 


3 
 
findings support the hypothesis of an association between IC/BPS and central autonomic and perhaps pain 
dysregulation. In aim 1, we expect that changes in ANS-R will predict and precede clinical change in IC/BPS, 
and less so in MPP.  
 
Aim 2 will modulate ANS-R with a beta-blocker or placebo using a crossover design and examine subject 
response to continued standard therapy.  Beta-blocker treatment improves ANS-R measures. For example 
atenolol increased lfHRV by 45%, hfHRV by 84% and total power (TP) by 68% in healthy adults [16], 
decreasing lf/hf power by 36%. In a large epidemiological study [17], subjects on beta-blockers increased TP by 
13%, hfHRV by 22%, and very low frequency (vlfHRV) by 25%, but with a 12% decrease in lf/hf power. In 
decompensated heart failure, which comes with high sympathetic stress, beta-blocker treatment resulted in 41% 
higher hfHRV [18]. After acute MI, beta-blockers increase hfHRV and reduce lfHRV [19], and improve 
parasympathetic tone recovery, which correlates with improved outcome, and decrease morning sympathetic 
predominance [20]. Subjects randomized to propranolol had a greater increase in hfHRV power at 6-weeks and 
after 21 months of follow up. In coronary artery disease subjects [21], hfHRV power increased by 64% after 
atenolol and by 62% after metoprolol for 2 weeks.  We expect the salutary effects of beta-blockade to manifest 
as better response to standard treatment in subjects with IC/BPS compared to MPP. 
 
Central sensitization, as seen in decreased pain tolerance, increased bladder sensitivity and hypervigilance, 
occurs in subjects with IC/BPS [22, 23]. These observations have not been studied by fMRI or DTI. The PFC–
PAG pathway is key to pain-inhibiting circuitry [24], and vmPFC connects tightly to PAG [25], and facilitates 
disease relevant pain only, implying that cortical settings can allow or disallow ascending signals leading to a 
pain experience [26].  In IBS, reduced lateral PFC influence on PAG appears to permit ascending nociceptive 
signals access to higher centers [27]. Consistent with this role, stimulating the lPFC-PAG pathway by 
transcranial magnetic stimulation [28] inhibits pain and the lPFC atrophies in the setting of chronic pain [29]. Of 
critical interest to this application, the vmPFC is not only anatomically linked to the PAG [25], and critical to 
pain regulation, it is also the cortical structure that is most closely linked to the brainstem autonomic networks 
that are reflected by ANS-R. 
 
Indeed, our studies [30] suggest that higher ANS-R indicates a greater capacity for context and goals to 
modulate emotion, closely linked to the output of vmPFC. Roy et al. [31] conceptualize the vmPFC as a 
“system of systems” linking conceptualization, context, emotion and response.  Thus, its connection to the PAG 
may bias more caudal brainstem networks to specific modes that reflect particular behavior patterns and their 
autonomic accompaniments.  ANS-R may be the “poor man’s” marker of vmPFC outflow to the PAG.   
Relevant to this proposal, vlPAG has just the right connections and functions to modulate flares and remissions 
in IC/BPS. It (a) receives input from the PFC, (b) modulates ascending C-fiber visceral nociceptive input [32], 
(c) integrates autonomic and nociceptive responses [33], (d) increases hfHRV, an indicator of parasympathetic 
activity, in proportion to chronic pain relief produced by deep brain stimulation [34], (e) is activated during 
voiding and micturition and triggers micturition [35-38] and (f) takes part in REM/non-REM switching during 
sleep, an area of significant dysfunction in most of our subjects with CPP.  
 
D. 
DESIGN AND METHODS  
This multi-site trial will recruit 3 groups of female subjects ages 18-80 years: 1) IC/BPS (n=60); 2) MPP with or 
without IC/BPS n=60); 3) 60 HCs [only for fMRI] (18 per group for MRI). Recruitment will occur from the 
prior ICEPAC cohort from Dr. Tu’s K award cohort at Northshore, and from specialty clinics associated with 
MCW and NorthShore University HealthSystem (Chicago). We expect to enroll 50 participants from each 
group at MCW/FMLH. We expect a 15% dropout over the 24 weeks, so that we expect 60 starters and 51 
completers in each group.  Please see Table 1 for a list of study activities and responsibilities for each study site.  
 
 
 
 
 


4 
 
 
Table 1. Site coordination, procedures and recruitment 
 
FMLH 
Case 
Northshore 
Coordination 
Responsibility for all 
activities, fMRI, HRV 
integrity, psychiatric red 
flags and data 
 
Psychiatric red flags and 
data 
Diagnostic accuracy 
Procedures 
Enroll, HRV, Home HRV 
(ACP), BRS, 
Computational model, 
analyze psychological 
data 
Analyze psychological data Enroll, on-site HRV 
(ACP) 
Peak Recruitment Rate 
(Total n at each site) 
30 per year with hope to 
collect complete from 79 
total participants 
Case has recruited 13 total 
but will no longer be 
recruiting and will only be 
analyzing data. 
12 per year, 46 total 
 
 
Overall Pelvic Pain Subject Inclusion & Exclusion criteria 
General inclusion criteria for subjects will include: 
• Women aged between 18 and 80 years old. 
• Healthy controls and subjects diagnosed with IC/BPS or MPP. 
• For 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 
urinary tract infection (UTI). 
• Women with 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.  
 
General exclusion criteria for all subjects will include: 
• 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 and uncontrolled 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 thyroid replacement or sex hormones. These may include the following birth 
control methods- IUD based, periodic injections, oral, patch, ring, and implant (3-year duration) which 
are acceptable). Hormone replacement therapy, such as growth hormone, is not acceptable. 
• Current, ongoing substance 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). 


5 
 
• Previous augmentation cystoplasty, cystectomy, cytolysis, or neurectomy.  
• General anesthesia for a non-traumatic procedure (e.g. colonoscopy, cystoscopy etc.) or minor procedure 
such as skin tag removal etc. in the past 2 weeks 
• A traumatic procedure that does NOT involve the pelvic floor (e.g. shoulder surgery, cardio-pulmonary 
surgery) in the past 4 weeks 
• A traumatic procedure that DOES involve the pelvic region (e.g. hysterectomy, hip surgery etc.) in the 
past 6 weeks 
• Current use or planned use of anticholinergic medications.  
• Current use or planned use of beta-agonists.  
• Unwillingness to take a beta-blocker and placebo, or planned use of beta-blocker(s) other than the study 
medication. 
• Previous allergic or serious reaction to beta-blockers. 
• Current use or planned use of certain prohibited medications-See Restricted and Prohibited 
Medications in Appendix 1 
• 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 subject’s ability to provide informed consent, comply with study instructions, place the subject 
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. 
• Inabilities to speak, read, and understand English.  
• Known 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: 
o Pelvic injection 
o Pelvic floor therapy 
o Agents with specific FDA approval for IC/BPS or MPP (e.g., Elmiron) 
o Anticonvulsants 
o Tricyclic agents 
o Intravesical therapy or Botox 
o Bladder hydrodistention 
  
Short term use of albuterol, levalbuterol, or pirbuterol is allowed while subjects are actively receiving 
metoprolol/ placebo for a maximum of 7 days duration.  If the acute illness requiring a short-acting beta agonist 
has not resolved in 7 days, metoprolol/ placebo can be held for up to 14 days.  After 14 days, metoprolol/ 
placebo can be resumed and the remainder of the 8-week treatment course may be completed.  Contact the PI if 
short-acting beta agonist use is required for more than 21 days. 
 
Healthy controls:  
Healthy female subjects will be recruited by nomination by patients, screening from the BANK Medical 
College of Wisconsin fMRI Research Program, flyers and advertisement. Only members of the ICECAN 
research team at MCW will have access to the fMRI Research bank. A history and physical will be obtained by 
a physician and controls will be required to have no history, symptoms or signs of all the exclusion criteria 
described above plus: 
• Chronic fatigue syndrome, Raynaud’s syndrome, Rheumatoid arthritis, Fibromyalgia, Temporo 
mandibular joint disorder, Dysmenorrhea, Endometriosis, Dyspareunia, Functional gastrointestinal 
disorders including Cyclic vomiting syndrome, Irritable bowel syndrome, Functional abdominal pain 
syndrome, Functional dyspepsia; Chronic idiopathic nausea, Migraine headaches, Abdominal migraine, 
Syncopal migraine; Reflex syncope, Postural tachycardia syndrome, Orthostatic intolerance syndrome, 


6 
 
Post-traumatic stress disorder, Panic disorder, Generalized anxiety disorder, Adjustment disorder with 
depressed mood, Major affective disorder, Complex regional pain syndrome, Diabetes, Glucose 
intolerance, Currently active asthma, Multiple chemical sensitivity, and Periodic limb movements in 
sleep. Diagnosis of IC/PBS, MPP or chronic pelvic discomfort or chronic pain disorder of any type that 
consistently interferes with life’s functions at work or home > 2 days/week for more than one month. 
 
Protocol and Procedures 
All IC/BPS and MPP subjects will participate in both Aim 1 and Aim 2. In contrast, aim 3 is an optional sub-
study and will only include 18 subjects from each group.   
 
All activities are identical for all sites except the breathing test (Valsalva maneuver is only conducted at 
MCW). See the Data Collection Schedule in Appendix 3.  
 
Aim 1 and Aim 2 – Experimental Group 
Baseline Visit: Week 0, Visit 1 
Recruitment will occur from the prior ICEPAC cohort from Dr. Tu’s K award cohort at Northshore, and from 
specialty clinics associated with MCW and NorthShore University Medical Group (Chicago).  Up to 120 
IC/BPS and MPP subjects (60 per each group) will be recruited study wide. We expect to enroll up to 100 
IC/BPS and MPP subjects (50 per group) from Froedtert Memorial Lutheran Hospital (FMLH). FMLH subjects 
will be recruited from the OB/GYN and Neurology Clinics.  A member of the research team at FMLH 
introduces subjects to this study.  Consent is obtained by a member of the research team. Once the subject has 
had adequate time to consider participation, understands all of the risks and benefits and would like to 
participate, the subject will sign informed consent and HIPAA documents.   
 
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 FMLH. 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[39], a set of questionnaires 
(Appendix 3), background history documenting date of diagnosis, medications tried, duration of each treatment 
and dosing, surgeries and therapeutic and exploratory procedures performed (Appendix 3).  A pelvic 
examination will be performed with Chronic Pelvic Pain subjects only.  HRV/BPS (See Active Change in 
Posture – ACP below) tests is administered to the subject (see procedures for details). Subjects will complete 
the uroflow 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 a week, subjects will complete a 24-
hour HR recording, voiding diary and the ACP recording using the eMotion Faros 360° portable EKG device.   
A member of the research team will contact the subject via phone, text, email or skype each week to remind 
them to complete the nighttime ACP, followed by the 24-hour HRV recording, voiding diary and the weekly 
questionnaires via the EMA App and link to RedCap (or via paper).  This will ensure compliancy and will give 
the subject the opportunity to ask any questions.  The researcher will contact them via phone or via skype to 
monitor the subject while the ACP recording is completed from home just prior to the subject’s bedtime for the 
first few recordings until the subject is comfortable completing the recording by herself. 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, texts or emails and recording flares in the EMA application 
(Appendix 2) 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 24 hours before visit 5, subjects will complete the final ACP 
recording prior to bedtime and 24-hr HRV 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-hr voiding diary, a set of 


7 
 
questions using the ICECAN mobile App installed on a pre-loaded smartphone and questionnaires via a Redcap 
link. The recorded HR data will be downloaded from the monitor and standard HRV analysis for steady state 
(supine rest phase of ACP test) and time-varying HRV analysis will be performed, as described above, 
extending over the 24-hr period, as we have shown [40]. Deidentified 24-hour HRV and ACP recordings will be 
sent to Dr. Julian Thayer’s research group at University of California Irvine 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, and HRV/BPS (ACP) tests. Subjects will complete the Valsalva maneuver 
in the MCW Neurology Research Rooms with a member of the research team present.  Chronic Pelvic Pain 
subjects will complete a repeat pelvic examination at Weeks 12 and 24.  
 
MPP and IC/BPS 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) using Piantadosi’s 
Randomization software [41], overseen by Dr. Pippa Simpson in Biostatistics.  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).   
 
If for some reason it is not possible for the patient to collect the study product while on-site during a study visit, 
the study drug may be mailed to the patient if the site pharmacy agrees to ship the study medication to their 
study participant. This will ensure the study team is able to provide the study product to subjects if the 
manufacturer is unable to refill the prescription prior to the site's supply running out. The research pharmacy in 
Froedtert has agreed to ship the study medication to the subject(s) via FedEx. The study team will provide the 
research pharmacy with the FedEx Airbill and will record the tracking number on the airbill to track the date 
and time of the delivery to the participant(s). Participants will then return the study medication at the next study 
visit. If for some reason the study participant(s) are unable to return the study medication to the site, they will be 
sent a FedEx airbill and supplies to use to return the study medication to the site. The study team will then 
record the tracking number of the package to track its return. The study team will also inform the participants to 
place the medication in the FedEx packaging, place the airbill on the packaging and drop it off at any FedEx 
location. 
 
Optional: 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). 
We will determine (1) if immune or inflammatory factors play a role in pain cycles and (2) if energy production 
in cells might be impaired in chronic pelvic pain.  A portion of the blood plasma/serum will be sent to Dr. Lori 
Birder’s laboratory at 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. We highly 
encourage subjects to participate in this portion of the study.  However, given how difficult it can be to obtain 
blood from some people with IC/BPS, we do allow subjects to opt out of the blood draw portion of this study 
and still participate in the other parts.  
 
Urine will also be collected (~ 50ml) 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). Samples will be sent to Dr. Lori Birder for related 
analysis.  
 
If for some unforeseen reason the physician assessment (MEDYSA) is unable to be completed during any of the 
study visits, the study investigator may complete this with the study participant over the phone. 
 


8 
 
Every subject will receive a general wellbeing follow-up phone call or email 4 weeks after their study 
completion. 
 
Healthy Controls 
50 healthy control subjects will be enrolled at FMLH and will also complete this study in 24 weeks that include 
4 long site visits and weekly home check visits. Subjects will complete the weekly home check visits during 
their first 3 weeks in the study and then again after week 12 or 20 for an additional 3 weeks.   
 
During the first long visit they will complete a general exam and physician evaluation, HRV/BRS (ACP), 
Valsalva maneuver (MCW only), and questionnaires (Appendix 3)).   
 
Subjects will complete a 24-hour HRV/BRS recording from home once a week for 6 weeks.  A member of the 
research team will contact the subject each week while they complete the weekly questionnaires and ACP 
recording until they are comfortable and understand this process.  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 for the first few 
recordings until they are comfortable completing this on their own.  
 
Subjects will return to the hospital 3 weeks later to complete the second long site visit procedures including a 
physician evaluation, HRV/BRS (ACP), Valsalva maneuver, and questionnaires (Appendix 3).  
 
When subjects return to the hospital for Visit 3, at either week 12 or 20, they will complete the third long site 
visit procedures including a physician evaluation, HRV/VRS (ACP), Valsalva maneuver, and questionnaires 
(Appendix 3).  
 
Subjects will complete a 24-hour HRV/BRS (ACP) recording from home once per week for the following 3 
weeks. A member of the research team will contact the subject each week to remind them to complete the 
weekly questionnaires and ACP recording.  
 
Subjects will then return to the hospital for their Final Visit/Visit 4 at either week 16 or week 24 to complete the 
last study procedures including a physician evaluation, HRV/BPS (ACP), Valsalva maneuver, and 
questionnaires (Appendix 3). 
 
Every subject will receive a general wellbeing follow-up phone call or email 4 weeks after their study 
completion. 
 
Aim 1 Observational Alternative Study: 
 
Subjects who meet the study eligibility criteria will be eligible to participate in the Observational Alternative 
Study. Recruitment will occur from the prior ICEPAC cohort from Dr. Tu’s K award cohort at Northshore, and 
from specialty clinics associated with MCW and NorthShore University Medical Group (Chicago).  Up to 20 
IC/BPS and MPP subjects from Froedtert Memorial Lutheran Hospital (FMLH) will be recruited to this study 
from the OB/GYN and Neurology Clinics.  A member of the research team at FMLH will introduce subjects to 
this study.  Consent is obtained by a member of the research team. Once the subject has had adequate time to 
consider participation, understands all of the risks and benefits and would like to participate, she will sign 
informed consent and HIPAA documents.   
 
If the subject is interested in this research study, she will first complete a pre-screen in person or on the phone to 
see if she is able to participate. An in-person pre-screen takes place in the MCW Neurology Research Rooms at 
Froedtert Hospital (FH), Neurology or OBGYN clinics at Moorland Reserve Health Center or Froedtert Main 
Campus, or at Westbrook Clinic or St. Joseph’s Health Center. 
 


9 
 
If the screening information shows that the subject meets the requirements, then she will be able to start. If the 
screening information shows that she cannot be in the research, the research doctor will discuss other options 
with her and/or refer her back to her regular doctor.  
 
If the subject is able to participate, she will complete 3 regular on-site long-visits at weeks 0, 4, and 12. The first 
long-visit (baseline evaluation) may occur either the same day she provided consent or at another date 
convenient for her. The baseline evaluation comprises a general and pelvic examination (no speculum), 
psychological questionnaires, detailed medical interview and a background history questionnaire. This exam 
may take up to 45 minutes to complete. She will also complete a urine flow measurement, a heart rate recording 
and a breathing test. The participant will also be asked to provide a urine sample and a blood sample. The blood 
sample is optional.  
 
Follow-Up Visits Weeks 4 and 12 
At each long-visit, the subject will complete a physician exam, a set of questionnaires, provide a 24-hour 
voiding diary and the following tests: breathing test, heart rate test and a “uroflow measurement,” A “uroflow 
measurement” measures the volume of urine, how long it takes to be released from the body and the speed. The 
subject will also complete a repeat pelvic examination at Week 12.  
 
The subject will be asked to complete questionnaires at each long-visit including: Hospital Anxiety and 
Depression Scale (HADS), State-Trait Anxiety Inventory (STAI), Thoughts About Symptoms (CSQ), 
Pennebaker Inventory of Limbic Languidness (PILL), Multidimensional Pain Inventory (MPI), Female 
Genitourinary Pain Index (FGUPI), Perceived Stress Scale (PSS), PROMIS Social Roles and Activities, 
PROMIS Physical Function, PROMIS Fatigue, PROMISE Sleep Disturbance, the Holmes-Rahe Life Stress 
Inventory, the MAPP II Interactive Brief Pain Inventory, and the Covid-19 Questionnaire. They will complete 
the Childhood and Recent Trauma Events Scale (RTES) during their first long-visit only. 
 
The subject can skip any question that they do not feel comfortable answering on any of the forms. Although 
the first questionnaires will be completed in the clinic to keep their answers private, the next will be completed 
while they are at home. We cannot guarantee that those responses will be kept private and there is a chance that 
answers may be seen by those who live in or visit their home. If their score is suggestive of emotional problems, 
study director  or a study Co-Investigator and/or Psychologist will provide them with places to help get 
treatment for these issues within 1 week of their participation. The researchers are required by law to report any 
abuse or neglect (or suspicion of abuse or neglect) if the subject mentions it to the researchers or if it is 
suspected.  
 
The 24-hour voiding diary consists of tracking how much liquid comes in and out of the subject’s body in a 24-
hour period, and how often they void. The subject will be required to measure the amount of everything they 
drink. The subject will also record the time and amount of each void for the 24-hour period. A special 
measuring “hat” that fits over the toilet seat will help the subject measure each void. The uroflow measurement 
requires the subject to urinate on a special toilet in the MCW Neurology Research Rooms at FH. The toilet 
contains sensors that measure the speed of the urine flow and amount of urine. About one hour prior to this test 
the subject will be asked to drink a quart of fluid. 
 
The subject will complete a “breathing test” (Valsalva Maneuver) in the MCW Neurology Research Rooms at 
FH. To complete this test the subject will have wrist straps secured to a table and asked to breathe in deeply and 
out forcefully through a tube. The subject will have a small band on their arm to measure their heart rate and 
blood pressure. The subject will complete 4 cycles of breathing: two cycles while lying down flat and two 
cycles while leaning slightly forward.  
 
The active posture change (ACP) heart rate recording (HRV) will take about 20 minutes to complete. The 
subject will complete this recording at each long-visit and each week that they are in this study. Heart rate will 
be recorded with an eMotion Faros 360° portable ECG device. It is small and lightweight, with 3-5 small 


10 
 
adhesive electrode patches placed on the skin of the subject’s chest and torso. The subject will lie down flat on a 
bed and rest for 10 minutes before the recording starts. After that, the subject will lie down for 5 more minutes 
while their heartbeat is recorded for 5 minutes. The subject will be asked to stand up as quickly as they can and 
stand still for an additional 5 minutes. The subject may sit down if this test becomes too much for them to 
complete. Coded 24-hour HRV and ACP recordings will be sent to Dr. Julian Thayer’s research group at 
University of California Irvine for analysis. The subject’s sample will be labeled by a number and will not 
contain any information that can be used to directly identify them. 
 
Blood (optional) will be drawn and urine will be collected (~ 50 mL, a little more than 3 tablespoons) at each 
in-person visit at weeks 0, 4, and 12. We will determine (1) if immune or inflammatory factors play a role in the 
subject’s pain cycles and (2) if energy production in the subject’s cells might be impaired. A portion of the 
subject’s blood plasma/serum and urine will be sent to Dr. Lori Birder’s laboratory at the University of 
Pittsburgh for additional related analysis. Both of the subject’s samples will be labeled by a number and will not 
contain any information that can be used to directly identify them. This portion of the study is critical for us to 
gather new information about pelvic pain, which is very poorly understood. We highly encourage the subject to 
participate in this portion of the study. However, given how difficult it can be to obtain blood from some people 
with IC/BPS, we do allow the subject to opt out of the blood draw portion of this study and still participate in 
the other parts. 
 
Weekly Home Checks will occur once a week for 12 weeks following consent. Each week, the subject will 
complete a 24-hour heart rate (HR) recording using the eMotion Faros 360° ECG device, the 24-hr voiding 
diary, answer a set of questions using the ICECAN mobile App installed on a preloaded smartphone, and 
complete questionnaires (those mentioned previously) that are sent to the subject’s personal e-mail account via 
a secure Internet connection. The questionnaires will be completed either electronically via REDCap or via 
paper. The heart rate recording will help us to study how the subject’s heart rate changes throughout the day. 
The subject will place the patches on their chest and torso to match the image found on the instruction sheet 
provided to them as soon as they get up in the morning. For the first few recordings, a member of the research 
team will contact the participant, either via telephone, email, skype or text, later in the evening, before the 
subject goes to bed, to complete an additional recording. The researcher will ask the subject to lie down flat on 
their bed for 15 minutes. After that, the researcher will instruct the subject to stand up as quickly as they can in 
front of their bed for another 5 minutes. The subject can sit down if they become too dizzy. The data from the 
subject’s heart rate recording will be uploaded to a secure server by a member of the research team. The 
researcher will ask whether the subject has had a chance to complete the questionnaires. If in any case the 
subject is unable to complete the questionnaires online, they will be asked to return paper copies of the 
questionnaires at their next in-person follow-up visit.  
 
The subject will also complete a Daily Flare Question which asks about flare activity, management and if the 
flares are affecting them. These Flare Questions will be monitored via phone calls and recording in the EMA 
application on the smartphone.  
 
After each site visit and the 24 hours prior to visit 3, the subject will repeat the ACP recording prior to bedtime 
and the 24-hr HR recording, as described above, to compare the HRV recording done at home to the one 
performed at the matching on-site visit.  
 
If the participants end up not answering some of the EMA questions, we will be asking them the following:  At 
any time during the study, did your pain affect your ability to answer any of the EMA questions?  When you 
didn't answer the EMA questions, what percentage of time was it due to pain?  These questions will be asked at 
each in-clinic visit appointment. 
 
If for some unforeseen reason the physician assessment (MEDYSA) is unable to be completed during any of the 
study visits, the study investigator may complete this with the study participant over the phone. 
 


11 
 
Every subject will receive a general wellbeing follow-up phone call or email 4 weeks after their study 
completion. 
 
Aim 1 -2: Incentives 
IC/BPS and MPP subjects will be compensated for their time and travel.  Travel will be reimbursed as follows:  
For travel time between 1 and 2 hours, subjects will be paid $20 per visit and for travel time between 2 and 4 
hours, subjects will be paid $40 per visit.   They will be compensated for participation a total of $400 by a 
preloaded credit card for completing at least 80% of the required items for the five major visits at the sites and 
the at-home monitoring sessions. Subjects will receive $50  after completing all study tasks and Visit 1,  $60  
after completing all study tasks and Visit 2,  $70  after completing all study tasks and Visit 3,  $80  after 
completing all study tasks and Visit 4,  $140  after completing all study tasks and Visit 5, and returning the 
Faros ECG monitor and the pre-loaded Smartphone.  
 
Healthy controls will receive a total of $400 by a preloaded credit card for completing at least 80% of the 
study activities, returning the Faros EKG, smartphone and completing the 4th and Final visit. This includes the 
general examination, psychological questionnaires, a breathing test, heart rate test, the uroflow 
measurement, and at-home participation. They will receive $50 after completing Visit 1/Baseline,$150 after 
completing all at-home study activities and Visit 2,  $100 after returning from the break and completing Visit 
3, $100  after completing all at-home study activities, completing Visit 4/Study Completion and returning all 
study materials. 
 
Observational Alternative Study Subjects will be compensated for their time and travel.  Travel will be 
reimbursed as follows: For travel time between 1 and 2 hours, subjects will be paid at $20 per visit and for 
travel time between 2 and 4 hours, subjects will be paid $40 per visit.  They will be compensated for 
participation in the study with $250 by a preloaded credit card for completing at least 80% of the required 
items for the three major visits at the site and the at-home monitoring sessions.  Subject will receive $50 after 
completing all study tasks and Visit 1, $50 after completing all study tasks and Visit 2, and $150 after 
completing all study tasks, Visit 3, and returning the Faros ECG monitor and the pre-loaded Smartphone. 
 
Subjects may be given the option to redo a study visit if the study data are incomplete or if they need to stop the 
study drug. If they redo a visit, they will receive payment for the visit which was repeated in the same amount 
as mentioned above for the corresponding visit. 
 
Subjects who complete the baseline evaluation but are found not to be eligible to participate will be mailed a 
$25 check. 
 
Aim 3 Optional MRI Sub-study 
Subjects who are enrolled in the Experimental Group or Healthy Control Group will be given the option to 
participate in the fMRI sub-study.  Chronic Pelvic Pain subjects will be asked to complete 3 fMRI scans that 
each take roughly 60 minutes to complete. Healthy controls will complete a total of 2 scans: one scan before 
their Week 4 visit and one scan before their Week 24 visit or final visit.  We will enroll 54 subjects able to 
commute to MCW, 18 IC/BPS, 18 MPP (none with both diagnoses) and 18 HCs.  The Safety Screening 
Questionnaire is completed prior to the scan and is verified by the fMRI technician. If it is determined that the 
subject is safe to complete the scan, the technician will introduce them to the scanning procedure. The MRI 
Experience Questionnaire (MEQ) is completed after the MRI procedure to assess the subjects experience during 
the MRI. 
Sub-study Inclusion and exclusion criteria: 
• Between 18 and 80 years old. 
• Must be female. 
• Must speak, read, and understand English. 


12 
 
• Must be right-handed. 
• Does not have orthodontic braces or permanent retainers. 
• Must pass the standard MR safety screening as required by the MR Safety Committee.  For  
example, subjects with aneurysm clips, pacemakers, implanted stimulators, and some types of prostheses 
will be excluded. 
• Active cyclic or chronic vomiting will be excluded. 
• Subjects who have phonophobia will be tested to see if the noise produced by the MRI is tolerated. 
Subjects who are unable to tolerate this noise will be excluded from the study. 
• Must be able to remain in the scanner for up to 1 hour without moving. 
• Carries a diagnosis of chronic pelvic pain x 3 months or more, either interstitial cystitis or myofascial 
pelvic pain. 
• Must not be pregnant or plan to become pregnant in the next 6 months. 
• No evidence of any neurologic disorder such as Parkinson’s disease, Diabetic Neuropathy, etc. 
• No subjects with chronic dizziness. 
 
MRI Sub-study Protocol and Procedures 
18 subjects from each sub-group will be approached, screen and consented to undergo an fMRI scan. 
A3T machine will be utilized for these studies. They will undergo fMRI for connectivity, DTI and VBM at 
weeks 0 (or within the 4 weeks prior to visit 2), 12 and 24 (inverted triangles Figure 1) with the regular major 
visit battery (Table 2).  Each subject is required to complete a urine pregnancy test prior to the scan unless they 
are no longer menstruating. 
 
Aim 3: Incentives 
IC/BPS and MPP subjects who complete the sub-study will be compensated for their time and travel following 
each scan.  Subjects will receive $75 by a preloaded credit card after completing each of the 3 fMRI scans.   
 
Healthy controls will receive $75 by a preloaded credit card following the completion the first fMRI scan and 
$75 after each subsequent fMRI scan.  
 
E. 
TOTAL NUMBER OF HUMAN RESEARCH SUBJECTS PROPOSED FOR THIS STUDY AT 
THIS SITE AND GLOBALLY.  WHAT ARE THESE NUMBERS BASED ON? 
At FH/MCW, we will enroll 3 groups of female subjects ages 18-80 years: 1) IC/BPS (n=50); 2) MPP with or 
without IC/BPS n=50); 3) HCs only (n=50) for fMRI (18 per group for MRI).  All subjects will participate in 
both Aim 1 and Aim 2. Recruitment will occur from the prior ICEPAC cohort from Dr. Tu’s K award cohort at 
Northshore, and from specialty clinics associated with MCW and NorthShore University HealthSystem 
(Chicago). We expect a 15% dropout over the 24 weeks, so that we will have 60 starters and 51 completers in 
each group.  Please see Human subject section for inclusion and exclusion criteria.   
 
We will enroll a total of 54 subjects to the fMRI sub-study who are able to commute to the Medical College of 
Wisconsin (MCW), 18 IC/BPS, 18 MPP (none with both diagnoses) and 18 HCs with the goal of completing all 
3 scans in 12 subjects per CPP group and two scans in HC’s. CPP subjects will undergo fMRI for connectivity, 
DTI, VBM, and spectroscopy of the PAG at weeks 0, 12 and 24 (inverted triangles Figure 1) with the regular 
major visit battery (Table 2). 
 
F. 
DRUGS OR PROCEDURES


13 
 
 
 
 
Physician Examination 
Detailed history of comorbidities including chronic fatigue 
syndrome, temporomandibular joint disorder, Raynaud’s, 
fibromyalgia, asthma, rheumatoid arthritis, syncope, 
postural tachycardia syndrome, chronic idiopathic nausea, 
functional dyspepsia, functional abdominal pain, IBS, 
migraine, syncopal migraines, panic disorders, PTSD, a 
screening questionnaire that will be completed by subjects 
and reviewed by the research coordinator. Positive answers 
are followed up by the physician-investigator to determine 
if the subject has the disorder (ranked as definite, probable, 
possible, absent). Severity is quantified on an 11-point 
disease activity numeric rating scale (NRS) for comparison with CPP disease activity. The PROMIS 
Sleep Disturbance will help quantify sleep effectiveness.  Chronic pelvic pain subjects will also have a 
pelvic examination completed at time of consent, week 12 and week 24. 
 
Questionnaires 
1. The Childhood and Recent Trauma Events Scale (RTES) includes 7 questions and will determine the 
independence of childhood trauma from adult trauma as a factor associated with IC/BPS.  
Questionnaires may be completed under the direct or indirect (via video link) supervision of a research 
coordinator to enhance adherence.  
 
2. Depressive symptomatology will be assessed with the Hospital Anxiety and Depression Scale 
(HADS). Adults rate each of the 14 items on a four-point Likert scale indicating how frequently they 
experience each symptom. 
 
3. Symptoms of anxiety will be assessed with the State-Trait Anxiety Inventory (STAI)[42]. The STAI 
is a self-report measure developed to help distinguish between a person’s state anxiety and their trait 
anxiety. Subjects complete 40 items on a four-point likert scale indicating how frequently they 
experience each symptom. 
 
4. Cognitive patterns of thinking about pain will be measured with the Thoughts About Symptoms 
(CSQ). The CSQ is a self-report measure developed for adults with chronic pain conditions to assess 
their negative thinking patterns regarding pain.  Adults will complete 8 items on a seven-point likert 
scale indicating the degree to which they catastrophize about different aspects of their pain. 
 
Visit 
1 
 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
 
Week 
0 
 
4 
12 
16 
24 
 
Duration 
3h 
 
3h 
3h 
3h 
3h 
General exam 
  
X 
 
  
  
  
  
Physician exam 
  
X 
 
X 
X 
X 
X 
Questionnaires 
  
X 
 
X 
X 
X 
X 
Heart rate test 
  
X 
 
X 
X 
X 
X 
Breathing test 
  
X 
 
X 
X 
X 
X 
Pelvic exam 
  
X 
 
 
X 
 
X1 
Home Checks 
 
Done weekly for 24 weeks (40 min) 
X1 Subjects in the experimental group only. 
 
Figure 1 and Table 2 summarize overall 
study design. (Note that Aim 1 Observational 
Study component applies to all subjects and 
should not be confused with the 
Observational Alternative Study) 
Psychological Scale Abbreviations  
BPI : Brief Pain Inventory 
HADS  : Hospital Anxiety and Depression Scale 
RTES: Childhood and Recent Trauma Event Scale  
FGUPI:  Female Genitourinary Pain Index  
MPI: Multidimensional Pain Inventory  
CSQ: Thoughts About Symptoms 
PILL: Pennebaker Inventory of Limbic Languidness 
PSS: Perceived stress scale  
STAI: Spielberger State-Trait Anxiety Inventory 
HRLSI: Holmes-Rahe Life Stress Inventory 


14 
 
 
5. Nervousness, distressed and unhappy physical symptoms will be measured using the Pennebaker 
Inventory of Limbic Languidness (PILL) Adults will rate a 54-question self-test 
(http://counsellingresource.com/lib/quizzes/misc-tests/pill/) [43] to quantify somatization.  
 
6. The Multidimensional Pain Inventory (MPI) is a self-report instrument composed of 61 items that 
form 13 scales assessing cognitive, behavioral and affective aspects of pain as well as three scales that 
measure impact on function. It has been rigorously examined for psychometric properties[44]. 
 
7. The Female Genitourinary Pain Index (FGUPI) is a valid and reliable condition-specific instrument 
that can be used to quantify symptoms in men and women with bladder/urologic pain. This 
questionnaire also discriminates between subjects with IC/BPS and other diagnoses. Clemens et al. 
demonstrated that the score in the GUPI and the scores in the Interstitial Cystitis Problem Index and 
Interstitial Cystitis Symptom Index correlated highly [45]. This questionnaire consists of 9 questions 
regarding location of pain, pain associated with certain activities frequency of urination, sensation of not 
emptying the bladder and how the symptoms affected daily activity [46].  This questionnaire has been 
chosen since it is currently used by the NIH-MAPP group and will allow for comparison of results. 
 
8. The Perceived Stress Scale (PSS) assesses an individual’s perception of stress over the past month 
[47]. The 10 item questionnaire will ask about thoughts and feelings the respondents have experienced 
during the last month (http://www.mindgarden.com/documents/PerceivedStressScale.pdf). This scale is 
designed to measure how subjects find their lives to be overloaded, unpredictable and uncontrollable. 
 
9. The NIH Patient-Reported Outcomes Measurement Information System –PROMIS Social Roles and 
Activities Short Form  and PROMIS Physical Function Short Form [Available at: 
http://www.nihpromis.org/about/overview (accessed December 30, 2014).] are self-report measures 
developed for adults with any medical disorder to measure social and physical these functioning. 
Subjects rank each of the 16 items on five-point Likert scales indicating how much difficulty they have 
doing common activities. 
 
10. The 8-item version of the PROMIS Sleep Disturbance will help quantify sleep effectiveness. 
 
11. The PROMIS Fatigue short form assesses fatigue over the past seven days. It evaluates a range of 
self-reported symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and 
sustained sense of exhaustion that likely decreases one’s ability to execute daily activities and function 
normally in family or social roles.  
 
12. The Holmes-Rahe Life Stress Inventory (HRLSI) is a self-report instrument composed of 43 life 
events.  Subjects are instructed to mark each life event that they have experienced in the previous month 
or two months.  
 
13. The MAPP II Interactive Brief Pain Inventory (BPI) will be used to conduct brief pain inventory at 
each in-person visit for pain intensity experienced by the subject in the past 7 days before their visit.  
 
14. If the participants end up not answering some of the EMA questions, we will be asking them the 
following:  At any time during the study, did your pain affect your ability to answer any of the EMA 


15 
 
questions?  When you didn't answer the EMA questions, what percentage of time was it due to pain?  
These questions will be asked at each in-clinic visit appointment if some questions were previously 
missed. 
 
15.  The Covid-19 questionnaire will be administered at each in-person visit and involves how Covid-19 
has affected the participant emotionally. 
 
Physiologic Studies Methodology  
During the following battery of tests (Active Change of Posture, and Valsalva Maneuver ), a surface 
ECG monitor (eMotion Faros 360°, Mega Electronics Ltd, Finland) and a noninvasive continuous 
hemodynamic monitoring system using the plethysmographic pulse pressure waveform from a finger 
cuff (Nexfin, Edwards Lifesciences Corp, Irvine, CA) will be attached to the subject. The Nexfin will 
only be used at the MCW site due to availability of equipment and expertise in the field. These devices 
will continuously record ECG and blood pressure waveforms and derived RR-intervals (heart rate) and 
beat-to-beat systolic, diastolic and mean arterial blood pressure [48, 49]. BRS parameters will be 
computed later, using both the time-domain sequence technique and the frequency-domain coherence 
method [50-52]. The HRV time- and frequency- domain parameters for steady state data such as supine 
rest periods will be computed later according to published standards [53-55]. In addition, time-frequency 
analysis (change of spectral parameters over time) will be computed for the ACP  test [56]. A physician 
will review the ECG for any abnormal findings and make appropriate clinical recommendations to the 
subject’s referring site physician by phone or make arrangements directly if the subject is a subject of 
one of the Principal Investigators.  
 
Active Change of Posture (ACP): Subjects will have a 3 to 5-lead Faros ECG monitor placed on them in 
a private room with white noise and dim lighting (matching lux and dB levels across sites).  Subjects 
will rest supine for 10 minutes followed by another 5 minutes of supine baseline. Subjects will then 
stand close to their bed within 3 seconds (or as quickly as they can) without reclining on any furniture 
and 5 more minutes will be recorded. The research coordinator’s presence in the room throughout the 
entire process will ensure compliance with the protocol and also document if the subject reports any 
symptoms (visits 1-5). We will use the supine baseline for HRV and spontaneous BRS analysis. The 
ACP procedure results in venous pooling. Characteristic HR change dynamics after stand up can index 
cardiovagal function, e.g. (R-R interval at beat 30)/(R-R interval at beat 15) [57-59]. The immediate 
response is a sharp decrease in BP and total systemic resistance at 5 to 10 seconds, followed by a rapid 
rebound and overshoot. A corresponding HR increase follows in 3 to 5 seconds and then attenuates. 
After 30 seconds, the hemodynamic parameters become relatively stable [60]. HRV and BP variability 
provide deeper insight in the time course of the autonomic response to ACP. Total and lf power are 
raised after standing and hf fraction is reduced [61]. Although complex physiological adjustments occur, 
the test is easy to administer and repeat by the subjects at home (see below). Time-frequency spectral 
analysis of HRV and BP data will detect changes in sympathetic and vagal function and BRS. Coded 24-
hour HRV and ACP recordings will be sent to Dr. Julian Thayer’s research group at University of 
California Irvine for analysis.  
 
Valsalva Maneuver: Only subjects enrolled at MCW will quantify the cardiovagal/adrenergic 
components of ascending and descending baroreflex functions. It provides a measure of BRS beyond the 
spontaneous BRS analysis from ACP [62]. After a 1-minute baseline, the Valsalva is performed by 
having the subject hold intrathoracic pressure of 40 mmHg for 15 seconds and then release. A series of 4 


16 
 
reproducible maneuvers will be performed, 2 while lying flat and 2 while tilted at 30°. The maneuver is 
repeated 4 times in total, not including practice runs. The Valsalva Ratio and beat-to-beat BP response 
are computed. Cardiac sympathetic function is inferred from the resulting increase in HR, while 
maintenance of mean pressure during the maneuver reflects vasomotor sympathetic function, with 
gender and age-based norms described for both. The bradycardia that occurs during the release phase 
represents a second, confirmatory measure of cardiac parasympathetic function [58, 63, 64]. 
 
Uroflow and 24h voiding diaries will be performed at major visits (visits 1-5) to evaluate the impact of 
changes in HRV on bladder physiology. Subjects will be asked to urinate on a special toilet in the FH 
Neurology Research Rooms during which the speed and pattern of their urine stream will be determined.  
Subjects will also be asked to monitor their drink intake and output for the same 24 hours they complete 
the 24-hour EMA.  They will measure their own output using a hat provided to them by the research 
team. 
 
Home checks (figure 1 small up-arrows) will occur once each week, even on-site visit weeks. 24-hour 
HR recording will use the Faros 360 (Mega Electronics Ltd, Finland) for RR-intervals & accelerometry 
during the following assigned activities and the surrounding 24-hour periods. On each night, subjects 
will go to a bedroom with minimal distractions (i.e. no TV or radio, only communication devices to 
communicate with research coordinator) and with dim lighting to rest supine for 10 minutes followed by 
another 5 minutes of supine baseline. Subjects will then stand up within about 3 seconds without 
reclining and stand still for 5 more minutes. The research coordinator will coach via phone or Skype to 
ensure compliance for the first few recordings, until the subject is comfortable with this process. An 
accelerometer built into the eMotion HRV 3D device will document position changes. Subjects will 
complete a weekly Ecological Momentary Assessment (Appendix 2) during the day of monitoring to 
assess adherence to the at-home ACP tests as well as to record any shifts in mood/affect or subjective 
pain experience. The 24-hr HR recording will later be analyzed for ANS-R parameters.  
 
Subjects will also complete the GUPI, Promis 8a and 8b, and a limited version of the MPI either online 
or via paper format. The subject’s completed questionnaires and the HR recording will be uploaded to a 
secure MCW server.  
 
After each site visit and the 24 hours before visit 5, subjects will complete the bedtime ACP recording 
followed by the 24-hr ANS-R screen, as described earlier, without any questionnaire (except diary as 
before) to ensure comparability of the HRV recording at home to the one performed at the matching on-
site visit. The recorded HR data will be downloaded from the monitor and standard HRV analysis for 
steady state (supine rest phase of ACP test) and time-varying HRV analysis will be performed, as 
described above, extending over the 24-hr period, as we have shown [40].  
 
Beta-Blocker vs Placebo  
All MPP and IC/BPS subjects in the Experimental Group will participate in this aim occurring 
simultaneously with aim 1 and employing a 4-8-4-8 week crossover design. A baseline of 4 weekly 
repeated measures will precede 8 weeks of placebo or beta-blocker, 4 weeks of washout, and 8 
additional weeks of crossover. Subjects will be adaptively randomized across all 3 sites in blocks of 4 to 
either beta-blocker or placebo for ANS-R modulation, stratified by the presence or absence of IC/BPS, 
using Piantadosi’s Randomization software [41], overseen by Dr. Pippa Simpson. We chose a β1-
adrenoceptors cardio-selective blocker because of its more restricted effects. Metoprolol is useful in the 


17 
 
treatment of arrhythmias, hypertension, angina, acute myocardial infarction and the prevention of 
migraine headaches. Based on personal communication with cardiology and psychiatry (R Josephson 
10-15-2014 and J Thayer 9-11-14), 8 weeks are adequate to observe a full effect, and 4 weeks for 
washout. This intervention aims at our prior cycle finding that 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 resting 
HR for the first week. A member of the research team will train the participant how to count her pulse. 
Chen W et al. [65] reported increased hfHRV and decreased lfHRV in 60 sleep-deprived young adults 
with this dose, noting a reduction in premature atrial and ventricular complexes. The subjects will then 
washout for 4 weeks and enter crossover in similar manner (red and green bands in figure 1). 
 
If for some reason it is not possible for the patient to collect the study product while on-site during a 
study visit, the study drug may be mailed to the patient. 
 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Unanticipated Problems Involving 
Risks to Human Subjects or Others (UPIRHSOs) 
 
Adverse Events   
Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of any study procedure or treatment, regardless of whether it is 
considered related to the study procedure or treatment. 
 
Serious Adverse Event 
Any adverse drug experience that: 
 
• 
Results in death; OR 
• 
Is life-threatening or places the subject at immediate risk of death; OR 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization; OR 
• 
Results in a persistent or significant disability/incapacity; OR 
• 
Results in a congenital anomaly/birth defect; OR 
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition 
 
Unanticipated Problems Involving Risks to. Human Subjects or Others (UPIRHSOs) 
Any incident, experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency.  (Not found in the current research related 
documents or in the characteristics of the subject population being studied); AND 
• 
Related or possibly related to participation in the research; AND 
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized 
 
Aim 3 Sub-study fMRI 
 
GE 3T MR750 MRI System The 3T will be used for this proposal 
Third Generation Magnet Design. Contains 18 superconducting higher-order shim coils, active-shielding 


18 
 
technology, and stainless steel foundation. The magnet’s high homogeneity delivers excellent fat-
saturation away from isocenter and ensures image quality over a full 48-cm field of view. Zero boil-off 
technology and remote magnet monitoring technology are incorporated. 
 
High-Performance Whole-Body Gradients. The MR750 incorporates the eXtreme Resonance Module 
(XRM). XRM gradients deliver 50 mT/m peak amplitude and 200 T/m/s maximum slew rate on each 
axis simultaneously. The gradients are water-cooled and equipped with integrated thermo-electric 
cooling panels to provide 100% duty-cycle and stability for advanced studies, such as fMRI. Acoustic 
noise is minimized, using a passive acoustic barrier material that reduces acoustic transmission by an 
average of 6 dB for enhanced patient comfort without compromising imaging performance. 
 
Higher-Order Shimming. The MR750 is equipped with five higher-order shim-resistive shim coils to 
minimize patient-induced field perturbations. In addition to the linear terms (X, Y, Z), the shim set 
includes XY, XZ, YZ, Y2, X2-Y2 compensation coils. 
 
RF Amplifier. To drive the MR 750 body coil, the system utilizes a water-cooled, solid-state 35 kW RF 
amplifier design. The amplifier supports a 100 W continuous-wave output mode for advanced proton- 
decoupling and spin-labeling research. 
 
Host Computing Platform, Reconstruction Engine, and Software. Version 20.x based software. The 
MR750 utilizes 2.6 GHz processing technology with VRE2.0 recon architecture. With its expansive 32 
GB memory, acquisition-to-disk technology, and 5400 2D FFT/s frame rate, the VRE 2.0 delivers the 
processing power to reconstruct 32 channels of high-resolution 3D volumetric data. 
 
This 3T scanner enhances the shared use of the centralized MRI resources, enrich ongoing research, 
promote new research directions, foster a cooperative and interactive research environment, and 
stimulate multidisciplinary approaches to neuroscience. MCW has provided strong institutional 
commitment toward the 3T imaging facility and maintenance. 
 
Version-20.x-based software will include all commercially available pulse sequences, spectroscopy, and 
imaging options, nominally equivalent in form and function to the MR750 (3T) platform. Dual CPU 
host-computer includes Linux OS, dualcore.  
 
Diffusion Kurtosis Imaging (DKI) scans use the SE-EPI pulse sequence with multiple non-collinear 
gradient directions and at least two b values such as 1000 and 2000, 4 reference scans will also be 
acquired in the axial orientation, aligned with the high resolution T1 weighted scans (8 minutes). Motion 
and eddy current related distortions will be corrected with FSL software (http://www.fmrib.ox.ac.uk/fsl/) 
[66, 67]. DKI data will be processed using software developed in-house that generates axial, radial and 
mean kurtosis maps (Kax, Krad and MK) in addition to conventional Fractional Anisotropy and Mean 
Diffusivity (FA and MD) maps. DKI measures non-Gaussianity of the diffusion signals and it has been 
shown to be a more sensitive marker of subtle changes in brain white matter compared to conventional 
DTI [68].  
 
Spectroscopy of PAG: single voxel magnetic resonance spectroscopy of the PAG to investigate relative 
distribution of brain metabolite spectra in the PAG of patients with CPP. 
 


19 
 
Resting-State fcMRI Acquisition. Subjects stay awake, eyes open, wakefulness monitored on a 10-point 
Likert scale, 1 ("very sleepy") to 10 ("very alert").  T2*-weighted functional images will be acquired 
with a gradient-echo EPI sequence using 45 interleaved axial contiguous 2.5-mm thick slices, along with 
respiratory and cardiac signals (2 imaging runs of 132 volumes and 6.5’ each).  Dr Lisa Conant will do 
pre-scan coaching in the mock MCW scanner and during scanning. 
  
G. 
RISKS AND THE PRECAUTIONS WHICH WILL BE TAKEN TO MINIMIZE RISK 
EXPOSURE 
Overall, potential risks associated with participation in the proposed study are similar to those 
experienced by women undergoing standard of care for chronic pelvic pain.  
 
Physical. Subjects participating in the phenotyping portion of the proposed research (Aim 1) will be 
exposed to physical risks associated with the standard of care for chronic pelvic pain, including but not 
limited to pelvic examination. The course of treatment is left to the discretion of each subject’s urologist, 
urogynocologist or pelvic pain specialist. In addition to the standard of care, research subjects will 
undergo non-invasive testing such as tender point evaluation, baroreflex and HRV assessment as part of 
study screening, baseline metrics, and follow-up visits.  Tender point evaluation is considered standard 
of care for myofascial pain disorders such as fibromyalgia and may lead to bruising and pain at the site 
of palpation.  Procedures used to assess baroreflex sensitivity and HRV are considered the standard of 
care for assessing autonomic nervous system deficiencies with minimal associated physical risks. 
Subjects may feel anxious, dizzy, nauseated or get a headache from breathing in and out as instructed 
during the breathing test. (HR and blood pressure monitoring during structured breathing and change of 
posture). Use of beta-blockers (Aim II) such as metoprolol can lead to diarrhea, stomach cramping, 
nausea, vomiting, rashes, blurred vision, muscle cramping, fatigue, depression, heart failure or heart 
block in subjects with heart problems (although known heart issues are an exclusion criteria), headaches, 
dizziness, nightmares, hallucinations, shortness of breath in asthmatics, sexual dysfunction, and may 
cause low or high blood glucose. Physical risks associated with fMRI (Aim III) are not fully known but 
current evidence indicates that there is minimal risk associated with the procedure. Because the MRI 
scanner produces a very strong magnetic field, there is some risk involved in the form of the potential 
for metallic objects to move through the room creating projectiles that could harm individuals and/or 
damage the scanner. Healthy controls will be screened for the absence of pelvic pain, and other 
pain/autonomic disorders, baseline metrics, psychological questionnaires will be determined, and 
subjects may partake in the HRV, baroreflex, and fMRI portions of the study. Potential physical risks 
will be discussed with all subjects and knowledge of these risks will be made evident through the 
consent form. 
 
Psychological. Risks associated with the psychological questionnaires are considered minimal.  Since 
self-disclosure of personal information may produce some transient emotional discomfort, the informed 
consent process makes clear that subjects may decline to participate in any aspect of the project, 
including completing questionnaires.  Although not a direct risk of the study, our instruments may 
expose levels of psychopathology that require clinical attention. Measures will be scored within 1 week 
and subjects whose scores exceed established cutoffs will be discussed and the senior investigator will 
be notified. Contact of the subject will be at the discretion of the principal investigator. If necessary, the 
subject will be provided a referral for further psychological or psychiatric evaluation. 
 


20 
 
H. 
PROVISION FOR THE PROTECTION OF PRIVACY OF SUBJECTS AND TO 
MAINTAIN THE CONFIDENTIALITY OF DATA 
 
All research projects that collect electronic data must use appropriate security measures to ensure 
that data is protected from theft or loss in order to prevent breaches of confidentiality.  You must 
indicate what encryption tools (or why they are not necessary) from the options below.  The IRB 
will not review this protocol unless you indicate the encryption tools being used to secure your 
research data.  If you do not have encryption in place on your systems, please contact your 
Information Systems support to arrange for one of the encryptions options listed below.  
 
The following encryption products employ cryptographic modules that the National Institute of 
Standards and Technology has certified as meeting FIPS 140-2 requirements.  Children’s Hospital 
and Health System endorsed the use of these products made to encrypt hard drives and removable 
media.  All electronic research data must be encrypted using one or more of these products.   
 
Please indicate which encryption tools you are using to secure your research data. 
___ Credent Mobile Guardian (RS, PD) 
___ GuardianEdge Hard Disk and GuardianEdge Removable Storage Encryption (HD, RS, PD) 
_X_ IronKey encrypted flash drives (RS) 
 ___ McAfee Endpoint Encryption (HD, RS) 
___ Microsoft Bitlocker (HD, RS when used with Windows 7 and FIPS compliant algorithms are 
enabled) 
___ PGP Whole Disk Encryption and PGP Portable (HD, RS) 
___ SafeNet Protect Disk and SafeNet Protect File (HD, RS) 
 ___ Seagate Secure Self-Encrypting Drives (HD when encryption option is enabled) 
___ Symantec Endpoint Encryption (HD, RS, PD) 
_X_ WinMagic SecureDoc encryption (HD) (for MCW owned computers) 
_X_ Other: Trucrypt 
 
Does not apply because: 
___   Data is de-identified – no PHI collected 
___   Data is stored on paper only 
___   Data is stored on CHW secured shared drives. 
_X_  Data is stored on MCW secured shared drives.  
 
Key 
HD = Hard Drive 
RS = Removable Storage (USB flash drive, CD, etc.) 
PD = Portable Device (iPod; iPhone; PDA, etc.) 
 
I. 
PROVISIONS FOR MONITORING DATA TO ENSURE THE SAFETY OF SUBJECTS; 
AND ADDITIONAL SAFEGUARDS TO PROTECT THE RIGHTS AND WELFARE OF 
SUBJECTS WHO ARE LIKELY TO BE VULNERABLE 
The Principal Investigator will monitor the health of all subjects in this study per standard clinical 
practice. Subjects who are found to have suicidal ideation will be contacted by study co-investigator and 
psychologist, Dr. Lisa Conant. Physician referrals will be provided as needed and as dictated by law to 


21 
 
ensure subject and family safety and to address psychosocial needs. The Principal Investigator will 
monitor protocol adherence and supervise data collection, entry, and analysis. The Research 
Coordinators will share their contact information with each subject in case of study-related emergency. 
If the Coordinator is contacted, they will direct the subject accordingly and contact the Principal 
Investigator immediately.  
 
J. 
ANTICIPATED BENEFITS ASSOCIATED WITH THE PROTOCOL TO HUMAN 
RESEARCH SUBJECTS AND SOCIETY  
The anticipated risks to subjects are reasonable in relation to the anticipated benefits and the importance 
of the knowledge that is expected to result from the study. While there may be no direct benefit of the 
study to subjects, the study has the potential of benefit of increasing our knowledge of factors 
contributing to chronic pelvic pain. Although this study does not focus on any specific treatment and 
does not depend on treatment fidelity, it will nonetheless benefit from this standard approach. 
 
K. 
STOPPING POINTS THAT WOULD NOT ALLOW THE STUDY TO CONTINUE AS 
PROPOSED  
The Primary Endpoint is whether change in ANS-R is accompanied by a change in the connectivity 
between PFC and PAG. We will use 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. 
 
The Secondary Endpoints are to ascertain structural changes that correlate with larger ANS-R, 1) 
changes in fiber bundles connecting PFC and PAG using DTI/DKI, and 2) changes in the size of PAG 
using VBM analysis.  We expect to see changes in structure at 24 weeks parallel with ANS-R change.  
  
L. 
IS THERE A DATA SAFETY MONITORING BOARD IN PLACE?  WHO ARE ITS 
MEMBERS?  HOW OFTEN DO THEY MEET?   
A DSMB of independent investigators will be established to advise the NIDDK and the study 
investigators. Their responsibilities include the annual review and evaluation of the accumulated study 
data for subject safety, study conduct and progress, and, to make recommendations to NIDDK 
concerning the continuation, modification, or termination of the trial. They will monitor adverse events, 
evaluate data quality, completeness and timeliness, examine performance of the individual sites, review 
adherence to the protocol and intervention fidelity across site, and oversee factors that might affect 
subject safety or data confidentiality. We will recruit national experts in CPP or autonomic function to 
be on the ICECAN advisory board and DSMB. All key investigators and the DSMB will meet once per 
year.  Any severe adverse events (SAEs) encountered that the principal investigator believes are severe 
and related to the study medication will be presented to the Board and reported to the IRB at the time of 
the occurrence. All other SAEs and adverse events (AEs) will be recorded and submitted annually to the 
DSMB. 
 
M. 
DESCRIBE HOW THE CONSENT PROCESS WILL TAKE PLACE.  INCLUDE A LIST 
OF APPROPRIATELY TRAINED PERSONNEL WHO WILL BE INVOLVED 
Written informed consent for participation will be obtained from the subjects.  Consent will be obtained 
by a study investigator or a CITI trained research team member at the subject’s OB/GYN or Neurology 
Clinic appointment in FMLH, either at the main campus or at a satellite clinic.  The subject’s consent 
will allow for accessing information collected for program evaluation/clinical purposes. Participating 


22 
 
1→2 2→3 3→4 4→5 1→3 2→4 3→5 1→4 2→5 1→5
1→2
1•1
1•1
1•1
1•2
1•2
1•3
2→3 1•1
1•1
1•1
1•2
3→4 1•1
1•1
1•1
4→5 1•1
1•1
1•1
1→3
2•2
2→4 2•1
3→5 2•1
2•1
2•2
1→4
2→5 3•1
1→5
Changes in HRV
Changes in Pain
Interval 
comparisons
Table 3. In each of the 22 cells for which there is no ambiguity 
regarding the sequence in which changes occur, the entry a•b is 
a pair of (major) interval lengths: a for changes in pain 
occurring first, b for changes in HRV occurring first. 
volunteers will have the option of having the consent document read aloud to them to facilitate 
understanding.  Copies of signed consent document will be given to subjects.  Consent will be obtained 
by the study principal investigator, co-investigators or other CITI trained research staff.  As additional 
research staff or team members are added, their names will be submitted to the IRB as a protocol 
amendment to allow them to obtain consent.  
 
Subjects who agree to the optional blood draws will initial the corresponding field on the consent form. 
Subjects who agree to provide the optional blood samples will be asked at each visit if they still agree to 
the blood collection. 
 
N. 
PROCEDURES TO BE EMPLOYED IN ANALYZING DATA AND THE 
ANTICIPATED SIGNIFICANCE OF THE PROPOSED STUDY 
Power: There is little prior information on which to perform a formal power analysis, so conservative 
assumptions determine the difference in correlations that will be detectable with 80% power at the 
.017% level (to allow for 3 independent tests – and more dependent ones – at the 5% level).  We assume 
an analysis of 102 subjects allowing for 15% dropout in which partial correlations (partialing out 
IC/BPS versus MPP and other relevant covariates i.e., age and treatment are analyzed. First, we use 
conservative assumptions to determine the difference in correlations that will be detectable with 80% 
power at the .017% level (to allow for 3 independent tests at the 5% level). Assuming an effective 
sample size of 102-3 =99 , the z-transform of a correlation will then have variance 1/96 (90) and the 
difference between two such correlations will be twice that, conservatively assuming zero correlation 
between the two correlations  It then follows that, for a two-sided test, a difference in correlation of ~0.4 
will be detectable. However, because we expect a strong positive correlation between the two 
correlations, a much smaller difference will be detectable.  
 
Analysis: Standard mixed model regression analysis will 
determine how well baseline measures predict later measures.  
Since all the measures will be continuous or quasi-continuous, 
all data will be transformed, as necessary, for residuals to be 
approximately normally distributed.  Although both predictors 
of interest and possible confounding covariates can be 
simultaneously included in the regression models, examining 
the outcome variables univariately or multivariately, to 
examine the order of time changes, we propose correlation of 
covariate-adjusted residuals using Fisher’s variance-stabilizing 
z-transformation, appropriately allowing for the correlation 
between correlations [69]. First, we will take a weighted 
average of the covariate-adjusted ANS-R variables to minimize the standard error of the weighted 
average (subject to the sum of the squared weights equaling 1), and similarly for the pain scores. With 5 
major time points there are 4-time intervals. We define a change as the (signed) difference in value of a 
variable between two time points, so that for each variable we have 10 changes (4 of length 1, 3 of 
length 2, 2 of length 3, and 1 of length 4 intervals). We thus have a 10x10 matrix of correlations when 
we pair a change in the ANS-R variable with a change in the clinical score: 11 of these correlations 
correspond to changes in ANS-R preceding changes in pain, and 11 to changes in pain preceding ANS-
R: the other 78 correlations are ambiguous regarding the order in which the changes occur (Table 3). We 
will calculate these 22 correlations and, separately in each of the three groups, test the equality of the 11 


23 
 
implying pain causes ANS-R to the 11 implying the converse, performing three two-sided tests: one on 
the average correlations where all intervals are of length 1; one on the average of those where the 
interval length is 1 for one variable and 2 for the other; and one for the correlations where the interval 
length is 2. If one of these is significant, similar detailed analyses with finer intervals will be warranted. 
 
The Primary Endpoint of aim 1 is the determination of time sequence between changes in ANS-R and 
changes in measures of daily pain and function (MPI, Promis 8a/8b, GUPI).  Secondarily, we will also 
assess sequence relationships between changes in ANS-R and changes in bladder function by the same 
methodology.  We expect ANS-R, a putative measure of the operating mode of vmPFC, to increase (both 
in total power and in HF fraction) before clinical improvement in subjects who fulfill the IC/BPS 
phenotype. Pitfalls and alternate approaches: if we do not demonstrate this specific relationship: 1) a 
different relationship may emerge, and we will explore its implications; 2) the relationship may exist in 
certain subgroups, for example predicted by other aspects of baseline phenotype such as ANS-R, or 
psychological features; 3) the relationship may exist only for major changes in clinical status as may 
happen during “flares” or “remissions”; 4) specific aspects of ANS-R responsiveness (such as change 
with standing ) may correlate better with clinical change than ANS-R itself in a particular state. 
 
Secondary Endpoint: 1) determination of whether ANS-R at baseline predicts clinical status (MPI, 
GUPI), bladder physiology, at 4, 12, 16 and 24 weeks.   Pitfalls and alternate approaches:  if this is 
not the case, we will examine other psychological measures for a similar predictive role, and ANS-R 
stimulus responsiveness rather than ANS-R itself.   
 
Technical Considerations: though this portion is not invasive and virtually without associated risks for 
the subjects, we may still struggle with poor home screen compliance. If so, we have considered sending 
the research coordinators to the homes (if budget allows) or change from weekly visits to every other 
week.   
 
Aim 3 Analysis, Endpoints, Expected Findings, Pitfalls and Alternate Approaches 
Analysis: VBM: Voxel based lesion-symptom mapping studies suggest a major role in organizing and 
planning goal-directed behavior for lPFC regions, while vmPFC provides insight and harmonizes 
behavior with emotional, social and cognitive forces (see for example [70]).  One might speculate that 
goal-directed behavior from lPFC regions must suppress ascending signals through PAG, while 
internally attentive behavior (through vmPFC) will want to enhance these signals to attend to them, 
potentially explaining the opposing forces these two areas exert over PAG. We will be examining these 
relationships in great detail across our subjects.  VBM will be compared between HCs, IC/BPS and MPP 
subjects, initially; paired sampling across time will be utilized to determine the change in PAG size 
across time; the magnitude of this change will be regressed against quantitation of improvement using 
mixed models as described in aim 2.  DTI/DKI: Kax, Krad, MK, FA and MD maps will be generated 
for statistical analysis, and changes in both associated with HRV index changes in tracts that connect the 
PFC to PAG and raphe will be analyzed using Tract-Based Spatial Statistics (TBSS), a non-parametric 
permutation test for analysis [71, 72]. Statistical tests will be thresholded at p<0.01 corrected for 
multiple comparisons using family-wise error rate.  We will test the hypothesis that the connecting 
bundles enlarge in those subjects whose HRV increases across the 3 time points. Connectivity: After 
standard image pre-processing using the AFNI software package [73], cardiac and respiratory cycle 
noise removal [74], band-pass filtering, Voxelwise multiple linear regression analysis (AFNI's 
3dDeconvolve [75]), we will analyze the correlation BOLD time-course coefficient maps for each 


24 
 
region of interest (ROI), and convert to Z-score maps. An automated affine transformation maps Z-score 
maps to stereotaxic atlas space, with standard smoothing and calculation of t-statistics for each ROI. 
Significance uses magnitude and extent (cluster size) criteria with permutation testing to select a whole-
brain corrected p < 0.01 threshold, along with ordinary least square to account for covariates. Changes in 
functional connectivity strength between PAG and PFC associated with HRV changes will be analyzed 
using resting state fcMRI results. Temporal data analysis will utilize 3dREMLfit 
(http://afni.nimh.nih.gov/pub/dist/doc/program_help/3dREMLfit.html). CSF pulsation and respiration 
signal contamination will be minimized by regressing out signals that correlate with EKG and 
respiratory cycles prior to rs-fMRI analysis. These are recorded with MRI compatible EKG system and a 
respiratory belt.  
 
Sample size justification: For a correlation of 0.5 with 18 in the sample, we will have 95% confidence 
interval of (0.043, .784). We will examine the change over time using a mixed effects model. We expect 
that brain maps of connectivity will show such a change, present when HRV has significantly increased, 
and more marked in IC/BPS than in MPP. Pitfalls and alternate approaches: connectivity changes 
may occur in other areas seeding from PAG.  We will use the information to generate hypotheses 
regarding the underlying neurophysiology of IC/BPS.  If the changes do not correlate with ANS-R 
change, we will re-explore the analysis using clinical improvement.  
Pitfalls and alternate approaches: should we not see changes in subjects with better ANS-R, we may 
consider extending the fMRI and 
DKI portion of the grant.   
 
Timeline (Table 4) and Data 
Management.  The NIH-MAPP data 
core at U Penn will manage all 
subject data while the UCLA 
imaging core will manage imaging 
data.  We will use REDCap onsite 
(Research operates within the Secure Socket 
Layer (SSL) 128-bit encryption Electronic Data Capture) a secure, web-based application designed for 
research data capture. Clinical data entry will occur on site and MCW will be responsible for the 
physiologic data entry. Sites will only see data from their site and access privileges will reflect need for 
and is fully in compliance with: (a) Guidance for Industry 21 CRF Part 11; Electronic Records; 
Electronic Signatures; Scope and Application [FDA]; (b) 21 CRF Part 820 (QSR); (c) Guidance for 
Industry; E6 Good Clinical Practice: Consolidated Guidance; (d) Guidance for Industry; Computerized 
Systems used in Clinical Investigations; (e) General Principals of Software Validation; Final Guidance 
for Industry and FDA Staff; (f) Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Missing Data. We will examine the pattern of missing data using logistic regression. Where it seems 
reasonable to assume the data are missing at random (MAR), we will use a mixed model approach or for 
any items missing such as demographics, we will use multiple imputation. We will conduct a sensitivity 
analysis to check other assumptions, if it appears data are not MAR. 
 
 
 
 
O. 
FINANCIAL RELATIONSHIPS  
Table 4. Projected study timeline for  Aims 1-3.  
Timeline for all Aims
Specific Aims
AIM 1: Observational Study
Clinical setup
Enroll patients
Data analysis & Manuscript preparation
AIM 2: HRV Modulation
Clinical & Pharmacy setup
Enroll patients
Data analysis & Manuscript preparation
AIM 3: fMRI and DTI
Protocol setup
Enroll patients
Data analysis & Manuscript preparation
Year 5
Year 3
Year 1
Year 2
Q1
Year 4
Q4
Q1
Q3
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q2
Q3
Q4
Q1
Q2


25 
 
This protocol is supported by a NIH grant. This grant provides funding for study related procedures 
(HRV, questionnaires, physician examinations, Valsalva maneuver), data analysis and study incentives 
to subjects. 
 
P. 
ADVERTISEMENTS / FLIERS  
Flyers, advertisements and MCW fMRI Bank (for MCW only) will be used to recruit healthy control 
subjects. Flyers will be posted throughout the Clinic Workrooms in FMLH and specialty clinics. 
Recruitment flyers will also be posted at Marquette University, University Wisconsin Milwaukee, and 
local churches. Advertisements will include an information page placed on the Medical College of 
Wisconsin’s Infoscope informational page as well as The Interstitial Cystitis Association web site 
(https://www.ichelp.org/research/clinical-trials/studies-seeking-patients/).   
 
Experimental subject recruitment flyers, and supplemental online pre-screen/ QR code ad will also be 
posted at area Universities within a 150-mile radius of MCW (ex. Marquette, UW-Milwaukee, UW-
Madison), area bus lines (ex. Metro, Badger bus), Wisconsin Athletic Clubs in the area, local churches, 
and local YMCAs.  These flyers will only be posted after the institution/company gives us the approval 
to do so.  This flyer will also be posted on Facebook and subjects will be encouraged to call or email the 
study team. 
 
Experimental subject supplemental online pre-screen/ QR code will also be posted at area universities, 
bus lines, athletic clubs within a 150-mile radio of Northshore University in Illinois. 
 
Additional advertisement will be used in the form of a TV ad, radio, and possible guest on Milwaukee 
Public Radio. 
 
Q. 
BIBLIOGRAPHY  
1. 
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2. 
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3. 
Stein, S.L., Chronic pelvic pain. Gastroenterol Clin North Am, 2013. 42(4): p. 785-800. 
4. 
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5. 
El Khoudary, S.R., et al., Severity of Interstitial Cystitis Symptoms and Quality of Life in Female 
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6. 
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7. 
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8. 
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9. 
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irritable bowel syndrome patients. Clin J Pain. 28(6): p. 519-26. 


26 
 
11. 
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15. 
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16. 
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17. 
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18. 
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21. 
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27. 
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gray matter density. J Neurosci, 2004. 24(46): p. 10410-5. 
30. 
Lane, R.D., et al., Neural correlates of heart rate variability during emotion. Neuroimage, 2009. 
44(1): p. 213-22. 


27 
 
31. 
Roy, M., D. Shohamy, and T.D. Wager, Ventromedial prefrontal-subcortical systems and the 
generation of affective meaning. Trends Cogn Sci, 2012. 16(3): p. 147-56. 
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33. 
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different types of stress. Neurosci Biobehav Rev, 2001. 25(7-8): p. 669-78. 
34. 
Pereira, E.A., et al., Ventral periaqueductal grey stimulation alters heart rate variability in 
humans with chronic pain. Exp Neurol, 2010. 223(2): p. 574-81. 
35. 
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42-8. 
36. 
Griffiths, D., et al., Brain control of normal and overactive bladder. J Urol, 2005. 174(5): p. 
1862-7. 
37. 
Griffiths, D., et al., Cerebral control of the bladder in normal and urge-incontinent women. 
Neuroimage, 2007. 37(1): p. 1-7. 
38. 
Kuhtz-Buschbeck, J.P., et al., Cortical representation of the urge to void: a functional magnetic 
resonance imaging study. J Urol, 2005. 174(4 Pt 1): p. 1477-81. 
39. 
Disorders, T.I.C.o.E.-D.S.R., EDS Diagnostics, D.C.f.H.E.-D.S. (hEDS), Editor. 2017, The 
Ehlers-Danlos Society. 
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Welzig, C.M., et al., Lipid lowering by pravastatin increases parasympathetic modulation of 
heart rate: Galpha(i2), a possible molecular marker for parasympathetic responsiveness. 
Circulation, 2003. 108(22): p. 2743-6. 
41. 
Piantadosi, S., Randomization ©. Block randomization software windows version 6.0. 2011, 
Cedars-Sinai Medical Center: Los Angeles, CA. 
42. 
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Inventory (STAI) and the State-Trait Anger Expression Inventory (STAXI), in The Use of 
Psychological Testing for Treatment Planning and OUtcomes Assessment, M. M, Editor. 1999, 
awrence Erlbaum Associates, Inc: Hahwah, NJ. 
43. 
Pennebaker, J., The Psychology of Physicial Symptoms. 1982, New York: Springer-Vale. 
44. 
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(WHYMPI). Pain, 1985. 23(4): p. 345-56. 
45. 
Clemens, J.Q., et al., Validation of a Modified National Institutes of Health Chronic Prostatitis 
Symptom Index to Assess Genitourinary Pain in Both Men and Women. Urology, 2009. 74(5): p. 
983-987.e3. 
46. 
Clemens, J.Q., et al., Validation of a Modified National Institutes of Health Chronic Prostatitis 
Symptom Index to Assess Genitourinary Pain in Both Men and Women. Urology, 2009. 74(5): p. 
983-987. 
47. 
Cohen, S., T. Kamarck, and R. Mermelstein, A global measure of perceived stress. J Health Soc 
Behav, 1983. 24(4): p. 385-96. 
48. 
Omboni, S., et al., Spectral and sequence analysis of finger blood pressure variability. 
Comparison with analysis of intra-arterial recordings. Hypertension, 1993. 22(1): p. 26-33. 
49. 
Parati, G., et al., Comparison of finger and intra-arterial blood pressure monitoring at rest and 
during laboratory testing. Hypertension, 1989. 13(6 Pt 1): p. 647-55. 
50. 
Parati, G., M. Di Rienzo, and G. Mancia, How to measure baroreflex sensitivity: from the 
cardiovascular laboratory to daily life. J Hypertens, 2000. 18(1): p. 7-19. 
51. 
Persson, P.B., et al., Time versus frequency domain techniques for assessing baroreflex 
sensitivity. J Hypertens, 2001. 19(10): p. 1699-705. 


28 
 
52. 
Westerhof, B.E., et al., Time-domain cross-correlation baroreflex sensitivity: performance on the 
EUROBAVAR data set. J Hypertens, 2004. 22(7): p. 1371-80. 
53. 
Heart rate variability: standards of measurement, physiological interpretation and clinical use. 
Task Force of the European Society of Cardiology and the North American Society of Pacing 
and Electrophysiology. Circulation, 1996. 93(5): p. 1043-65. 
54. 
Berntson, G.G., et al., Heart rate variability: origins, methods, and interpretive caveats. 
Psychophysiology, 1997. 34(6): p. 623-48. 
55. 
Acharya UR, J.K., Kannathal N, Lim CM, Suri JS, Heart rate variability: a review. Med Biol 
Eng Comput, 2006. 44(12): p. 1031-51. 
56. 
Tarvainen, M.P., et al., Time-varying analysis of heart rate variability signals with a Kalman 
smoother algorithm. Physiol Meas, 2006. 27(3): p. 225-39. 
57. 
Ewing, D.J., et al., Immediate heart-rate response to standing: simple test for autonomic 
neuropathy in diabetes. Br Med J, 1978. 1(6106): p. 145-7. 
58. 
Low PA, B.E., Laboratory Evaluation of Autonomic Failure, in Clinical Autonomic Disorders. 
2008. 
59. 
Smith, J.J., C.M. Porth, and M. Erickson, Hemodynamic response to the upright posture. J Clin 
Pharmacol, 1994. 34(5): p. 375-86. 
60. 
Wieling, W., et al., Initial orthostatic hypotension: review of a forgotten condition. Clin Sci 
(Lond), 2007. 112(3): p. 157-65. 
61. 
Sanderson, J.E., et al., Impact of changes in respiratory frequency and posture on power spectral 
analysis of heart rate and systolic blood pressure variability in normal subjects and patients with 
heart failure. Clin Sci (Lond), 1996. 91(1): p. 35-43. 
62. 
Yang, H. and J.R. Carter, Baroreflex sensitivity analysis: spontaneous methodology vs. 
Valsalva's maneuver. Clin Auton Res. 23(3): p. 133-9. 
63. 
Levin, A.B., A simple test of cardiac function based upon the heart rate changes induced by the 
Valsalva maneuver. Am J Cardiol, 1966. 18(1): p. 90-9. 
64. 
Smith, M.L., et al., Valsalva's maneuver revisited: a quantitative method yielding insights into 
human autonomic control. Am J Physiol, 1996. 271(3 Pt 2): p. H1240-9. 
65. 
Chen, W.R., et al., Protective effect of metoprolol on arrhythmia and heart rate variability in 
healthy people with 24 hours of sleep deprivation. J Interv Card Electrophysiol. 36(3): p. 267-72; 
discussion 272. 
66. 
Behrens, T.E., et al., Characterization and propagation of uncertainty in diffusion-weighted MR 
imaging. Magn Reson Med, 2003. 50(5): p. 1077-88. 
67. 
Smith, S.M., et al., Advances in functional and structural MR image analysis and 
implementation as FSL. Neuroimage, 2004. 23 Suppl 1: p. S208-19. 
68. 
Jensen, J.H., et al., Diffusional kurtosis imaging: the quantification of non-gaussian water 
diffusion by means of magnetic resonance imaging. Magn Reson Med, 2005. 53(6): p. 1432-40. 
69. 
Elston, R., On the Correlation Between Correlations. Biometrika, 1975. 62: p. 133-140. 
70. 
Robinson H, C.M., Glascher J, Bruss J, Tranel D, Neuroanatomical Correlates of Executive 
Functions: A Neuropsuchological Approach Using the EXAMINER Battery. Journal of the 
International Neuropsychological Society 
2013. 19: p. 1-12. 
71. 
Nichols, T.E. and A.P. Holmes, Nonparametric permutation tests for functional neuroimaging: a 
primer with examples. Hum Brain Mapp, 2002. 15(1): p. 1-25. 
72. 
Smith, S.M., et al., Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion 
data. Neuroimage, 2006. 31(4): p. 1487-1505. 


29 
 
73. 
Cox, R.W., AFNI: software for analysis and visualization of functional magnetic resonance 
neuroimages. Comput Biomed Res, 1996. 29(3): p. 162-73. 
74. 
Glover, G.H., T.Q. Li, and D. Ress, Image-based method for retrospective correction of 
physiological motion effects in fMRI: RETROICOR. Magn Reson Med, 2000. 44(1): p. 162-7. 
75. 
Ward, B.D. and Y. Mazaheri, State-space estimation of the input stimulus function using the 
Kalman filter: a communication system model for fMRI experiments. J Neurosci Methods, 2006. 
158(2): p. 271-8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


30 
 
Appendix 1 Restricted and Prohibited Medications  
 
The following medications are Prohibited while subjects are actively receiving treatment with 
metoprolol/ placebo:  
• 
Amiodarone (Pacerone), Ceritinib (Zykadia), Clonidine (Catapres), Ergotamine 
(Cafergot, Ergomar), Other Ergots, Floctafenine (NSAID), Propafenone (Rhthmol), 
Reserpine, Rivastigmine (Exelon), insulin, verapamil, diltiazem, monoamine oxidase 
inhibitors 
• Other beta-blockers: ((Acebutolol (Sectral), Atenolol (Tenormin), Betaxolol (Kerlone), 
Bisoprolol (Zebeta), Carteolol (Ocupress), Carvedilol (Coreg), Esmolol (Brevibloc), 
Labetalol (Trandate), Nadolol (Corgard), Nebivolol (Bystolic), Penbutolol (Levatol), 
Pindolol (Visken), Propranolol (Inderal), Sotalol (Betapace), Timolol (Blocadren, 
Betimol), arformoterol, bambuterol, clenbuterol, formoterol, salmeterol) 
• Anticholinergic medications 
The following medications are Restricted—allowed while subjects are actively receiving 
treatment with metoprolol/ placebo, but should be used with caution. Monitor subject’s HR 
closely. 
• 
Cholinergics: Benztropine (Cogentin), Methacholine (Provocholine), Orphenadrine 
(Norflex) 
• Antivertigo agents: Meclizine (Dramamine, Bonine), Scopolamine (Transderm Scop.) 
• Urinary incontinence agents: Oxybutynin (Ditropan), Solifenacin (VESIcare), 
Tolterodine (Detrol)  
• GI Medications: Dicyclomine (Bentyl), Hyoscyamine (Levsin), Diphenoxylate (Lomotil)  
• H1 Blockers: Chlorpheniramine (Chlor-Trimeton), Diphenhydramine (Benadryl)  
• Antipsychotics: Chlorpromazine (Thorazine), Clozapine (Clozaril), Olanzapine 
(Zyprexa), Prochlorperazine (Compro) 
• Muscle Relaxants: Dantrolene (Dantrium), Orphenadrine (Norflex) 
• Strong 2D6 Inhibitors: Bupropion (Wellbutrin), Cinacalcet (Sensipar), Fluoxetine 
(Prozac), Paroxetine (Paxil), Quinidine (Quinidex)     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 2 Ecological Momentary Assessment 
 


31 
 
Sample COMPUTER-GENERATED EMA survey set 
 
PROMPT EACH DAY AROUND 6pm (coordinator can change this time if easy to 
program)  
WILL YOU BE STARTING YOUR WEEKLY RECORDING THIS EVENING? 
YES -> initiate program 
NO -> repeat prompt next day 
NOT SURE -> contact coordinator 
 
QUESTIONS Upon waking: 
 
When did you lay down to go to bed last night? ____________ am / pm 
 
How long did it take you to fall asleep last night?  
NUMBER OF MINUTES ___________ 
 
When did you get up this morning? ____________ am / pm 
 
-------------------------------------NEXT SCREEN 
SLEEP 
Last night, how many times did you awaken?  Pull down 0- 5+ 
 
If above > 0: 
 
Which factors below was the biggest contributor  to your awakenings? 
 
Urination 
Pain 
Anxiety 
Other 
 
Perhaps have the same pull-down 4 times with  
Biggest reason 
Second biggest reason 
Third biggest reason 
Fourth biggest reason 
 
 
Last night, did you take medicine (prescribed or over the counter) to help you sleep? (yes/no)  
 
Which ones?__________(open space to type) 
-------------------------------------NEXT SCREEN 
 
Overall, how refreshed do you feel this morning?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5  
 
 
 
-------------------------------------NEXT SCREEN 
 
 
 
GREAT JOB! THANK YOU FOR COMPLETING THIS SURVEY! You will be asked to complete interviews 
throughout the day.  Please do not turn off the phone.  


32 
 
 


33 
 
Questions to be completed every 85 minutes 
 
Displayed Instructions:  
 
-------------------------------------NEXT SCREEN 
MOOD EXPERIENCES 
 
-------------------------------------NEXT SCREEN 
 
 
 
Start the survey when you have 5 minutes without interruptions to complete all questions at once. 
 
 
 
 Think about how you were feeling when you STARTED the survey;  
 
-------------------------------------NEXT SCREEN 
 
When you STARTED the survey how much were you feeling:  (Same header for all questions below, take out “at 
the time of the beep” 
Sad 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Angry 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Serene 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Relaxed 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Excited 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
 


34 
 
-------------------------------------NEXT SCREEN 
 
 
 
At the time of the beep… 
Happy 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Tired 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Pleasant 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Unpleasant 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Activated 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Calm 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Enthusiastic 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
------------------------------------NEXT SCREEN 
 
At the time of the beep… 
Worried 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
At the time of the beep… 
Bored 


35 
 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
 
 
-------------------------------------NEXT SCREEN 
At the time of the beep… 
Stressed 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
 
When you STARTED the survey how much were you feeling (use the same heading below):  
 
Unable to control important things in life? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
 
Confident about your ability to handle personal problems?            
 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
 
Things were going your way? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
 
Difficulties were piling up so high that you couldn’t overcome them? 
Not at all  
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
Pain ANYWHERE? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Any urgency to urinate:  
Not at all  
 
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
Are you in a pain flare now: 
I do not have a pain flare 
 
I have a mild pain flare 
 
I have a moderate pain flare 
 
I have a severe pain flare 
 
INTERVAL EXPERIENCES 
SINCE YOUR LAST INTERVAL SURVEY 
Did you feel any urgency to urinate?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 


36 
 
Did you feel  pain IN THE PELVIS? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Did you experience a FLARE in your pelvic pain?  
            Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
 
Did you feel pain IN THE HEAD? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Did you feel pain ELSEWHERE IN THE BODY (Not the pelvis or head)? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5  
 
-------------------------------------NEXT SCREEN 
 
How much did pain anywhere interfere with yoru daily routine? 
            Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
SINCE YOUR LAST INERVAL SURVEY, 
Did you have a void(s)?  
 
No 
 
Yes – recorded in event record 
 
Yes – NOT recorded in event record 
 
What were you doing AT THE TIME OF THE BEEP? 
Describe ___________________________________ 
-------------------------------------NEXT SCREEN 
        4   
5 
 
 
When did your most recent social interaction occur? 
 
Less than 10 minutes ago 
 
10-30 minutes ago 
 
30-60 minutes ago 
 
More than 60 minutes ago 
 
 
____________(hh:mm) Need room for up to 10 entries 
 
-------------------------------------NEXT SCREEN 
 
 
 
-------------------------------------NEXT SCREEN 
Who were you socializing?  
 
 
 
 
CB family member? 
 
 
Subsequent questions conditional on yes to first 
one  
With co-worker? 
 
 
 


37 
 
With friend? 
 
 
 
With stranger? 
 
 
 
With other? 
 
 
 
-------------------------------------NEXT SCREEN 
 
Was the interaction in person (1), by phone (2), or online (3)? __ 
 
Was the interaction friendly? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
Was the interaction hostile? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
At the time of the beep…             
 
 
What was your position?                           
   
(1) Standing 
(2) Sitting  
(3) Lying down 
 
-------------------------------------NEXT SCREEN 
At the time of the beep…  
 
 
Describe your physical movement-   
(1) None (Rest or Nap) 
(2) Limited (Write)  
(3) Light (Walk)  
(4) Moderate (Jog) 
(5) Heavy (Run) 
 
-------------------------------------NEXT SCREEN 
At the time of the beep…                    
 
Temperature comfort?             
 
(1) Comfortable  
(2) Too cold 
(3) Too hot 
 
-------------------------------------NEXT SCREEN 
At the time of the beep…  
 
 
Your location?                
 
 
(1) Home  
(2) Other’s Home  
(3) Work  
(4) Vehicle  
(5) Outside  
(6) Other 
 


38 
 
 
1. RECORD INDIVIDUAL EVENTS EVENT: BATHROOM  
When did/will this activity occur? _________ AM/PM 
What type of activity are you recording (Check all that apply) 
Urination (ounces measured with “hat”_____) 
Bowel Movement (Description: Check all that apply)  
 
Hard, Normal, Loose, Painful, Straining 
GREAT JOB! THANK YOU FOR COMPLETING THIS SURVEY! Press the Exit button if you are satisfied with 
your responses. Reminder: Do not turn off  the phone! 
 
2. EVENT: ACTIVITY 
  
When did/will this activity occur? _________ AM/PM 
What type of activity are you recording (Check all that apply) 
 
 
Exercise (Mild, Moderate, Strenuous) 
 
 
 
How long did you exercise in minutes?  
 
 
Sex 
 
 
Stressful Experience  
 
 
 
Please describe the experience  
GREAT JOB! THANK YOU FOR COMPLETING THIS SURVEY! Press the Exit button if you are satisfied with 
your responses. Reminder: Do not turn off  the phone! 
 
3. EVENT: TOBACCO 
When did/will this activity occur? _________ AM/PM 
What type (Cigarette, Cigar, Chew, Other (Type)) 
How many? 0 – 5+ 
4. EVENT: CONSUMPTION 
When did/will this acitivity occur? _________ AM/PM 
What type of consumption event?  
 
Meal (Meal type: Snack, Light, Moderate, Heavy)  
 
Caffeinated drink (What type: Tea, Coffee, Soda, Other) 
 
 
How much in ounces (needed for voiding diary)?  
 
Non-caffeinated non-alcoholic drink  
How much in ounces (needed for voiding diary)?  
GREAT JOB! THANK YOU FOR COMPLETING THIS SURVEY! Press the Exit button if you are satisfied with 
your responses. Reminder: Do not turn off  the phone! 
5. EVENT: ALCOHOL/DRUGS 
When did/will this activity occur? _________ AM/PM 
What type of event? (Check all that apply) 
 
 
Alcoholic drink (What type: Beer, Wine, Hard liquor) 
 
 
 
How much in ounces (needed for voiding diary)? 
Recreational drug  
 
Which one? 
GREAT JOB! THANK YOU FOR COMPLETING THIS SURVEY! Press the Exit button if you are satisfied with 
your responses. Reminder: Do not turn off  the phone! 
 
6. EVENT: MEDICATION 
When did/will this activity occur? _________ AM/PM 
What type of event? (Check all that apply) 
 
 
Allergy medication (Name : e.g. Benadryl, Zyrtec, Claritin, Allegra) 
 
 
Cold or cough decongestant (Name: e.g. Sudafed, Mucinex, Nyquil, Robitusin) 
 
 
Anti-inflammatory (Name: e.g. Ibuprofen, Naproxen, Advil, Alleve, Motrin) 
 
 
Non-study medications (Which one(s)?) 
 
 
Beta blocker or placebo (How many pills?)  
GREAT JOB! THANK YOU FOR COMPLETING THIS SURVEY! Press the Exit button if you are satisfied with 
your responses. Reminder: Do not turn off  the phone! 
 
7. EVENT: PAIN 


39 
 
When did/will this activity occur? _________ AM/PM 
Pain Flare: How high would you rate the pain (0-10)?  
Pain Flare: Location? (Check all the apply) 
 
 
Pelvic 
 
 
Body 
 
 
Head 
GREAT JOB! THANK YOU FOR COMPLETING THIS SURVEY! Press the Exit button if you are satisfied with 
your responses. Reminder: Do not turn off  the phone! 
 
ENGENDERS VOIDING DIARY COMPONENTS 
Just prior to this void, did you have urgency (strong urge to urinate) … 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5  
Just prior to this void, were you feeling pain IN THE PELVIS? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
Just after this void, were you feeling pain IN THE PELVIS? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
Pain Flare: How high would you rate the pain (0-10)?_____  Location check box (could be all of these): pelvic, 
body, head 
Caffeinated drink: Radio buttons: Tea, Coffee, Soda, Other, how much in ounces (needed for voiding diary) 
Alcoholic drink: Radio buttons Beer, Wine, Hard Liquor, how much in ounces (needed for voiding diary) 
Non-alcoholic non-caffeinated drink:  how much in ounces (needed for voiding diary) 
Meal (radio buttons: snack, light, moderate, heavy) 
Tobacco (Radio buttons: cigarette, cigar, chew, other________________; how many? 1-5) 
Bowel Movement (Checkboxes: Hard, Normal, Loose, Painful, Straining) 
Exercise (radio buttons mild moderate strenuous; how long in minutes_____?) 
Sex  
Stressful Experience (describe_____________________________) 
Allergy medication (eg benadryl, zyrtec, Claritin, allegra, etc.) 
Cold or cough decongestant (eg Sudafed, mucinex, Nyquil, robitusin etc.) 
Anti-inflammatory (eg ibuprofen, Naproxen, advil, alleve, motrin,  etc.) 
Recreational Drug (Which one? _____________________) 
Other ________________ 
 
 
Thanks, you are finished with this entry.  


40 
 
End of day items 
-------------------------------------NEXT SCREEN 
On the following pages are descriptions of how you might have felt in the last 24 hours.  Please select how you 
felt in general in the last 24 hours.  
-------------------------------------NEXT SCREEN 
What type of day was today? (Check all that apply) 
Regular work day 
Short work day 
Work from home 
Non-work day 
Sick day 
Vacation day 
Holiday 
Other type of day (____________) 
 
For the type of day you picked, was this day in any way unusual?   
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
Please describe your day in a few words, focusing on what was different than a “typical day”: 
_____________________________________________________________________ 
-------------------------------------NEXT SCREEN 
Menstrual cycle questions:   
If yes screen:  
1) If you are having periods, when was the first day of your last menstrual period?  (NA Free text vs 
Calendar  depending on extent of programming)______________ 
2) This question conditional on not saying “NA” on last question –  
Was this period painful?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
         1 
 
         2  
            3  
             4  
 
5  
 
-------------------------------------NEXT SCREEN 
Over the last 24 hours… 
Did you engage in any kind of sexual activity? 
(1) Yes  
(0) No 
 
If yes, what time did you start this activity? ____________(hh:mm)  
How many minutes did this activity last? ____________ 
-------------------------------------NEXT SCREEN 
 
Were you feeling pain ANYWHERE over the last 24 hours?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
Were you feeling pain in your PELVIC AREA over the last 24 hours? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 


41 
 
Were you feeling pain OUTSIDE the pelvis over the last 24 hours?  
 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Were you feeling urgency to urinate over the last 24 hours? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5  
 
-------------------------------------NEXT SCREEN 
Which of the following physical symptoms did you experience over the last 24 hours?  
 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Headache?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Constipated/diarrhea?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Muscle soreness?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Tightness/pain in chest?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Chills?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Backache?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Cold/flu symptoms?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Joint pain?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5  
 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Nausea/upset stomach?  
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5  
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Congestion? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 


42 
 
Over the last 24 hours…             
 
 
Poor appetite? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Sore throat? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
-------------------------------------NEXT SCREEN 
Over the last 24 hours…             
 
 
Dizziness? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
-------------------------------------NEXT SCREEN 
Were there any unusually stressful events in the last 24 hours that you either missed in your survey entries or were 
noteworthy in their impact on your day? If so, please briefly describe it/them in the box below.  
_____________________________________________________________________________________________ 
-------------------------------------NEXT SCREEN 
Thanks, you are finished with this entry.  
EVENT DRIVEN RECORD 
 
Event driven items – for each one upon confirmation need to ask: 
 
Event time: 5’ from now; NOW, < 5’ ago; 5-10’ ago >10’ ago;  
 
 
ITEMS: 
 
Urination (ounces measured with “hat”_____) 
 
ENGENDERS VOIDING DIARY COMPONENTS 
Just prior to this void, did you have urgency (strong urge to urinate) … 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
Just prior to this void, were you feeling pain IN THE PELVIS? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
Just after this void, were you feeling pain IN THE PELVIS? 
           Not at all   
A Little bit 
     Somewhat 
     Quite a bit 
      Very much    
          
   1 
 
         2  
            3  
             4  
 
5 
 
Pain Flare: How high would you rate the pain (0-10)?_____  Location check box (could be all of these): pelvic, body, head 
Caffeinated drink: Radio buttons: Tea, Coffee, Soda, Other, how much in ounces (needed for voiding diary) 
Alcoholic drink: Radio buttons Beer, Wine, Hard Liquor, how much in ounces (needed for voiding diary) 
Non-alcoholic non-caffeinated drink:  how much in ounces (needed for voiding diary) 
Meal (radio buttons: snack, light, moderate, heavy) 
Tobacco (Radio buttons: cigarette, cigar, chew, other________________; how many? 1-5) 
Bowel Movement (Checkboxes: Hard, Normal, Loose, Painful, Straining) 
Exercise (radio buttons mild moderate strenuous; how long in minutes_____?) 
Sex  
Stressful Experience (describe_____________________________) 
Allergy medication (eg benadryl, zyrtec, Claritin, allegra, etc.) 
Cold or cough decongestant (eg Sudafed, mucinex, Nyquil, robitusin etc.) 
Anti-inflammatory (eg ibuprofen, Naproxen, advil, alleve, motrin,  etc.) 


43 
 
Recreational Drug (Which one? _____________________) 
Non-study Medications (Which ones? _________________) 
Beta-blocker or placebo (How many pills? _____________) 
Other ________________ 
 
 


44 
 
Appendix 3 ICECAN Data Collection Schedule (Appendix 3 Grid is stored separately) 
 
ICECAN: Summary of required activities and evaluations according to time points of ascertainment 
 
X 
Required evaluations 
 
 
 
 
 
Xp 
Tasks and visits to be completed by CPP subjects 
 
 
 
 
Xc 
Tasks and visits to be completed by Healthy subjects 
 
 
 
 
1 
The informed consent must be signed BEFORE baseline evaluations are performed 
 
 
2 
All females of child-bearing age/capability must take a pregnancy test within 24 hours before enrollment  
3 
Questionnaires to be completed by subjects weekly at home 
 
 
 
 
4 
Each week subjects complete a weekly version at home 
 
 
 
 
5 
Subjects complete the full STAI questionnaire at baseline and complete only the State portion weekly and at each major visit 
6 
Valsalva maneuver is only performed at MCW 
 
 
 
 
 
7 
Subjects complete this once preferably the same day each week until Week 24 and the day before Visit 5 
8 
Subjects complete this on the same day as the ACP and 24-h HRV recording 
 
 
9 
Study physicians complete this at baseline, 12-week and 24-week visits.  
 
 
 
10 
Randomization takes place centrally at MCW 
 
 
 
 
 
11 
Blood draw is only performed at MCW and is optional  
 
 
 
 
12 
If SAE, that is severe and related scan and email to MCW within 24hr of knowledge of event or as early as possible 
 
13 
Healthy subjects complete study at Week 4 and then resume 
study at week 12 or 20 for another 4 weeks. 
 

ICF_000.pdf: 
Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
Page 1 of 14 
Version: Observational Alternative Study Group ICF 02APR2021 
 
EFFECTIVE 
 
6/8/2021 
 
MCW/FH IRB 
 
Medical College of Wisconsin and Froedtert Hospital 
INTRODUCTION TO THE INFORMED CONSENT 
 
Name of Subject: ____________________________ 
 
 
Study Title: Interstitial Cystitis-Examination of the Central Autonomic Network (ICECAN) 
 
Thomas Chelimsky, M.D. 
Department of Neurology 
414-805-5246 
Medical College of Wisconsin 8701 
Watertown Plank Road 
Milwaukee, WI 53226 
 
Gisela Chelimsky, M.D. 
Department of Pediatric Gastroenterology 
414-266-3690 
Medical College of Wisconsin 8701 
Watertown Plank Road Milwaukee, 
WI 53226 
 
 
You are invited to take part in this research. You can decide whether to take part in this project 
or not. You are free to say yes or no. If there is anything that you do not understand, please ask 
questions. 
 
 
 
Definitions 
 
 
Interstitial Cystitis/Bladder Pain Syndrome- is a type of chronic pain that affects the 
bladder. Symptoms include feeling the need to urinate right away, needing to urinate often, 
and pain with sex 
 
Myofascial Pelvic Pain- is a source of chronic pelvic pain in women and men that 
is defined by short, tight, tender pelvic floor muscles that include palpable nodules or trigger 
points that cause referred pain. The pain can be continuous or episodic. MPPS can impact 
urinary, bowel, and sexual function. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
Page 2 of 14 
Version: Observational Alternative Study Group ICF 02APR2021 
 
EFFECTIVE 
 
6/8/2021 
 
MCW/FH IRB 
 
Purpose 
This project is being done to determine 
whether brain circuits that control the body 
affect the clinical course of patients with 
chronic pelvic pain. 
Length 
 You will be in this research project for 12 
weeks.  
 We will also follow up with you 4 weeks 
after your study completion. 
Risks 
This is a brief list of the most commonly seen 
risks The full consent form after this 
introduction contains a more complete list of 
potential research risks. 
 
Device risks: 
 
redness from patches used to record 
your heart rate 
 
you may feel dizzy, nauseated, or get a 
headache from the breathing test 
 
 
Non-Physical Risks: 
 
Your personal information and the data 
collected from you for this study will be 
kept confidential and, the extent 
permitted by law, will not be made 
publicly available.  However, there is a 
risk of loss of confidentiality of your 
information.  You will read more about 
the protection of your information later 
in this form.  Please ask the study 
doctor or study staff if you would like to 
know more about how your information 
will be protected while you are in this 
study.   
 
Procedures or Activities 
 
After reading and signing this informed 
consent document, you will be given a pre-
screen to determine if you qualify to 
participate 
 
List of visits: 
 
On-sire long visits 
- Total Number: 3 
- Total Time: 3 hours per visit 
 
 
At-home monitoring 
- Total Number: 12 
- Total Time: 24 hours, 1x/week 
 
Procedures/Activities that will occur at 
various visits: 
 
Invasive Procedures 
- Blood sample collection  
- pelvic exam 
 
 
Non-invasive Procedures 
- 
Medical history questionnaire 
- 
Breathing test  
- 
Heart rate test 
- 
Urine sample collection 
- 
General exam 
- 
Questionnaires 
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
Page 3 of 14 
Version: Observational Alternative Study Group ICF 02APR2021 
 
EFFECTIVE 
 
6/8/2021 
 
MCW/FH IRB 
 
My Other Options 
You do not have to join this project. You are 
free to say yes or no. 
 Whether or not you join this project, you 
are free to seek services from this or 
other agencies. 
 Whether or not you join this project, your 
usual medical services will not change. 
Benefits 
This project may not help you, but we hope 
the information from this project will help us 
develop a better understanding of IC/BPS 
and MPP. 
If you have more questions about this project at any time, you can call Thomas Chelimsky, 
M.D. Principal Investigator at 414-805-5246 OR Gisela Chelimsky, M.D. at 414-266-3690. 
 
If you have questions about your rights as a participant, want to report any problems or 
complaints, or offer input, you can call the MCW/Froedtert Hospital Research Subject 
Advocate at 414-955-8844. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
Page 4 of 14 
Version: Observational Alternative Study Group ICF 02APR2021 
 
EFFECTIVE 
 
6/8/2021 
 
MCW/FH IRB 
CONSENT TO PARTICIPATE IN RESEARCH 
A1. INTRODUCTION – WHY ARE WE ASKING YOU TO PARTICIPATE? 
You are invited to participate in this research study because you have been diagnosed with 
chronic pelvic pain (CPP) such as Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) or 
Myofascial Pelvic Pain (MPP) and you are not pregnant. If you have been diagnosed with 
IC/BPS, you may have experienced symptoms such as painful urination and pressure in the 
pelvis or bladder. If you have been diagnosed with MPP you may have experienced pain and 
spasm in the pelvic muscles that may spread to other areas like the abdomen, legs and back. 
 
A total of about 180 people are expected to participate in this research at Froedtert Hospital 
(FH) and Northshore Hospital in Chicago. We expect to enroll up to 150 at FH.   
 
The Directors of the project are Dr. Thomas Chelimsky, Dr. Gisela Chelimsky, Dr. Lisa Conant, 
Dr. Jeffrey Janata, and Dr. Frank Tu in the departments of Neurology and Gastroenterology at 
MCW, Case Western Reserve University in Cleveland, and Northshore in Chicago. A research 
team works with Dr. Chelimsky, and Jeffrey Janata, and Dr. Frank Tu. You can ask who these 
people are.  
 
The National Institutes of Health (NIH) is funding this study. 
 
A2. DO I HAVE TO PARTICIPATE? 
You can decide whether to take part in this research or not. You are free to say yes or no. If you 
say no, your regular medical care will not change. Even if you join this project, you do not have 
to stay in it. You may stop at any time. 
A3. WHY IS THIS PROJECT BEING DONE? 
The purpose of this project is to determine whether brain circuits that control the body affect the 
clinical course of patients with chronic pelvic pain.    
 
B1. WHAT WILL HAPPEN IF I PARTICIPATE? 
Screening procedures:  If you are interested in this research study, you will first complete a 
pre-screen in person or on the phone to see if you are able to participate. An in-person pre-
screen takes place in the MCW Neurology Research Rooms or Neurology Clinic at Froedtert 
Hospital (FH) or OBGYN clinics at Moorland Reserve Health Center, Westbrook Clinic or St. 
Joseph’s Health Center. 
 
If the screening information shows that you meet the requirements, then you will be able to start. 
If the screening information shows that you cannot be in the research, the research doctor will 
discuss other options with you and/or refer you back to your regular doctor.  
 
If you are able to participate, you 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 you. The baseline evaluation comprises a general and pelvic 
examination (no speculum), psychological questionnaires and a background history 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
Page 5 of 14 
Version: Observational Alternative Study Group ICF 02APR2021 
 
EFFECTIVE 
 
6/8/2021 
 
MCW/FH IRB 
questionnaire. You will complete a urine flow measurement, a heart rate recording and a 
breathing test. You will also be asked to provide a urine sample and a blood sample. The blood 
sample is optional.  
 
We will also contact you 4 weeks after your study completion to follow-up with you. 
 
Summary of Procedures: 
At each long visit, you will complete a physician exam, a set of questionnaires, provide a 24-
hour voiding diary and the following tests: breathing test, heart rate test and a “uroflow 
measurement.” You will also complete a pelvic exam at week 0 (visit 1) and week 12 (visit 3).   
 
The first physician exam will include a detailed medical interview and a pelvic exam. This exam 
may take up to 45 minutes to complete. If the physician questionnaire is unable to be completed 
during the study visit, the study doctor may complete this with you over the phone at a more 
convenient time. 
 
You will be asked to complete questionnaires at each long-visit including: Hospital Anxiety and 
Depression Scale (HADS), State-Trait Anxiety Inventory (STAI), Thoughts About Symptoms 
(CSQ), Pennebaker Inventory of Limbic Languidness (PILL), Multidimensional Pain Inventory 
(MPI), Female Genitourinary Pain Index (FGUPI), Perceived Stress Scale (PSS),  PROMIS 
Social Roles and Activities, PROMIS Physical Function, PROMIS Fatigue, PROMISE Sleep 
Disturbance, the Holmes-Rahe Life Stress Inventory, the MAPP II Interactive Brief Pain 
Inventory, and the Covid-19 Questionnaire. You will complete the Childhood and Recent 
Trauma Events Scale (RTES) during your first long visit only. 
 
You can skip any question that you do not feel comfortable answering on any of the forms. 
Although the first questionnaires will be completed in the clinic to keep your answers private, the 
next will be completed while you are at home. We cannot guarantee that those responses will 
be kept private and there is a chance that answers may be seen by those who live in or visit 
your home. If your score is suggestive of emotional problems, study directors Dr. Thomas 
Chelimsky or Dr. Gisela Chelimsky or study Co-Investigator and Psychologist, Dr. Lisa Conant 
will provide you with places to help get treatment for these issues within 1 week of your 
participation. The researchers are required by law to report any abuse or neglect (or suspicion 
of abuse or neglect) if you mention it to the researchers or if it is suspected.  
 
You will complete a “breathing test” in the MCW Neurology Research Rooms at FH. To 
complete this test, you will have wrist straps secured to a table and asked to breathe in deeply 
and out forcefully through a tube. You will have a small band on your arm to measure your heart 
rate and blood pressure. You will complete 4 cycles of breathing: two cycles while lying down 
flat and two cycles while leaning slightly forward.  
 
The heart rate variability (HRV) and active posture change (ACP) recording will take about 20 
minutes to complete. You will complete this recording at each long-visit and each week that you 
are in this study. Heart rate will be recorded with an eMotion Faros 360° portable ECG device. It 
is small and lightweight, with 3-5 small adhesive electrode patches placed on the skin of your 
chest and torso. You will lie down flat on a bed and rest for 10 minutes before the recording 
starts. After that, you will lie down for 5 more minutes while your heartbeat is recorded. You will 
be asked to stand up as quickly as you can and stand still for an additional 5 minutes. You may 
sit down if this test becomes too much for you to complete. Coded 24-hour HRV and ACP 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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recordings will be sent to Dr. Julian Thayer’s research group at University of California Irvine for 
analysis. Your sample will be labeled by a number and will not contain any information that can 
be used to directly identify you. 
 
A “uroflow measurement” measures the volume of urine, how long it takes to be released from 
the body and the speed. The uroflow measurement requires you to urinate on a special toilet in 
the MCW Neurology Research Rooms at FH. The toilet contains sensors that measure the 
speed of the urine flow and amount of urine. About one hour prior to this test you will be asked 
to drink a quart of fluid. 
 
Weekly Home Checks will occur once a week for 12 weeks following consent. Each week, you 
will complete a heart rate recording just before you go to bed. The heart rate recording will help 
us to study how your heart rate changes throughout the day. You will place the patches on your 
chest and torso to match the image found on the instruction sheet provided to you as soon as 
you get up in the morning. A researcher will remind you via skype, email, text or telephone to 
remind you to complete the recording. The researcher will coach you the first few times you 
complete this recording until you are comfortable completing it on your own. The researcher will 
ask you to lie down flat on your bed for 15 minutes. After that, the researcher will instruct you to 
stand up as quickly as you can in front of your bed for another 5 minutes. You can sit down if 
you become too dizzy. You will need to bring the Faros 360 device with you to each of your in-
person visits. The data from your heart rate recording will be uploaded to a secure server by a 
member of the research team. 
 
You will complete the following each week from home: a 24-hour heart rate (HR) recording 
using the eMotion Faros 360° ECG device, the 24-hour voiding diary, answer a set of questions 
using the ICECAN mobile App installed on a preloaded smartphone, and complete 
questionnaires (those mentioned previously) that are sent to your personal e-mail account via a 
secure Internet connection. If in any case you are unable to complete the questionnaires online, 
you will be asked to return paper copies of the questionnaires at your next in-person follow-up 
visit.  
 
The 24-hour voiding diary consists of tracking how much liquid comes in and out of your body in 
a 24-hour period, and how often you void. You will be required to measure the amount of 
everything you drink. You will also record the time and amount of each void for the 24-hour 
period. A special measuring “hat” that fits over the toilet seat will help you measure each void.   
 
You will also complete a Daily Flare Question which asks about flare activity, management and 
if the flares are affecting you. These Flare Questions will be monitored via phone calls and 
recording in the EMA application on the smartphone.  
 
Once per week, every week for 12 weeks, you will repeat the 24-hr HR recording, as described 
above, to compare the HRV recording done at home to the one performed at the matching on-
site visit.  
 
If you end up not answering some of the EMA questions, we will be asking you the following:  At 
any time during the study, did your pain affect your ability to answer any of the EMA 
questions?  When you didn't answer the EMA questions, what percentage of time was it due to 
pain?  These questions will be asked at each in-clinic visit appointment. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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During your follow-up visits at weeks 4 and 12, you will arrive to the MCW Neurology Research 
Rooms to repeat the following: a review of your symptoms, a brief physician exam, a uroflow 
measurement, questionnaires, and heart rate recording. You will complete the breathing test in 
the MCW Neurology Research Rooms with a member of the research team present. You will 
also complete a repeat pelvic examination at Week 12.  
 
Blood (optional) will be drawn and Urine will be collected (~ 50 mL, a little more than 3 
tablespoons) at each in-person visit at weeks 0, 4, and 12. We will determine (1) if immune or 
inflammatory factors play a role in your pain cycles and (2) if energy production in your cells 
might be impaired.  
 
A portion of your blood plasma/serum and urine will be sent to Dr. Lori Birder’s laboratory at the 
University of Pittsburgh for additional related analysis. Both of your samples will be labeled by a 
number and will not contain any information that can be used to directly identify you. This 
portion of the study is critical for us to gather new information about pelvic pain, which is very 
poorly understood. We highly encourage you to participate in this portion of the study. However, 
given how difficult it can be to obtain blood from some people with IC/BPS, we do allow you to 
opt out of the blood draw portion of this study and still participate in the other parts. 
 
Please initial your choice below regarding blood sample collection. 
 
_______ Yes, I agree to provide blood samples for this research project.  
INITIALS 
 
_______ No, I do not agree to provide blood samples for this research project.  
INITIALS 
 
B2. HOW LONG WILL I BE IN THE PROJECT? 
 You will be in this research project for about 12 weeks  
 We will also follow-up with you 4 weeks after your study completion. 
 
B3. CAN I STOP BEING IN THE PROJECT?   
You may stop at any time. If you decide to leave the project, please let the research team know.  
 
The research doctor may stop your participation in the project at any time for any reason without 
your consent.  He / She will tell you if this happens. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE PROJECT? 
We watch everyone in the project for unexpected problems and side effects. You need to tell 
the research doctor or a member of the research team immediately if you experience any 
problems or become too upset. 
 Questionnaires: The psychological questionnaires may upset you. You can skip any 
question that you do not want to answer. If your responses are suggestive of emotional 
problems, a study Investigator will discuss your response(s) and will document this 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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discussion in your medical record. The Investigator will provide you with places to help get 
treatment. 
 
 Physician Exam: The physician exam includes a tender point evaluation that is standard of 
care for myofascial pain disorders such as fibromyalgia and may lead to tenderness and 
pain at the site of contact. 
 
 Breathing Test:  You may feel anxious, dizzy, nauseated or get a headache from breathing 
in and out as instructed during the breathing test. 
 
 Heart Rate Test: There is a chance that you may develop redness from the patches used to 
record your heart rate during the heart rate test. These red marks are temporary and 
generally go away within an hour. If you are allergic to adhesives, you cannot participate in 
this study. 
 
 Blood Draw: The side effects that you might experience as a consequence of donating a 
blood sample for this project include possible discomfort and bruising at the needle entry 
site. Rare complications of any venipuncture (drawing blood from a vein) include fainting, 
arterial puncture, peripheral nerve injury, local infection, and local blood clot. There may be 
other unanticipated risks, but every precaution will be taken to assure your personal safety 
and to minimize discomfort. The person drawing your blood will observe you for side effects, 
but please inform him or her if you experience any discomfort or feel faint. 
 
Another risk may be loss of confidentiality. Every effort will be made to keep your research 
records confidential but we cannot guarantee it. Depending on the kind of information being 
collected, if your research information were accidentally seen, it might be used in a way that 
could embarrass you or affect your ability to get insurance. If you have questions, you can talk 
to the project director about whether this could apply to you. 
 
C2. RISKS TO WOMEN WHO COULD BECOME PREGNANT 
Birth control methods for all subjects 
Check with the research doctor about the birth control methods needed for this project and how 
long to use them. Some methods might not be good enough for this project. If you are having 
sex that could lead to pregnancy, you should use birth control while you are in this project.   
This may include: 
 
Not having vaginal sex (abstinence) 
 
Taking birth control pills orally 
 
Having birth control shots or patches such as Depo-Provera 
 
Surgical sterilization (hysterectomy or tubal ligation) 
 
Use of an intrauterine device (IUD) 
 
Use of diaphragm with contraceptive jelly 
 
Use of condoms with contraceptive foam 
 
Use of diaphragm with condoms (“double barrier”) 
 
Limiting sexual activity to a male partner who has had a vasectomy 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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C3. ARE THERE ANY BENEFITS TO TAKING PART IN THE PROJECT? 
This project may not help you, but we hope the information from this project will help us develop 
a better understanding of IC/BPS and MPP. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE PROJECT? 
There are no costs to you for any of the visits or services you receive in this project. If you have 
questions regarding costs, please contact Dr. Chelimsky. 
 
If you participate in this research, the costs of any necessary emergency medical treatment in 
the event of a research-related injury will be billed to you or your health insurance. 
D2. WILL I BE PAID FOR PARTICIPATING IN THE PROJECT? 
You will be paid $250 for completing at least 80% of the required items for the 3 major on-site 
visits and 12 minor at-home monitoring sessions.  
o You will receive a $50 payment on a preloaded credit card after completing all 
study tasks and Visit 1 
o You will receive a $50 payment on a preloaded credit card after completing all 
study tasks and Visit 2 
o You will receive a $150 payment on a preloaded credit card after completing all 
study tasks, visit 3, and returning the Faros ECG monitor and the pre-loaded 
Smartphone. 
o If you complete the baseline evaluation but are found to not be eligible to 
participate in this study, you will be mailed a $25 check 
 
You may be given the option to redo a study visit if the study data are incomplete or if you need 
to stop the study drug. If you redo a visit, you will receive payment for the visit which was 
repeated in the same amount as mentioned above. 
 
Travel reimbursements 
o If travel time is between 1 and 2 hours, you will be paid at a rate of $20 per visit 
on a preloaded credit card. 
o If travel time is between 2 and 4 hours, you will be paid at a rate of $40 per visit 
on a preloaded credit card. 
 
To pay you, we need your social security number.  Any payment may be reportable as income 
on your taxes. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this project. You are free to say yes or no. Whether or not you join this 
project, you are free to seek services from this or other agencies. Whether or not you join this 
project, your usual medical services will not change 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE PROJECT? 
After the project has been completed, we will notify you of when the results will be available to 
the public. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
Page 10 of 14 
Version: Observational Alternative Study Group ICF 02APR2021 
 
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When research data are collected and analyzed , there is the chance of finding something 
clinically relevant. There may be benefits to learning such results (such as early detection and 
treatment of a medical condition), but there are risks as well (such as feeling worried about a 
finding for which no treatment is required or appropriate).   
In this study, you will be informed of any findings of possible clinical significance that may be 
discovered during review of results from your research data. The results of your research data 
will not be placed in your medical record.  
 
The results from the data we collect in this research study are not the same quality as what you 
would receive as part of your health care. The data will not be reviewed by a physician who 
normally reads such results. We will provide you with this information so that you may discuss it 
with your primary care physician.  
 
D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE PROJECT?  
Emergency medical treatment for injuries directly related to your participation in this research 
project will be provided to you. You or your health insurance will be billed for the costs of this 
emergency treatment.  MCW will decide on a case by case basis if they will reimburse you or 
your insurer for emergency treatment costs.  If your research-related injury requires medical 
care beyond this emergency treatment, you or your insurer will be responsible for the costs of 
this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this project, contact 
the research doctors right away.  Contact information: Thomas Chelimsky, MD, 414-955-0619 
or Gisela Chelimsky, MD, 414-266-3690.  
 
Nothing in this consent form affects any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE PROJECT? 
 
If you have more questions about this project at any time, you can call Thomas Chelimsky 
at 414-955-0619 or Gisela Chelimsky at 414-266-3690. 
 
If you have questions about your rights as a research participant, want to report any 
problems or complaints, or offer input, you can call the MCW/Froedtert Hospital Research 
Subject Advocate at 414-955-8844. 
 
 
 
 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this project? 
To be in this research project, the research team needs your permission to access, collect and 
use some of your health information. If you say no, you cannot be in the project. This 
information may come from questions we ask, forms we ask you to fill out, or your medical 
record, as described below. We will only collect and use information needed for the project. 
 
The protected health information (PHI) originates from services you will or have received at one 
or more of the following locations: the Medical College of Wisconsin (MCW); BloodCenter of 
Wisconsin (BCW); Children’s Hospital of Wisconsin (CHW); any Froedtert Health Affiliate- 
Froedtert Memorial Lutheran Hospital (FMLH), Inc.; Community Memorial Hospital (CMH) 
Menomonee Falls, Inc.;  St. Joseph’s Community Hospital (SJH) West Bend, Inc.;  Froedtert & 
The Medical College of Wisconsin Community Physicians Clinics, Inc. (FMCWCP); the West 
Bend Surgery Center, LLC; and the Froedtert Surgery Center, LLC.  
 
The health information we will collect and used for this project is: 
 
 
 
To do this research study, we need your permission to collect and use some of your health 
information, or you cannot be in the study. This information may come from questions we ask, 
forms we ask you to fill out, or your medical records of care you receive from this project.  
Health information such as your clinical and laboratory information will be collected and shared.  
Researchers will also access your entire medical record for relevant study data such as your 
medical history, radiology scans, or lab data to help analyze the data collected.  We will only 
collect and use information needed for the study. 
 
E2. Who will see the health information collected for this project? 
The only people allowed to handle your health information are those on the research team at 
MCW/Froedtert Hospital those on the Institutional Review Board (IRB) and those who check on 
the research activities to make sure the hospital’s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-related 
injury are billed to your health insurance, your health information may need to be disclosed to 
the insurer for billing purposes. 
 
The research team may share your information with people who are not part of the research 
team because they planned, pay for, or work with us on this project. The federal Privacy Rule 
may no longer protect your health information once it leaves MCW/Froedtert Hospital.  For this 
project, we plan to share information with those doctors, researchers or government 
representatives working with us on this project at the institutions or companies listed here: 
 
 
U.S. Food and Drug Administration, Rockville, MD  
 
Northshore Hospital in Chicago, IL Medical College of Wisconsin & Froedtert Hospital 
 
Case Western Reserve University in Cleveland, OH 
 
Multi-Disciplinary Approach to the study of Chronic Pelvic Pain (MAPP) Research 
Network, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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Because this project involves the use of drugs and/or devices, the FDA also has the right to 
inspect all project records. 
 
We may record your research information, including results of tests, procedures or 
questionnaires done for research, in your Froedtert Hospital and/or Medical College of 
Wisconsin medical record  As a result, this research information may be seen by people allowed 
to see your medical records for healthcare operations or treatment, by those you allow to see 
your medical records by giving written permission, and by others when required by law. 
We will not use your personal health information for a different project without your permission 
or the permission of a hospital research review board (IRB). Once all personal identification is 
removed from your health information, and/or biospecimens, the information and/or 
biospecimens may be used for future research or distributed to another investigator for future 
research without additional informed consent from you or your legally authorized representative. 
The information might also be used or released for other purposes without asking you. Results 
of the project may be presented in public talks or written articles, but no information will be 
presented that identifies you. 
  
E3. What are the risks of sharing this health information? 
One risk of taking part in a research project is that more people will handle your personal health 
information collected for this project. The research team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 
embarrass you or affect your ability to get insurance. If you have questions, you can talk to the 
research doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this project? 
If you sign this form, we plan to keep your information for 10 years after the research project 
ends in case we need to check it again for this project. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to Dr. Thomas Chelimsky or Dr. Gisela Chelimsky at 8701 Watertown 
Plank Road, Department of Neurology, Milwaukee, WI, 53226. The letter must say that you 
have changed your mind and do not want the researcher to collect and share your health 
information. At that time, we may decide that you cannot continue to be part of the project. We 
may still use the information we have already collected. 
 
F1.  FOR MORE INFORMATION ABOUT THE PROJECT 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.   
You can look up this project by referring to the ClinicalTrials.gov number NCT03008382 or by 
asking the research team for a printed copy. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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CERTIFICATE OF CONFIDENTIALITY  
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health. The study team can use this Certificate to legally refuse to disclose 
information that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings, for example, if there is a court subpoena. The study team will 
use the Certificate to resist any demands for information that would identify you, EXECPT   as 
explained below:  
The Certificate cannot be used to resist a demand for information from personnel of the United 
States federal or state government agency sponsoring the project and that will be used for 
auditing or program evaluation of agency funded projects or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, medical care provider, or other person obtains your written consent to 
receive research information, then the researchers will not use the Certificate to withhold that 
information. 
CONSENT TO PARTICIPATE 
 
By signing my name below, I confirm the following: 
 
I have read (or had read to me) this entire consent document. All of my questions have been 
answered to my satisfaction. 
 
The project’s purpose, procedures, risks and possible benefits have been explained to me.   
 
I agree to let the research team use and share the health information and other information 
gathered for this project. 
 
I voluntarily agree to participate in this research project. I agree to follow the procedures as 
directed. I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date/Time 
 
 
 
 
Name of Witness please print 
Signature of Witness 
 
Date/Time 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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Rationale for Use of Witness 
 Subject has limited/no literacy 
 Subject has limited English 
proficiency 
 Subject has limited/no vision 
 
 Sponsor requirement 
 Other ____________________ 
 
 
 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date/Time 
* A member of the research team trained and authorized by the Principal Investigator to act on 
her/his behalf in obtaining informed consent according to the protocol. The Principal Investigator 
is responsible and accountable for the research project. 
 
 
 
 
Name of Principal Investigator        
please print  
__ I participated in consent process 
__ I acknowledge enrollment of this 
subject into the project 
Signature of Principal 
Investigator 
Date/Time 
 
Attachment 1 – Details of project schedule and procedures 
 
 
 
Visit 1 
Visit 2 
Visit 3 
4 Weeks 
Post Visit 3 
 
 
Week 
0 
4 
12 
16 
Schedule of Events 
 
Time to 
complete 
 
 
 
 
 
General exam 
180 minutes 
 
x 
 
 
 
Physician Exam 
10 minutes 
 
x^ 
x 
x^ 
 
Questionnaires 
 
50 minutes 
 
x 
x 
x 
x* 
Heart Rate Test 
20 minutes 
 
x 
x 
x 
 
Breathing Test 
 
10 minutes 
 
x 
x 
x 
 
Participant Incentive 
 
 
x 
x 
x 
 
Home Checks, App & Diary 
Variable 
Done once 
a week for 
12 weeks 
 
 
 
 
x^ Physician Exam and a pelvic exam will be completed 
x* Study team will contact you to complete a general wellbeing check with you. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
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Medical College of Wisconsin and Froedtert Hospital 
INTRODUCTION TO THE INFORMED CONSENT 
 
Name of Subject: ____________________________ 
 
 
 
Study Title: Interstitial Cystitis-Examination of the Central Autonomic Network (ICECAN) 
 
Thomas Chelimsky, M.D. 
Department of Neurology 
414-805-5246 
Medical College of Wisconsin 8701 
Watertown Plank Road 
Milwaukee, WI 53226 
 
Gisela Chelimsky, M.D. 
Department of Pediatric Gastroenterology 
414-266-3690 
Medical College of Wisconsin 8701 
Watertown Plank Road Milwaukee, 
WI 53226 
 
 
You are invited to take part in this research. You can decide whether to take part in this project 
or not. You are free to say yes or no. If there is anything that you do not understand, please ask 
questions. 
 
 
 
Definitions 
Interstitial Cystitis/Bladder Pain Syndrome- is a type of chronic pain that affects the 
bladder. Symptoms include feeling the need to urinate right away, needing to urinate often, 
and pain with sex 
 
Myofascial Pelvic Pain- is a source of chronic pelvic pain in women and men that 
is defined by short, tight, tender pelvic floor muscles that include palpable nodules or trigger 
points that cause referred pain. The pain can be continuous or episodic. MPPS can impact 
urinary, bowel, and sexual function. 
 
Metoprolol- a beta-blocking drug related to propranolol, used to treat hypertension and 
angina. 
 
Placebo- A pill that doesn’t contain an active drug ingredient, often called a “sugar pill” 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
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Purpose 
This project is being done to determine 
whether brain circuits that control the body 
affect the clinical course of patients with 
chronic pelvic pain.  
Length 
 You will be in this research project for 25 
weeks. 
 We will also follow up with you 4 weeks 
after your study completion.  
Risks 
This is a brief list of the most commonly seen 
side effects. The full consent form after this 
introduction contains a more complete list of 
potential research risks. 
 
Metoprolol risks: 
 
diarrhea, stomach cramping, nausea, 
vomiting, rashes, blurred vision, 
muscle cramping, fatigue, depression, 
heart failure or heart block in patients 
with heart problems, headaches, 
dizziness, nightmares, shortness of 
breath in asthmatics, sexual 
dysfunction and may cause low or high 
glucose 
 
Device Risks: 
 
redness from patches used to record 
your heart rate 
 
you may feel dizzy, nauseated, or get a 
headache from the breathing test 
 
Non-Physical Risks: 
 
Your personal information and the data 
collected from you for this study will be 
kept confidential and, the extent 
permitted by law, will not be made 
publicly available.  However, there is a 
risk of loss of confidentiality of your 
information.  You will read more about 
the protection of your information later 
in this form.  Please ask the study 
doctor or study staff if you would like to 
know more about how your information 
will be protected while you are in this 
study.   
Procedures 
After reading and signing this informed 
consent document, you will be given a pre-
screen to determine if you qualify to 
participate. 
 
List of visits: 
 
On-site long visits 
- Total Number: 5 
- Total Time: about 3 hours per visit 
 
At- home monitoring 
- Total Number: 24 
- Total Time: 24 hours, 1x/week 
 
Procedures that will occur at various 
visits: 
 
Invasive Procedures 
- Blood sample collection  
- pelvic exam 
 
Non-invasive Procedures 
- 
Medical history questionnaire 
- 
Breathing test  
- 
Heart rate test 
- 
Urine sample collection 
- 
General exam 
- 
Questionnaires. 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 3 of 17 
Version: Experimental ICF 02APR2021 
 
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My Other Options 
You do not have to join this project. Your other 
options may include: 
 Joining a different project 
 Routine care for this condition  
 Getting no treatment for this condition 
 
Benefits 
We don’t know if this project will help you. Your 
condition may get better but it could stay the 
same or even get worse. 
If you have more questions about this project at any time, you can call Thomas Chelimsky, 
M.D. Principal Investigator at 414-805-5246 OR Gisela Chelimksy, M.D. at 414-266-3690. 
 
If you have questions about your rights as a participant, want to report any problems or 
complaints, or offer input, you can call the MCW/Froedtert Hospital Research Subject 
Advocate at 414-955-8844. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 4 of 17 
Version: Experimental ICF 02APR2021 
 
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CONSENT TO PARTICIPATE IN RESEARCH 
A1. INTRODUCTION – WHY ARE WE ASKING YOU TO PARTICIPATE? 
You are invited to participate in this research study because you have been diagnosed with 
chronic pelvic pain (CPP) such as Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) or 
Myofascial Pelvic Pain (MPP) and you are not pregnant. If you have been diagnosed with 
IC/BPS, you may have experienced symptoms such as painful urination and pressure in the 
pelvis or bladder. If you have been diagnosed with MPP you may have experienced pain and 
spasm in the pelvic muscles that may spread to other areas like the abdomen, legs and back. 
 
A total of about 180 people are expected to participate in this research study at Froedtert 
Hospital (FH) and Northshore Hospital in Chicago. We expect to enroll 150 participants from 
FH. 
 
The Directors of the project are Dr. Thomas Chelimsky, Dr. Gisela Chelimsky, Dr. Lisa Conant, 
Dr. Jeffrey Janata, and Dr. Frank Tu in the departments of Neurology and Gastroenterology at 
MCW, Case Western Reserve University in Cleveland, and Northshore in Chicago. A research 
team works with Dr. Chelimsky, Dr. Jeffrey Janata and Dr. Frank Tu. You can ask who these 
people are.  
 
The National Institutes of Health (NIH) is funding this study. 
 
A2. DO I HAVE TO PARTICIPATE? 
You can decide whether to take part in this research or not. You are free to say yes or no. If you 
say no, your regular medical care will not change. Even if you join this project, you do not have 
to stay in it. You may stop at any time.  
 
A research project is different from routine medical care in three ways: 1) there are extra risks 
that we will tell you about in this form; 2) you may have some extra medical tests and visits; 3) 
the research procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS PROJECT BEING DONE? 
This drug has been approved by the U.S. Food and Drug Administration, and in this study we 
want to learn more about how it can affect the brain circuits that control the body and thereby 
affect the clinical course of patients with chronic pelvic pain. 
 
B1. WHAT WILL HAPPEN IF I PARTICIPATE? 
Screening procedures:  If you are interested in this research study, you will first complete a 
pre-screen in person or on the phone to see if you are able to participate. An in-person pre-
screen takes place in the MCW Neurology Research Rooms or Neurology Clinic at Froedtert 
Hospital (FH) or OBGYN clinics at Moorland Reserve Health Center, Westbrook Clinic or St. 
Joseph’s Health Center. 
 
If the screening information shows that you meet the requirements, then you will be able to start. 
If the screening information shows that you cannot be in the research, the research doctor will 
discuss other options with you and/or refer you back to your regular doctor.  


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 5 of 17 
Version: Experimental ICF 02APR2021 
 
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If you are able to participate, you will complete 5 regular on-site long-visits at weeks 0, 4, 12, 16 
and 24. We will also contact you 4 weeks after your study completion to follow-up with you.  
 
The first long visit (baseline evaluation) may occur either today following consent or at another 
date convenient for you. The baseline evaluation comprises a general and pelvic examination 
(no speculum), psychological questionnaires and a background history questionnaire. You will 
complete a pregnancy test (if you are still menstruating), a urine flow measurement, a heart rate 
recording and a breathing test. You will also be asked to provide a urine sample and a blood 
sample. The blood sample is optional.  
 
If you join this project, you will be given one of two drugs without knowing exactly which one (a 
“blinded” project). If you ask to see your health records during this “blinded” project, the 
research team cannot tell you which drug you are being given. This is because the research 
team also remains “blinded” about which drug the pharmacy has randomly assigned to you. You 
would have to wait until the time given below. We cannot do the project unless you agree. 
However, if the blinded information is needed to treat you, it will be provided to the research 
doctor. 
• 
What are the blinded options? You will get one of these drugs: metoprolol or placebo 
• 
When can you find out which drug you were given? You can find out at the project end 
date in June 2021. 
Starting at Week 4, you will be randomized to a group that will receive 8 weeks of either placebo 
(contains no real medicine and we do not expect it will do anything for your health) 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 migraine.  
Randomized means that you are put into a group by chance, like flipping a coin. A computer 
decides the group you are put into. Neither you nor the researcher will choose what group you 
will be in. You will have an equal chance of being placed in either group. Using randomization 
helps to improve the chance of determining which (if either) treatment is better. Neither you nor 
the researcher will know which group you are in, only the pharmacy will know. 
You will be asked to stop taking the metoprolol or placebo from Weeks 12 to 16. After that, you 
will be asked to take the other medication (metoprolol or placebo, whichever you did not receive 
the first time) for 8 weeks. For example, if you were randomized to start taking metoprolol during 
Weeks 4-12, you will switch to start taking the placebo for Weeks 16-24. 
Summary of Procedures: 
At each long visit, you will complete a physician exam, a set of questionnaires, and the following 
tests: breathing test, heart rate test and a “uroflow measurement.” You will also complete a 
pelvic exam on visits 1, 3 and 5.  
 
The first physician exam will include a detailed medical interview and a pelvic exam. This exam 
may take up to 45 minutes to complete. If the physician questionnaire is unable to be completed 
during the study visit, the study doctor may complete this with you over the phone at a more 
convenient time. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 6 of 17 
Version: Experimental ICF 02APR2021 
 
EFFECTIVE 
 
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You will be asked to complete questionnaires at each long-visit including: Hospital Anxiety and 
Depression Scale (HADS), State-Trait Anxiety Inventory (STAI), Thoughts About Symptoms 
(CSQ), Pennebaker Inventory of Limbic Languidness (PILL), Multidimensional Pain Inventory 
(MPI), Female Genitourinary Pain Index (FGUPI), Perceived Stress Scale (PSS), PROMIS 
Social Roles and Activities, PROMIS Physical Function, PROMIS Fatigue, PROMISE Sleep 
Disturbance, the Holmes-Rahe Life Stress Inventory, the MAPP II Interactive Brief Pain 
Inventory, and the Covid-19 Questionnaire. You will complete the Childhood and Recent 
Trauma Events Scale (RTES) during your first long visit only. 
 
You can skip any question that you do not feel comfortable answering on any of the forms. 
Although the first questionnaires will be completed in the clinic to keep your answers private, the 
next will be completed while you are at home. We cannot guarantee that those responses will 
be kept private and there is a chance that answers may be seen by those who live in or visit 
your home. If your score is suggestive of emotional problems, study directors Dr. Thomas 
Chelimsky or Dr. Gisela Chelimsky or study Co-Investigator and Psychologist, Dr. Lisa Conant 
will provide you with places to help get treatment for these issues within 1 week of your 
participation. The researchers are required by law to report any abuse or neglect (or suspicion 
of abuse or neglect) if you mention it to the researchers or if it is suspected.  
 
You will complete a “breathing test” in the MCW Neurology Research Rooms at FH. To 
complete this test, you will have wrist straps secured to a table and asked to breathe in deeply 
and out forcefully through a tube. You will have a small band on your arm to measure your heart 
rate and blood pressure. You will complete 4 cycles of breathing: two cycles while lying down 
flat and two cycles while leaning slightly forward.  
 
The heart rate variability (HRV) and active posture change (ACP) recording will take about 20 
minutes to complete. You will complete this recording at each long-visit and each week that you 
are in this study. Heart rate will be recorded with an eMotion Faros 360° portable ECG device. It 
is small and lightweight, with 3-5 small adhesive electrode patches placed on the skin of your 
chest and torso. You will lie down flat on a bed and rest for 10 minutes before the recording 
starts. After that, you will lie down for 5 more minutes while your heartbeat is recorded for 5 
minutes. You will be asked to stand up as quickly as you can and stand still for an additional 5 
minutes. You may sit down if this test becomes too much for you to complete. Coded 24-hour 
HRV and ACP recordings will be sent to Dr. Julian Thayer’s research group at University of 
California Irvine for analysis. Your sample will be labeled by a number and will not contain any 
information that can be used to directly identify you. 
 
A “uroflow measurement” measures the volume of urine, how long it takes to be released from 
the body and the speed. The uroflow measurement requires you to urinate on a special toilet in 
the MCW Neurology Research Rooms at FH. The toilet contains sensors that measure the 
speed of the urine flow and amount of urine. About one hour prior to this test you will be asked 
to drink a quart of fluid. 
 
Weekly Home Checks will occur once a week for 24 weeks following consent. Each week, you 
will complete a heart rate recording just before you go to bed. The heart rate recording will help 
us to study how your heart rate changes throughout the day. You will place the patches on your 
chest and torso to match the image found on the instruction sheet provided to you as soon as 
you get up in the morning. A researcher will remind you via skype, email, text or telephone to 
complete the heart rate recording. The researcher will coach you the first few times you 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 7 of 17 
Version: Experimental ICF 02APR2021 
 
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complete this recording until you are comfortable completing it on your own. The researcher will 
ask you to lie down flat on your bed for 15 minutes. After that, the researcher will instruct you to 
stand up as quickly as you can in front of your bed for another 5 minutes. You can sit down if 
you become too dizzy. You will need to bring the Faros 360 device with you to each of your in-
person visits. The data from your heart rate recording will be uploaded to a secure server by a 
member of the research team. 
 
You will complete the following each week from home: a 24-hour heart rate (HR) recording 
using the eMotion Faros 360° ECG device, the 24-hour voiding diary, answer a set of questions 
using the ICECAN mobile App installed on a preloaded smartphone, and complete 
questionnaires (those mentioned previously) that are sent to your personal e-mail account via a 
secure Internet connection. If in any case you are unable to complete the questionnaires online, 
you will be asked to return paper copies of the questionnaires at your next in-person follow-up 
visit.  
 
The 24-hour voiding diary consists of tracking how much liquid comes in and out of your body in 
a 24-hour period, and how often you void. You will be required to measure the amount of 
everything you drink. You will also record the time and amount of each void for the 24-hour 
period. A special measuring “hat” that fits over the toilet seat will help you measure each void.  
 
You will also complete a Daily Flare Question which asks about flare activity, management and 
if the flares are affecting you. These Flare Questions will be monitored via phone calls and 
recording in the EMA application on the smartphone.  
 
Every week for 24 weeks you will repeat the 24-hr HR recording, as described above, to 
compare the HRV recording done at home to the one performed at the matching on-site visit.  
 
If you end up not answering some of the EMA questions, we will be asking you the following:  At 
any time during the study, did your pain affect your ability to answer any of the EMA 
questions?  When you didn't answer the EMA questions, what percentage of time was it due to 
pain?  These questions will be asked at each in-clinic visit appointment. 
 
During your follow-up visits at weeks 4, 12, 16, and 24, you will arrive to the MCW Neurology 
Research Rooms to repeat the following: a review of your symptoms, a brief physician exam, a 
uroflow measurement, questionnaires, and heart rate recording. You will complete the breathing 
test in the MCW Neurology Research Rooms with a member of the research team present. You 
will also complete a repeat pelvic examination at Weeks 12 and 24.  
 
Blood will be drawn (optional) and urine will be collected (~ 50 mL, a little more than 3 
tablespoons) at each in-person visit at weeks 0, 4, 12, 16, and 24. We will determine (1) if 
immune or inflammatory factors play a role in your pain cycles and (2) if energy production in 
your cells might be impaired.  
 
A portion of your blood plasma/serum and urine will be sent to Dr. Lori Birder’s laboratory at the 
University of Pittsburgh for additional related analysis. Both of your samples will be labeled by a 
number and will not contain any information that can be used to directly identify you. This 
portion of the study is critical for us to gather new information about pelvic pain, which is very 
poorly understood. We highly encourage you to participate in this portion of the study. However, 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 8 of 17 
Version: Experimental ICF 02APR2021 
 
EFFECTIVE 
 
6/8/2021 
 
MCW/FH IRB 
given how difficult it can be to obtain blood from some people with IC/BPS, we do allow you to 
opt out of the blood draw portion of this study and still participate in the other parts. 
 
Please initial your choice below regarding blood sample collection. 
 
_______ Yes, I agree to provide blood samples for this research project.  
INITIALS 
 
_______ No, I do not agree to provide blood samples for this research project.  
INITIALS 
 
 
B2. HOW LONG WILL I BE IN THE PROJECT? 
 You will be in this research project for about 25 weeks.   
 You will take the drug/placebo for a total of 16 weeks.   
 We will also follow-up with you 4 weeks after your study completion. 
 
B3. CAN I STOP BEING IN THE PROJECT?   
You are free to withdraw from the project at any time. If you leave, your regular medical care will 
not change. If you are thinking about leaving, please tell the research doctor.  
 You will be asked to return any unused research drug and its containers. 
 
The research doctor may take you out of this project at any time. This would happen if: 
 
They think it is in your best interest. 
 
You do not follow the project rules. 
 
The whole project is stopped. 
If this happens, the research doctor will tell you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE PROJECT?  
It is important that you stay on the same medication regimen while you are participating in this 
study unless directed by your physician. Please notify the study Principal Investigators if your 
regimen changes.  
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE PROJECT? 
There are risks to taking part in any research project. There is a risk that you may get 
metoprolol and that it does not help your condition or may make it worse.  There also may be 
problems (side effects) we do not know about yet, from metoprolol itself, or how it combines with 
other drugs you are taking. If we learn about new important side effects, we will tell you.  
 
We watch everyone in the project for problems (side effects). You need to tell the research 
doctor or a member of the research team immediately if you experience any problems, 
side effects, or changes in your health.  If you have:  
 
Shortness of breath 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 9 of 17 
Version: Experimental ICF 02APR2021 
 
EFFECTIVE 
 
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 
Wheezing 
 
Swelling of the hands, feet, ankles, or lower legs 
 
Unusual weight gain 
 
Fainting 
 
Rapid, pounding, or irregular heartbeat 
Call Dr. Thomas Chelimsky immediately at 414-955-0619. In an emergency, call 911. 
 
C2. RISKS OF Metoprolol 
Metoprolol itself may cause problems (side effects).  Side effects may be mild or very serious.  
Some can last a long time or never go away.   
 
The side effects that other people have experienced so far with metoprolol are:  
 
Dizziness or lightheadedness 
 
Diarrhea 
 
Blurred Vision 
 
Muscle cramping 
 
Fatigue 
 
Headaches 
 
Nightmares 
 
Sexual dysfunction 
 
Low or high glucose 
 
Tiredness 
 
Depression 
 
Nausea 
 
Dry mouth 
 
Stomach pain 
 
Vomiting 
 
Gas or bloating 
 
Heartburn 
 
Constipation 
 
Rash or itching 
 
Cold hands and feet 
 
Runny nose 
 
Heart failure or heart block in patients with heart problems 
 
Shortness of breath in asthmatics  
 
C3. OTHER RISKS OF THIS RESEARCH PROJECT  
Other procedures that are part of the research also involve some risks: There is a chance that 
you may develop redness from the patches used to record your heart rate during the heart rate 
test. These red marks are temporary and generally go away within an hour. If you are allergic to 
adhesives, you cannot participate in this study. 
 
You may feel anxious, dizzy, nauseated or get a headache from breathing in and out as 
instructed during the breathing test. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 10 of 17 
Version: Experimental ICF 02APR2021 
 
EFFECTIVE 
 
6/8/2021 
 
MCW/FH IRB 
 
The physician exam includes a tender point evaluation that is considered to be standard of care 
for myofascial pain disorders such as fibromyalgia and may lead to tenderness and pain at the 
site of contact. 
 
You may develop pain/bruising at the site of your blood draw.  You also may feel dizzy 
during/after having your blood drawn. 
 
The psychological questionnaires may upset you. You can skip any question that you do not 
want to answer. If your responses are suggestive of emotional problems, a study Investigator 
will discuss your response(s) and will document this discussion in your medical record. The 
Investigator will provide you with places to help get treatment. 
 
C4. REPRODUCTIVE RISKS 
Risks to women who could become pregnant 
The drug Metoprolol in this project might affect a baby, before or after the baby is born. We do 
not know if the metoprolol causes harm to a baby, so we do not want anyone who might be 
pregnant to enter the project. You should not become pregnant or nurse a baby while in this 
project. You must tell the research doctor right away if you think you are pregnant. You will be 
asked to have a pregnancy test to be sure you are not pregnant at the start of the project  
 
Birth control methods for all subjects 
Check with the research doctor about the birth control methods needed for this project and how 
long to use them. Some methods might not be good enough for this project. If you are having 
sex that could lead to pregnancy, you should use birth control while you are in this project.   
This may include: 
 
Not having vaginal sex (abstinence) 
 
Taking birth control pills orally 
 
Having birth control shots or patches such as Depo-Provera 
 
Surgical sterilization (hysterectomy or tubal ligation) 
 
Use of an intrauterine device (IUD) 
 
Use of diaphragm with contraceptive jelly 
 
Use of condoms with contraceptive foam 
 
Use of diaphragm with condoms (“double barrier”) 
 
Limiting sexual activity to a male partner who has had a vasectomy 
 
You should continue using birth control for 1 month after stopping the test drug metoprolol.  
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE PROJECT? 
This study could help you, as we believe beta-blockers may change the brain circuits that 
control your body and therefore your pain responses, be we do not know this, and there is no 
guarantee. That is why we are doing the study. We believe the information from this study will 
help us develop a better understanding of brain circuits that affect chronic pelvic pain. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 11 of 17 
Version: Experimental ICF 02APR2021 
 
EFFECTIVE 
 
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D1. ARE THERE ANY COSTS TO BEING IN THE PROJECT? 
There are no costs to you for any of the visits, drugs or services you receive in this project.  All 
costs will be paid by the project. If you have questions regarding costs, please contact Dr. 
Chelimsky.  
 
If you participate in this research, the costs of any necessary emergency medical treatment in 
the event of a research-related injury will be billed to you or your health insurance. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE PROJECT? 
You will receive $400 for completing at least 80% of the required items for the five major visits at 
the sites and 25 minor at-home monitoring sessions 
 
You will receive a $50 payment on a preloaded credit card after completing all study 
tasks and Visit 1 
 
You will receive a $60 payment on a preloaded credit card after completing all study 
tasks and Visit 2  
 
You will receive a $70 payment on a preloaded credit card after completing all study 
tasks and Visit 3  
 
You will receive a $80 payment on a preloaded credit card after completing all study 
tasks and Visit 4 
 
You will receive a $140 payment on a preloaded credit card after completing all study 
tasks and Visit 5 and returning the Faros ECG monitor and the pre-loaded Smartphone. 
 
You may be given the option to redo a study visit if the study data are incomplete or if you need 
to stop the study drug. If you redo a visit, you will receive payment for the visit which was 
repeated in the same amount as mentioned above. 
 
If you complete the baseline evaluation but are found to not be eligible to participate in this 
study, you will be mailed a $25 check. 
 
Travel reimbursements: 
 
If travel time is between 1 and 2 hours, you will be paid at a rate of $20 per visit on a 
preloaded credit card 
 
If travel time is between 2 and 4 hours, you will be paid at a rate of $40 per visit on a 
preloaded credit card 
 
To pay you, we need your social security number. Any payment may be reportable as income 
on your taxes. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this project. You are free to say yes or no. If you do not join this project, 
your research doctor can discuss other healthcare choices with you.  
 
The drug offered to you may also be available without being in any research project. 
 
The research doctor can explain both the possible benefits and the risks of other options that 
are available to you. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 12 of 17 
Version: Experimental ICF 02APR2021 
 
EFFECTIVE 
 
6/8/2021 
 
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D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE PROJECT? 
If we learn any important new information about metoprolol that might change your mind about 
being in the project, we will tell you about it right away.  You can then decide if you want to stay 
in the project. 
 
When research data are collected and analyzed, there is the chance of finding something 
clinically relevant. There may be benefits to learning such results (such as early detection and 
treatment of a medical condition), but there are risks as well (such as feeling worried about a 
finding for which no treatment is required or appropriate).   
 
In this study, you will be informed of any findings of possible clinical significance that may be 
discovered during review of results from your research data. The results of your research data 
will not be placed in your medical record.  
 
The results from the data we collect in this research study are not the same quality as what you 
would receive as part of your health care. The data will not be reviewed by a physician who 
normally reads such results. We will provide you with this information so that you may discuss it 
with your primary care physician. 
 
After the project has been completed, we will notify you of when the results will be available to 
the public. 
 
D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE PROJECT?  
Emergency medical treatment for injuries directly related to your participation in this research 
project will be provided to you. You or your health insurance will be billed for the costs of this 
emergency treatment.  MCW will decide on a case by case basis if they will reimburse you or 
your insurer for emergency treatment costs.  If your research-related injury requires medical 
care beyond this emergency treatment, you or your insurer will be responsible for the costs of 
this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this project, contact 
the research doctors right away. Contact information: Thomas Chelimsky, MD, 414-955-0619 or 
Gisela Chelimsky, MD, 414-266-3690.  
 
Nothing in this consent form affects any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE PROJECT? 
 
If you have more questions about this project at any time, you can call Thomas Chelimsky 
at 414-955-0619 or Gisela Chelimsky at 414-266-3690. 
 
If you have questions about your rights as a research participant, want to report any 
problems or complaints, or offer input, you can call the MCW/Froedtert Hospital Research 
Subject Advocate at 414-955-8844. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 13 of 17 
Version: Experimental ICF 02APR2021 
 
EFFECTIVE 
 
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E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this project? 
To be in this research project, the research team needs your permission to access, collect and 
use some of your health information. If you say no, you cannot be in the project. This 
information may come from questions we ask, forms we ask you to fill out, or your medical 
record, as described below. We will only collect and use information needed for the project. 
 
The protected health information (PHI) originates from services you will or have received at one 
or more of the following locations: the Medical College of Wisconsin (MCW); BloodCenter of 
Wisconsin (BCW); Children’s Hospital of Wisconsin (CHW); any Froedtert Health Affiliate- 
Froedtert Memorial Lutheran Hospital (FMLH), Inc.; Community Memorial Hospital (CMH) 
Menomonee Falls, Inc.;  St. Joseph’s Community Hospital (SJH) West Bend, Inc.;  Froedtert & 
The Medical College of Wisconsin Community Physicians Clinics, Inc. (FMCWCP); the West 
Bend Surgery Center, LLC; and the Froedtert Surgery Center, LLC.  
 
The health information to be collected and used for this project is:  
 
To do this research study, we need your permission to collect and use some of your health 
information, or you cannot be in the study. This information may come from questions we ask, 
forms we ask you to fill out, or your medical records of the care you receive from this project.  
Health information such as your clinical and laboratory information will be collected and shared.  
Researchers will also access your entire medical record for relevant study data such as your 
medical history, radiology scans, or lab data to help analyze the data collected. We will only 
collect and use information needed for the study.  
 
E2. Who will see the health information collected for this project? 
The only MCW/Froedtert Hospital employees allowed to handle your health information are 
those on the research team, those on the Institutional Review Board (IRB) and those who check 
on the research activities to make sure the hospital’s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-related 
injury are billed to your health insurance, your health information may need to be disclosed to 
the insurer for billing purposes. 
 
The research team may share your information with people who don’t work at MCW/Froedtert 
Hospital because they planned, pay for, or work with us on this project.  The federal Privacy 
Rule may no longer protect your health information once it leaves MCW/Froedtert Hospital.  For 
this project, we plan to share information with those doctors, researchers or government 
representatives working with us on this project at the institutions or companies listed here: 
 
 
 
U.S. Food and Drug Administration, Rockville, MD  
 
Northshore Hospital in Chicago, IL Medical College of Wisconsin & Froedtert Hospital 
 
Case Western Reserve University in Cleveland, OH 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 14 of 17 
Version: Experimental ICF 02APR2021 
 
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 
Multi-Disciplinary Approach to the study of Chronic Pelvic Pain (MAPP) Research 
Network, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 
Because this project involves the use of drugs and/or devices, the FDA also has the right to 
inspect all project records. 
 
We may record your research information, including results of tests and procedures done for 
research, in your Froedtert Hospital and/or Medical College of Wisconsin medical record.  As a 
result, this research information may be seen by people allowed to see your medical records for 
healthcare operations or treatment, by those you allow to see your medical records by giving 
written permission, and by others when required by law. 
 
We will not use your personal health information for a different project without your permission 
or the permission of a hospital research review board (IRB). Once all personal identification is 
removed from your health information and/or biospecimens, the information and/or 
biospecimens may be used for future research or distributed to another investigator for future 
research without additional informed consent from you or your legally authorized representative. 
The information might also be used or released for other purposes without asking you. Results 
of the project may be presented in public talks or written articles, but no information will be 
presented that identifies you. 
 
E3. What are the risks of sharing this health information? 
One risk of taking part in a research project is that more people will handle your personal health 
information collected for this project. The research team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 
embarrass you or affect your ability to get insurance. If you have questions, you can talk to the 
research doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this project? 
If you sign this form, we plan to keep your information for 10 years after the research project 
ends in case we need to check it again for this project. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to Dr. Thomas Chelimsky or Dr. Gisela Chelimsky at 8701 Watertown 
Plank Road, Department of Neurology, Milwaukee, WI, 53226. The letter must say that you 
have changed your mind and do not want the researcher to collect and share your health 
information. At that time, we may decide that you cannot continue to be part of the project. We 
may still use the information we have already collected. 
 
 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
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F1. FOR MORE INFORMATION ABOUT THE PROJECT 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
You can look up this project by referring to the ClinicalTrials.gov number NCT03008382 or by 
asking the research team for a printed copy.    
 
CERTIFICATE OF CONFIDENTIALITY  
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health.  The study team can use this Certificate to legally refuse to 
disclose information that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings, for example, if there is a court subpoena.  The 
study team will use the Certificate to resist any demands for information that would identify you, 
EXCEPT as explained below: 
 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States federal or state government agency sponsoring the project and that will be used for 
auditing or program evaluation of agency funded projects or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, medical care provider, or other person obtains your written consent to 
receive research information, then the researchers will not use the Certificate to withhold that 
information. 
 
CONSENT TO PARTICIPATE 
 
By signing my name below, I confirm the following: 
 
I have read (or had read to me) this entire consent document and attachment 1.  
All of my questions have been answered to my satisfaction. 
 
The project’s purpose, procedures, risks and possible benefits have been explained to me.   
 
I agree to let the research team use and share the health information and other information 
gathered for this project. 
 
I voluntarily agree to participate in this research project. I agree to follow the procedures as 
directed. I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date/Time 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
Page 16 of 17 
Version: Experimental ICF 02APR2021 
 
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Name of Witness please print 
Signature of Witness 
 
Date/Time 
Rationale for Use of Witness 
 Subject has limited/no literacy 
 Subject has limited English 
proficiency 
 Subject has limited/no vision 
 
 Sponsor requirement 
 Other ____________________ 
 
 
 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date/Time 
* A member of the research team trained and authorized by the Principal Investigator to act on 
her/his behalf in obtaining informed consent according to the protocol.  The Principal 
Investigator is responsible and accountable for the research project. 
 
 
 
 
Name of Principal Investigator        
please print  
__ I participated in consent process 
__ I acknowledge enrollment of this 
subject into the project 
Signature of Principal 
Investigator 
Date/Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
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Attachment 1 – Details of project schedule and procedures 
 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
4 Weeks 
Post Visit 
5 
 
 
Week 
0 
4 
12 
16 
24 
28 
Schedule of 
Events 
 
Time to 
complete 
 
 
 
 
 
 
 
General exam 
180 
minutes 
 
x 
 
 
 
 
 
Physician 
Exam  
10 minutes 
 
x^ 
x 
x^ 
x 
x^ 
 
Questionnaires 
 
50 minutes 
 
x 
x 
x 
x 
x 
 
Heart Rate 
Test 
20 minutes 
 
x 
x 
x 
x 
x 
 
Breathing Test 
 
10 minutes 
 
x 
x 
x 
x 
x 
 
Participant 
Incentive 
 
 
x 
x 
x 
x 
x 
 
Home Checks, 
App & Diary 
Variable 
Done 
once a 
week for 
24 
weeks 
 
 
 
 
 
x* 
x^ Physician Exam and a pelvic exam will be completed 
x* Study team will contact you to complete a general wellbeing check with you. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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Medical College of Wisconsin and Froedtert Hospital 
INTRODUCTION TO THE INFORMED CONSENT 
 
Name of Subject: ____________________________ 
 
 
 
Study Title: Interstitial Cystitis-Examination of the Central Autonomic Network (ICECAN) 
 
Thomas Chelimsky, M.D. 
Department of Neurology 
414-805-5246 
Medical College of Wisconsin 8701 
Watertown Plank Road 
Milwaukee, WI 53226 
 
Gisela Chelimsky, M.D. 
Department of Pediatric Gastroenterology 
414-266-3690 
Medical College of Wisconsin 8701 
Watertown Plank Road Milwaukee, 
WI 53226 
 
 
You are invited to take part in this research. You can decide whether to take part in this project 
or not. You are free to say yes or no. If there is anything that you do not understand, please ask 
questions. 
 
 
Definitions 
 
Interstitial Cystitis/Bladder Pain Syndrome- is a type of chronic pain that affects the 
bladder. Symptoms include feeling the need to urinate right away, needing to urinate often, 
and pain with sex 
 
Myofascial Pelvic Pain- is a source of chronic pelvic pain in women and men that 
is defined by short, tight, tender pelvic floor muscles that include palpable nodules or trigger 
points that cause referred pain. The pain can be continuous or episodic. MPPS can impact 
urinary, bowel, and sexual function. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
Page 2 of 11 
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Purpose 
This project is being done to understand how 
the brain controls the bodies of women who 
are not diagnosed with IC or MPP compared 
to women who are diagnosed with IC/BPS or 
MPP. 
Length 
 You will be in this research project sub-
study for about 4.5 hours while you 
complete the safety forms, pregnancy 
tests (if applicable) and fMRI scans.  
  
Risks 
This is a brief list of the most commonly seen 
risks The full consent form after this 
introduction contains a more complete list of 
potential research risks. 
 
Device risks: 
 
Headaches 
 
Tinnitus 
 
Claustrophobia 
Procedures or Activities 
If you choose to participate in this research 
sub-study, you will first complete an MRI 
safety form to make sure that it is safe for you 
to participate in this study. 
 
List of visits: 
 
MRI Visits 
- Total Number: 3 
- Total Time: 4.5 hours 
 
Procedures/Activities that will occur at 
various visits: 
 
Invasive Procedures 
- None 
 
Non-invasive Procedures 
- Pregnancy Tests 
- MRI Scans 
- MRI Experience Questionnaire 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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My Other Options 
You do not have to join this project. You are 
free to say yes or no. 
 Whether or not you join this project, you 
are free to seek services from this or 
other agencies. 
 Whether or not you join this project, your 
usual medical services will not change. 
Benefits 
This project will not help you, but we hope the 
information from this project will help us 
develop a better understanding of IC/BPS 
and MPP. 
If you have more questions about this project at any time, you can call Thomas Chelimsky, 
M.D. Principal Investigator at 414-805-5246 or Gisela Chelimsky, M.D. at 414-266-3690. 
 
If you have questions about your rights as a participant, want to report any problems or 
complaints, or offer input, you can call the MCW/Froedtert Hospital Research Subject 
Advocate at 414-955-8844. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
Page 4 of 11 
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CONSENT TO PARTICIPATE IN RESEARCH 
A1. INTRODUCTION – WHY ARE WE ASKING YOU TO PARTICIPATE? 
You are being invited to participate in this research because you have been diagnosed with 
Interstitial Cystitis (IC), Myofascial Pelvic Pain (MPP) and you are not pregnant. We believe the 
brain plays a major role in this type of pain and would like to learn more about what it is doing. 
A total of 18 women who have not been diagnosed with IC/BPS or MPP and 36 women who 
have been diagnosed with IC/BPS or MPP. 
 
A total of about 54 people are expected to participate in this research study at the Medical 
College of Wisconsin/Froedtert Hospital.   
 
The Directors of the project are Dr. Thomas Chelimsky, Dr. Gisela Chelimsky, Dr. Sumana 
Koduri, and Dr. Camila Bomtempo in the Departments of Neurology, Pediatric 
Gastroenterology, and the Department of OB/GYN. A research team works with them. You can 
ask who these people are.  
 
The National Institute of Health, a government agency, is funding the research.  
 
A2. DO I HAVE TO PARTICIPATE? 
You can decide whether to take part in this research or not. You are free to say yes or no. If you 
say no, your regular medical care will not change. Even if you join this project, you do not have 
to stay in it. You may stop at any time. 
A3. WHY IS THIS PROJECT BEING DONE? 
The purpose of this project is to understand how the brain controls the bodies of women who 
are not diagnosed with IC or MPP compared to women who are diagnosed with IC/BPS or MPP. 
 
B1. WHAT WILL HAPPEN IF I PARTICIPATE? 
MRI (Magnetic Resonance Imaging) is a way for us to see inside your body.  MRI uses a 
powerful magnet, radio waves and a computer to produce detailed pictures of organs, bones 
and other internal body structures. For the MRI, you will lie on a table inside a scanner tube for 
about 60 minutes, while the scanner moves the reading unit over the areas of your body to be 
scanned. 
If you choose to participate in this research sub-study, you will first complete an MRI safety form 
to make sure that it is safe for you to participate in this study. If you are able to participate, you 
will complete a pregnancy test prior to each scan (if applicable) and a total of 3 fMRI scans. You 
will complete one scan within the four weeks prior to visit 2, another 12 weeks later and the last 
one 24 weeks into this study. Each fMRI session will take about 60 minutes to complete. The 
MRI Experience Questionnaire (MEQ) is completed after the fMRI procedure to assess your 
experience during the MRI. 
  
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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As a precaution, you will complete a pregnancy test (if applicable) and an MRI safety screening 
form at each visit before you enter the scanner room. This test must be negative for you to 
safely continue with the scan. You will also be given the option of lying in a mock (fake) scanner 
to prepare yourself for the fMRI before completing it.  
  
Information collected in clinic (form you fill out, information about your symptoms) may be used 
for research. 
 
There is no penalty for not participating. 
 
B2. HOW LONG WILL I BE IN THE PROJECT? 
You will be in this research project for about 4.5 hours while you complete the safety forms, 
pregnancy tests (if applicable) and fMRI scans. 
 
B3. CAN I STOP BEING IN THE PROJECT?   
You may stop at any time. If you decide to leave the project, please let the research team know. 
 
You may stop at any time, including during the MRI scan. 
 
The research doctor may stop your participation in the project at any time for any reason without 
your consent.  He / She will tell you if this happens. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE PROJECT? 
We watch everyone in the project for unexpected problems. You need to tell the research 
doctor or a member of the research team immediately if you experience any problems or 
become too upset. 
 
There is a chance that you could be injured if you fail to tell the research staff that you have any 
of the following and try to complete the fMRI session:  
  
• A pacemaker or any other metal, such as an aneurysm clip, ear implants, or nerve stimulator 
in your body. If you do have any of these things then you cannot have an MRI and will be 
considered ineligible for the study. It is also important to know if you have any metal on your 
body. If a piece of metal (such as a tool or key) is released into the MRI room, you could be 
injured. 
 
Certain risks and discomforts may be associated with fMRI.  
  
• There is no exposure to X-rays or radioactivity during MRI (Magnetic Resonance Imaging), 
and the risk of injury is very low. However, MRI is not safe for everyone. Serious injury or death 
can result if you go into the scanner with certain metal objects in, on, or attached to your body. 
For example, it is not safe to have an MRI scan if you have a cardiac pacemaker or defibrillator. 
• The loud "banging" sounds made by the MRI scanner may cause you to have a headache or 
to develop ringing in your ears called tinnitus. To reduce this risk, we will provide you with 
earplugs.  


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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• The loud “banging” sounds made by the MRI scanner can cause hearing damage, but with 
earplugs properly worn, there is no known risk of permanent hearing damage. Rarely, you may 
find that your hearing is less sensitive for several days after an MRI scan. When this occurs, 
hearing should return to normal within a few days. 
 • You may experience some discomfort because you are lying still for a long time, or because 
of the padding used to keep your head from moving.  You may also become hot or dizzy. 
• You may also experience claustrophobia (fear of closed or narrow spaces) in the MRI scanner. 
The scanner operator will be in constant contact with you, and you can be removed quickly from 
the scanner if necessary.  
• In addition, there may be some unknown or unanticipated risks or discomforts in addition to 
those specified above because some of the procedures are relatively new and are attempts to 
advance medical knowledge. Every known precaution will be taken to ensure your personal 
safety and to minimize discomfort.  
  
Many questions will be asked as part of your safety screening. If you prefer not to answer a 
question because it causes you to be upset, you may tell the study team member and not 
provide that information. If your responses are suggestive of emotional problems, a study 
Investigator will discuss your response(s) and will document this discussion in your medical 
record. The Investigator will provide you with places to help get treatment. 
 
Another risk may be loss of confidentiality. Every effort will be made to keep your research 
records confidential but we cannot guarantee it. Depending on the kind of information being 
collected, if your research information were accidentally seen, it might be used in a way that 
could embarrass you or affect your ability to get insurance. If you have questions, you can talk 
to the project director about whether this could apply to you. 
 
C2. RISKS TO WOMEN WHO COULD BECOME PREGNANT 
The MRI in this project might affect a baby, before or after the baby is born. We do not know if 
the MRI would cause harm to a baby, so we do not want anyone who might be pregnant to 
enter the project. You should not become pregnant or nurse a baby while in this project. You 
must tell the research doctor right away if you think you are pregnant. You will be asked to have 
a pregnancy test to be sure you are not pregnant at the start of the project.  
 
If you become pregnant during the project, you will be dropped from participation for safety 
reasons. We ask that you inform the research doctor immediately. The research doctor will ask 
you for written permission to obtain information from you or your obstetrician on your pregnancy 
and the health of the baby. 
 
Birth control methods for all subjects 
Check with the research doctor about the birth control methods needed for this project and how 
long to use them. Some methods might not be good enough for this project. If you are having 
sex that could lead to pregnancy, you should use birth control while you are in this project.   
This may include: 
 
Not having vaginal sex (abstinence) 
 
Taking birth control pills orally 
 
Having birth control shots or patches such as Depo-Provera 
 
Surgical sterilization (hysterectomy or tubal ligation) 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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 
Use of an intrauterine device (IUD) 
 
Use of diaphragm with contraceptive jelly 
 
Use of condoms with contraceptive foam 
 
Use of diaphragm with condoms (“double barrier”) 
 
Limiting sexual activity to a male partner who has had a vasectomy 
 
C3. ARE THERE ANY BENEFITS TO TAKING PART IN THE PROJECT? 
This project will not help you, but we hope the information from this project will help us develop 
a better understanding of IC/BPS and MPP. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE PROJECT? 
There are no costs to you for any of the visits or services you receive in this project. If you have 
questions regarding costs, please contact Dr. Chelimsky. If you participate in this research, the 
costs of any necessary emergency medical treatment in the event of a research-related in jury 
will be billed to you or your health insurance. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE PROJECT? 
You will be paid a total of $225. $75 after completion of each scanning visit on a preloaded 
credit card.  To pay you, we need your social security number. Any payment may be reportable 
as income on your taxes. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this project. You are free to say yes or no. Whether or not you join this 
project, you are free to seek services from this or other agencies. Whether or not you join this 
project, your usual medical services will not change 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE PROJECT? 
After the project has been completed, we will notify you of when the results will be available to 
the public. 
 
When research data are collected and analyzed , there is the chance of finding something 
clinically relevant. There may be benefits to learning such results (such as early detection and 
treatment of a medical condition), but there are risks as well (such as feeling worried about a 
finding for which no treatment is required or appropriate).   
 
In this study, you will be informed of any findings of possible clinical significance that may be 
discovered during review of results from your research data. The results of your research data 
will not be placed in your medical record.  
 
The results from the data we collect in this research study are not the same quality as what you 
would receive as part of your health care. The data will not be reviewed by a physician who 
normally reads such results. We will provide you with this information so that you may discuss it 
with your primary care physician. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE PROJECT?  
Emergency medical treatment for injuries directly related to your participation in this research 
project will be provided to you. You or your health insurance will be billed for the costs of this 
emergency treatment.  MCW will decide on a case by case basis if they will reimburse you or 
your insurer for emergency treatment costs.  If your research-related injury requires medical 
care beyond this emergency treatment, you or your insurer will be responsible for the costs of 
this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this project, contact 
the research doctors right away.  Contact information: Dr. Thomas Chelimsky at 414-805-5246 
or Dr. Gisela Chelimsky at 414-266-3690.  
 
Nothing in this consent form affects any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE PROJECT? 
 
If you have more questions about this project at any time, you can call Dr. Thomas 
Chelimsky at 414-805-5246, Dr. Gisela Chelimsky at 414-266-3690. 
 
 
If you have questions about your rights as a research participant, want to report any 
problems or complaints, or offer input, you can call the MCW/Froedtert Hospital Research 
Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this project? 
To be in this research project, the research team needs your permission to access, collect and 
use some of your health information. If you say no, you cannot be in the project. This 
information may come from questions we ask, forms we ask you to fill out, or your medical 
record, as described below. We will only collect and use information needed for the project. 
 
The protected health information (PHI) originates from services you will or have received at one 
or more of the following locations: the Medical College of Wisconsin (MCW); BloodCenter of 
Wisconsin (BCW); Children’s Hospital of Wisconsin (CHW); any Froedtert Health Affiliate- 
Froedtert Memorial Lutheran Hospital (FMLH), Inc.; Community Memorial Hospital (CMH) 
Menomonee Falls, Inc.;  St. Joseph’s Community Hospital (SJH) West Bend, Inc.;  Froedtert & 
The Medical College of Wisconsin Community Physicians Clinics, Inc. (FMCWCP); the West 
Bend Surgery Center, LLC; and the Froedtert Surgery Center, LLC.  
 
The health information we will collect and use for this project is: 
 
 
 
Health information collected during this project, such as safety screening form and fMRI scans. 
Researchers will also access your medical record for relevant study data such as your medical 
history, radiology scans, or lab data to help analyze the data collected. The brain scans will not 


Medical College of Wisconsin & Froedtert Hospital 
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Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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be used to diagnose any existing brain disorders. 
 
E2. Who will see the health information collected for this project? 
The only people allowed to handle your health information are those on the research team at 
MCW/Froedtert Hospital, those on the Institutional Review Board (IRB) and those who check on 
the research activities to make sure the hospital’s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-related 
injury are billed to your health insurance, your health information may need to be disclosed to 
the insurer for billing purposes. 
 
The research team may share your information with people who are not part of the research 
team because they planned, pay for, or work with us on this project. The federal Privacy Rule 
may no longer protect your health information once it leaves MCW/Froedtert Hospital.  For this 
project, we plan to share information with those doctors, researchers or government 
representatives working with us on this project at the institutions or companies listed here: 
 
• U.S. Food and Drug Administration, Rockville, MD 
• Northshore Hospital in Chicago, IL 
• Case Western Reserve University in Cleveland, OH  
• Multi-Disciplinary Approach to the study of Chronic Pelvic Pain (MAPP) Research Network,   
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 
Because this project involves the use of drugs and/or devices, the FDA also has the right to 
inspect all project records. 
 
We may record your research information, including results of tests, procedures or 
questionnaires done for research, in your Froedtert Hospital and/or Medical College of 
Wisconsin medical record.  As a result, this research information may be seen by people 
allowed to see your medical records for healthcare operations or treatment, by those you allow 
to see your medical records by giving written permission, and by others when required by law.   
 
We will not use your personal health information for a different project without your permission 
or the permission of a hospital research review board (IRB).  Once all personal identification is 
removed from your health information and/or biospecimens, the information and/or 
biospecimens may be used for future research or distributed to another investigator for future 
research without additional informed consent from you or your legally authorized representative.  
The information might also be used or released for other purposes without asking you.  Results 
of the project may be presented in public talks or written articles, but no information will be 
presented that identifies you. 
 
E3. What are the risks of sharing this health information? 
One risk of taking part in a research project is that more people will handle your personal health 
information collected for this project. The research team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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embarrass you or affect your ability to get insurance. If you have questions, you can talk to the 
research doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this project? 
If you sign this form, we plan to keep your information for 10 years after the research project 
ends in case we need to check it again for this project. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to Dr. Thomas Chelimsky or Dr. Gisela Chelimsky at 8701 Watertown 
Plank Road, Milwaukee, WI 53226. The letter must say that you have changed your mind and 
do not want the researcher to collect and share your health information. At that time, we may 
decide that you cannot continue to be part of the project. We may still use the information we 
have already collected. 
 
F1.  FOR MORE INFORMATION ABOUT THE PROJECT 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results.  You can search this Web site at any time.  You can look 
up this project by referring to the ClinicalTrials.gov number NCT03008382 or by asking the 
research team for a printed copy. 
CERTIFICATE OF CONFIDENTIALITY  
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health. The study team can use this Certificate to legally refuse to disclose 
information that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings, for example, if there is a court subpoena. The study team will 
use the Certificate to resist any demands for information that would identify you, EXECPT   as 
explained below:  
 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States federal or state government agency sponsoring the project and that will be used for 
auditing or program evaluation of agency funded projects or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, medical care provider, or other person obtains your written consent to 
receive research information, then the researchers will not use the Certificate to withhold that 
information. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Minimal Risk template - Version: March 30, 2018 
 
IRB Protocol Number: PRO25031 
IRB Approval Period: 6/8/2021 – 6/7/2022 
 
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Version: fMRI Sub-Study (Experimental Group)  
15MAR2021 
 
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CONSENT TO PARTICIPATE 
 
By signing my name below, I confirm the following: 
 
I have read (or had read to me) this entire consent document. All of my questions have been 
answered to my satisfaction. 
 
The project’s purpose, procedures, risks and possible benefits have been explained to me.   
 
I agree to let the research team use and share the health information and other information 
gathered for this project. 
 
I voluntarily agree to participate in this research project. I agree to follow the procedures as 
directed. I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date/Time 
 
 
 
 
 
Name of Witness please print 
Signature of Witness 
 
Date/Time 
Rationale for Use of Witness 
 Subject has limited/no literacy 
 Subject has limited English 
proficiency 
 Subject has limited/no vision 
 
 Sponsor requirement 
 Other ____________________ 
 
 
 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date/Time 
* A member of the research team trained and authorized by the Principal Investigator to act on 
her/his behalf in obtaining informed consent according to the protocol. The Principal Investigator 
is responsible and accountable for the research project.