Clinical trial NCT03697720
Conditions: Dysmenorrhea Pain
Keywords: cross-organ sensitivity bladder pain NSAID visceral pain
Sponsor: Endeavor Health
Start date: 2018-05-09; Completion date: 2023-09-27
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this study is to see if optimized use of naproxen for treatment of dysmenorrhea will improve pain report from baseline. In addition, we will determine whether cross-organ influences from the uterus on bladder pain sensitivity change from baseline after reduced menstrual pain experience over six months. Finally, a battery of quantitative sensory tests and EEG measures of sensory sensitivity will be used to evaluate mechanisms associated with improvements in menstrual and bladder pain.

Detailed description:
Endometrial shedding during the menstrual cycle elicits profound changes in neuronal activity and cytokine concentrations producing moderate to severe pelvic pain in more than 20% of reproductive-age women. One out of every five of those women in turn will experience chronic pelvic pain (CPP) which may be in part due to cross-organ neural sensitization.

In this study we will establish whether prophylactic and adequate dosages of naproxen are capable of reducing menstrual pain more than \*\*\* use.

Arms: arm 1: We will look at the effects of naproxen 500mg use on pain starting just before and during menses.
Interventions: intervention 1: Naproxen
Intervention descriptions: intervention 1: Participants will take naproxen 500mg BID before and for the first 3 days of their period.

Protocol documents:
Prot_SAP_000.pdf: 
IRB PROTOCOL 
EH18-128: Examining the role of improved NSAID 
management in treating dysmenorrhea NCT03697720, May 31 
2018 
PI: FRANK F. TU, MD MPH 
EH18-128
Version 
1.1 


 
 
I R B  P R O T O C O L  
Examining the role of improved NSAID 
management in treating dysmenorrhea  
 The Gyrl Lab 2018 
 
 


N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
1 
Table of Contents 
Protocol: Revision 1 dated 5/4/18 .................................................................... 2 
Overview: .................................................................................................... 2 
Study participants ....................................................................................... 3 
Inclusion Criteria: ............................................................................. 3 
Exclusion criteria: ............................................................................ 3 
Recruitment: .................................................................................... 3 
Phone Screen .................................................................................. 4 
Study Visits ................................................................................................. 4 
Consent ........................................................................................... 4 
Questionnaires ................................................................................ 4 
Rapid Bladder Test .......................................................................... 5 
Assessments ................................... Error! Bookmark not defined. 
Naproxen: ........................................................................................ 9 
Between visit measurements: .......................................................... 9 
Repeat Assessment: ....................................................................... 9 
Power Analysis/Data Analysis: .................................................................. 10 
Bibliography .............................................................................................. 10 
 
 
 
Chapter 
1 


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2 
 
Protocol Version: 1.1  
Overview:  
Many of the women experience severe menstrual pain, yet undermanage their pain level by 
not taking a sufficient amount of NSAIDs. Notably, biochemical analyses demonstrate that the 
administration of naproxen prior to the initiation of the COX-2 cascade results in nearly complete 
suppression of prostaglandin synthesis; attempting to block synthesis afterwards only leads to a 
gradual and incomplete suppression.1 The single, but underpowered trial, comparing menstrual pain 
relief between prophylactic versus response use to pain with ibuprofen did not find a difference.2 It 
is possible that differences in prophylactic use of naproxen and ibuprofen could be due to different 
preferential binding to COX-1 and COX-2 receptors. Aside from this trial, clinical investigators have 
not sufficiently investigated prophylactic use of NSAIDs prior to the onset of menses. Although an 
educational trial regarding prophylaxis did demonstrate increased patient knowledge, reduction of 
menstrual pain was not evaluated.3 Therefore, in the present study we will establish whether 
prophylactic and adequate dosages of Naproxen are capable of reducing menstrual pain more than 
response use. Secondly, we will establish whether reduction of menstrual pain with optimized 
naproxen use can reduce bladder pain via cross-organ sensitization or central sensitization. We 
hypothesize that cross-organ sensitization (COS) is the mechanism by which dysmenorrhea may 
lead to some forms of chronic pelvic pain. Uterine inflammation during menstruation likely 
contributes to chronic pelvic pain (CPP) by triggering neurogenic inflammation in adjacent organs.4 
This COS has been demonstrated with experimental injury and infection in animal models.5,6 Our 
prior findings discussed above7,8 motivate our present central hypothesis: dysmenorrhea produces CPP 
via repetitive COS episodes. 
In our ongoing study looking at the relationship between dysmenorrhea, COS and CPP 
(EH13-094), we planned to determine whether oral contraceptive pills (OCPs), by alleviating 
menstrual pain could reverse the development of COS. However, our interim analyses of 
participants in this study identify that many are unwilling to initiate OCPs due to the perceived side 
effects and fear of hormones. Other interventions to reduce the development of COS also plausibly 
exist, notably NSAIDs. Therefore, we propose to re-enroll many of the participants from EH13-094 
who gave permission for future contact.  We will utilize their baseline assessment visit data in order 
to establish whether naproxen can improve menstrual and bladder outcomes. After consent, prior 
data will be linked with the current study. We will also open this study to new participants who will 
be asked to perform a baseline visit (bladder test, pressure tests, EEG, questionnaires and blood 
draw). Participants will be invited to an open label (non-randomized) prospective trial of naproxen. 
After six to eight months of diary data, urine monitoring, and blood samples, a repeat visit (bladder 
test, pressure tests, EEG, questionnaires, and blood draw) will be conducted. The majority of the 
testing details below have been previously approved for the ongoing study EH13-094.  
Additionally, we will investigate whether mechanisms involved in pain sensitivity predict 
responses to effectiveness of NSAID treatment for menstrual or bladder pain.  Several studies 
identify that women with menstrual pain have central sensory processing abnormalities akin to what 
is observed in women with chronic pelvic pain states.9–11  Focused investigation into gynecological 
risk factors for bladder pain syndrome is of particularly high value, as it more commonly affects 
women 12, and current treatments, such as pentosan polysulfate,13 amitriptyline, 14 or cystoscopic 
hydrodistension15 are only modestly effective. The limited efficacy of these treatments reflects the 
multifactorial mechanisms underlying BPS, particularly in later stages, which may include cross-
organ sensitization, central nervous system sensitization, mucosal inflammation, and 
neuropsychological factors.16 One underlying hypothesis for this finding is that repetitive episodes of 


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3 
dysmenorrhea promote cross-organ or central sensitization. This is supported by clinical 
observations17 and experimentally in animal models of provoked uterine inflammation.6 Mechanisms 
involved in central pain modulation can be evaluated with conditioned pain modulation and pressure 
pain testing10,18 and both will be used in this proposal. Additionally, we will look at neural 
mechanisms using audio and visual tasks19 with EEG. We will determine whether baseline 
mechanisms are correlated with menstrual and bladder outcomes. The within subject design also 
allows us to determine if changes in mechanisms (baseline vs repeat visit) are associated with better 
outcomes.  
 
Study participants 
Inclusion Criteria:  
Reproductive-age women (age 18-45) with dysmenorrhea will be recruited. Cases will have: 
a) average menstrual pain ≥ 5/10 (0=no pain and 10=the worst imaginable pain) on at least one day 
during menses or during withdrawal uterine bleeding from cyclic OCs without painkillers, b) 
menstrual pain in the region between the umbilicus and the perineum, above the level of the inguinal 
ligament, and c) indication the participant has attempted to resolve pain by medical means (including 
NSAIDs and/or OCPs). In the circumstance that a participant originally assigned to the 
dysmenorrhea group does not reach a pain of 5 on any days on the daily diary, this will be handled 
on a case-by-case basis particularly if they used a continuous around-the-clock, effective pain 
treatment regimen. Participants who endorse bladder symptoms (subclinical urgency, frequency, 
bladder pain) on the phone screen or bladder symptoms as reported in EH13-094 will be 
preferentially recruited (at least 50% of enrolled participants); those who do not endorse bladder 
symptoms may be determined ineligible. They must not have a formal urological diagnosis such as 
overactive bladder or painful bladder syndrome.  
 
Exclusion criteria:  
Includes: a) presence of active pelvic or abdominal malignancies (primary or metastatic), b) 
absence of regular menses (including current pregnancy, recent pregnancy, or active breast feeding), 
c) active genitourinary infection in the last four weeks, d) unable to read or comprehend the 
informed consent in English, e) unwilling to complete study procedures, and f) presence of 
hypertension or risk for developing hypertension, g) unwillingness to take naproxen and/or placebo, 
h) or contradictions to taking naproxen (allergies, kidney disease, anemia, alcoholism, cardiovascular 
disease, stomach or intestinal ulcer or abnormal liver function). Participants with a history of 
epilepsy will not complete the visual unpleasantness task.  
 
Recruitment: 
Participants will primarily be recruited based on prior participation in the parent study 
(EH13-094), which has currently more than 100 potential participants. Additional recruitment may 
occur from NorthShore’s clinical sites in the Chicago-area and from the community through 
advertising in: NorthShore University HealthSystem’s outpatient clinics; web-based advertising; 
posters and flyers in local businesses (coffee shops, athletic clubs) and on college campuses; referrals 


N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
4 
from local gynecologists; and the Illinois Women’s Health Registry based at Northwestern 
University’s Feinberg School of Medicine. All flyers and ads will be IRB approved. We will use IRB 
approved ads from our Recruitment Registry (EH16-117) that informs participants about any of our 
open studies in our lab. Participants may call our research hotline directly, respond to our online 
pre-screen, or after they indicate interest and give permission, their doctor will send us their contact 
information and a research coordinator will call the patient to formally assess eligibility using a 
phone screen. At the end of the phone screen, participants will be asked if we have permission to 
put their phone screen and contact information into our recruitment registry (EH16-117).  
 
Phone Screen 
All callers will complete a phone screen to assess eligibility before being scheduled for a 
screen visit. At the end of the phone screen, all callers will be asked if we have their permission to 
keep their phone screen information and contact them for future studies. Participants who indicate 
yes will be added to our recruitment registry (EH16-117) study upon study closeout. Eligible callers 
will be scheduled for a screen visit. We may attempt to match groups for age and demographics. 
Thus, in some cases, eligibility on the phone screen may vary based on the study’s current need for 
individuals with certain demographics for each group. We may also require dysmenorrhea 
participants to endorse bladder symptoms on the phone screen in order for them to be eligible to 
come in for a screen visit. During the phone screen, we will discuss when their last period occurred 
and when they anticipate their next period to schedule the study visits. Participants will be instructed 
not to donate blood before the study visit to avoid excessive blood draw. Participants will receive 
directions from well-known medical educational web sites (such as 
https://www.mayoclinic.org/diseases-conditions/menstrual-cramps/ , 
https://www.webmd.com/women/menstrual-cramps ). Our trial is in consensus with expert 
recommended medical guidelines that are suggested on these web sites.    
Study Visits 
We will perform 3-4 study visits: a screen visit, a baseline study visit, a blood draw study visit, and a 
follow-up study visit. Participants that have participated in EH13-094 in the last 12 months will not 
need to participate in the baseline study visit as the data was collected during the EH13-094 
assessment visit.  
 
Consent  
Informed consent will be obtained by a trained research assistant at the screen visit before 
any questionnaires or study procedures are completed.  
 
Questionnaires 
At the screen, baseline and follow-up visit (either in person or over the web using a 
REDCAP, secure interface) participants will complete the following questionnaires: a) complete 
medical, surgical, and gynecological history, and b) a psychosocial assessment using short-form 
PROMIS instruments (pain behavior, pain interference, fatigue, sleep, anxiety, depression, physical 
function, satisfaction with participation in social roles, and 10 item global health scale).20 Participants 
will also complete the following pain rating questionnaires (the Interstitial Cystitis Problem and 
Symptom Indices, the Pain Catastrophizing Scale, Revised Short-form McGill Pain Inventory72 and 
MIDAS headache questionnaire.)67 These scales have been linked to pain intensity and quality of life 


N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
5 
in CPP sufferers, and catastrophizing (rumination, magnification, and feelings of helplessness about 
pain) is a well-validated intervention target for many cognitive-behavioral approaches for chronic 
pain.21–24 Validated, CPP-specific assessment tools will be used to characterize IBS (Rome III 
criteria)25 and bladder pain symptoms (Genitourinary Pain Index).26 Subjects will also complete the 
Female Sexual Function Index (FSFI)68 and Brief Symptom Inventory (BSI)- based questionnaire 
containing 6 somatization questions selected from the BSI-1869 plus a vision question, and the 
Complex Medical Symptoms Inventory (CMSI)-General, Fibromyalgia Symptoms, Fatigue, and 
Vulvodynia sections.70,71  
 
Rapid Bladder Test 
 
At the screen visit, all participants will be asked to undergo a “rapid bladder test.” Participants will 
be asked to rate their bladder pain on a 0-100 VAS scale when they reach “first urge.” If a participant 
arrives to the visit already at first urge, we will have them rate their pain and if not ≥ 10 we will wait 15 
minutes past first urge and have them rate their pain again. This is because the participant may not have 
been focusing on the feeling of their bladder. Participants not already at first urge will be encouraged to 
drink water (at least 20 oz) during the screening visit until they reach first urge at which point a pain rating 
will be attained. After they reach first urge, they can go to the bathroom and leave their urine sample. 
Pelvic Floor Exam: 
The baseline and follow-up visit includes internal vaginal pressure-pain threshold testing, which is 
similar in nature to the pelvic floor portion of a gynecological exam. Thus, for participants who have 
never had a gynecological exam, a study nurse or study doctor may complete a simple exam of the 
pelvic floor at the screen to promote understanding of the internal vaginal pressure-pain threshold 
testing that will be completed at the baseline and follow-up visit. This ensures that the integrity of 
our data is not biased by unfamiliar experience. Participants will be asked whether they have ever 
had a gynecological exam on the phone screen and a simple exam of the pelvic floor for those that 
say they have never had an exam will be scheduled into their screen.  
 
Creatinine Test:  
A creatinine test will be conducted to check for kidney function for all participants. This will be 
done via blood draw at the screen visit.  
 
  
Menstrual Diaries: 
All participants will be asked to complete daily diaries for a full menstrual cycle to assess their 
baseline scores.  
 
Baseline Visit: 
A baseline visit will be performed for all participants that have not conducted an assessment 
visit for EH13-094 in the last 12 months: [Note all of these assessments are the same as the 
assessments approved in EH13-094].  The baseline visit will be scheduled to occur during the 
luteal phase (15 to 25 days after the start of the prior menstrual cycle). Participants will be asked to 
confirm that menstrual pain or bleeding has not started during the baseline visit. 
Food: Baseline Visits are very long so we will offer snacks to the participants (e.g., teddy grahams 
and fruit roll-ups).  


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Instrumentation: During the baseline visit, EMG and EKG electrodes, and respiratory rate monitors 
will be applied and information will be recorded throughout the visit.  EMG leads will be placed on 
the lower abdomen during the bladder testing to measure muscular recruitment. The abdominal 
EMG leads will be moved to the knees once the bladder pain test is completed.  The EKG leads and 
respiratory belt are placed to measure autonomic activity. The autonomic activity will be recorded to 
verify nociceptive experience.  During each testing session, participants will also have their blood 
pressure and pulse taken.  
Bladder pain test: All participants will first undergo bladder pain testing described in our validation 
study7. Subjects will be provided directions for the bladder study. The bladder study involves voiding 
and obtaining baseline measurements of bladder volume with a 3D ultrasound abdominal transducer 
(GE Voluson 750, Wauwatosa, WI). After hydration with 20 oz of water, participants are instructed 
to report when they reach standard levels of bladder urgency: first sensation, first urge, and 
maximum tolerance and volumetric measurements of the bladder will be made. At each of these 
time points and every 15 minutes, 0-100 VAS measurements of pain and urgency are recorded. After 
scanning at maximum tolerance, subjects will urinate in a graded toilet hat to allow for measurement 
and saving a urinary specimen.  Samples will be banked for analyses. If the participant gives 
permission in the consent form, urine samples will continue to be stored after the study is completed 
for possible future analyses by our lab on women’s health conditions. If the participant does not give 
permission in the consent form for analyses beyond the current study, their sample will be destroyed 
upon study completion.  
 
Pressure Pain Threshold Test:  Participants will undergo body and pelvic floor pressure pain 
threshold testing following the same validated protocols in our published studies27,28 using digital 
external and internal vaginal pressure algometers. The body algometer (for example models see 
www.paintest.com) is a commonly used hand-held device in pain research that measures the 
4 
1 
3 
2 
View of introitus in lithotomy position with relative 
position of pelvic floor exam points (exam finger 
inserts into introitus at these sites) (Lewis, 1918) 
Diagram 3: 
All points are examined 3 cm proximal to the vaginal introitus 
#1: right iliococcygeus - located medial to the length of the tendinous arch 
#2: left iliococcygeus  
#3: 12 o’clock position, anterior vaginal wall (adjacent to the bladder) 
#4: 6 o’clock position, posterior vaginal wall (adjacent to the rectum) 
Cutaway of pelvis showing index finger 
examining left iliococcygeus site (#5) 
(adapted from (Peters, et al., 2007)) 
2 
Vaginal introitus 


N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
7 
amount of pressure applied to a 1 cm2 circular rubber tip. The vaginal algometer consists of 2.5 cm2 
circular force sensitive resistor, which fits over the pad of the examiner’s index finger under an exam 
glove (Detailed documentation was provided in a separate earlier supplement to the IRB). Prior to 
evaluation, subjects will report their baseline pain on a NRS 0-10 scale and will be asked to identify 
any painful body sites.  
To evaluate bodily pain pressure thresholds, we will assess three external measurement sites 
corresponding to American College of Rheumatology fibromyalgia tender point sites: the right 
trapezius, the right medial knee fat pad, and the right greater trochanter.29 One additional site will be 
a sham tender point, the middle of the forehead. A digital algometer (described above) will be used 
to conduct the external site measurements using a ramp rate of 0.5 kg/cm2/s. Trials of the shoulder, 
hip, and knee may be terminated by examiner at 7.0 kg/cm2 and trials of the forehead may be 
terminated at 4.0 kg/cm2 in the case that the subject does not reach pressure pain threshold before 
then. Subjects will report level of pain at the time they pressed the button on a NRS 0-10 scale 
immediately after testing each individual site. After a two minute break, the sites will be retested 
again. 
Next, we will use the vaginal algometer (described above), The four pelvic sites will be 
accessed by intravaginal exam, with all measurements conducted using the right index finger 
(Diagram 3) and a ramp rate of 0.5 kg/cm2/s. Internal trials may be terminated by examiner at 3.0 
kg/cm2.  A trained clinician will perform all pressure-pain tests.  Subjects will report the pain at the 
time they pressed the button on a NRS scale immediately after testing each individual site. After a 
two minute break, the sites will be retested again. In order to compare within-subject results from 
the baseline and follow-up visits and in order to standardize timing of post-testing time scores 
(collected every 5 minutes as described below), the order of testing sites will not be counterbalanced.   
Subjects will be allowed to rest for another 5 minutes, and subject will be queried on the level of 
NRS pain at each site again (shoulder, hip, knee, forehead, global vagina). Subjects will be queried 
every 5 minutes until pain returns to baseline levels or up to 30 minutes (the time of resolution in 
minutes will also be recorded).  
Conditioned Pain Modulation (CPM) : CPM testing involves repeating pressure pain threshold 
testing in the presence of a heterotopic stimulus (in this case cold water). The testing stimulus will be 
a mechanical pressure on the left medial knee fat pad. As in the first task, pressure will be applied 
(0.5 kg/cm2/s ramp) until the participant achieves pressure pain threshold. Baseline pressure pain 
thresholds of the testing stimulus on the left knee and left shoulder will be determined. After waiting 
approximately 2 minutes, the conditioning stimulus will be applied by instructing the subject to 
insert their right hand up to their wrist into a bucket of water maintained between 0-6° C. After 10 s 
of immersion, subjects will be asked to rate their level of hand pain on a NRS 0-10 scale. After 20s 
of immersion, the pressure pain threshold will be re-applied using a 0.5 kg/cm2/s ramp rate at the 
knee and the participant will be asked to rate their knee pain at the time they reached threshold (i.e. 
pressed the button) on a NRS 0-10 scale. After testing (~20s of immersion), subjects will 
immediately remove their hand and the pressure pain threshold will be determined at the shoulder. 
After waiting 5- and 10-minutes after water immersion, the testing stimuli will be re-applied. This 
paradigm combines a method for measuring CPM used by Dr. Clauw30 and methods for accurately 
measuring participation of descending inhibition by Dr. Hellman.31 CPM will be measured by the 
standardized differences in pain threshold, EMG activity and autonomic responses before and after 
heterotopic stimulation. This strategy will provide the most reliable measurement of descending 
inhibition.31,32  
Temporal Summation (TS): Participants will be instrumented to undergo tests of spinal pain 
modulation. Temporal summation will be tested using an algometer on the right medial knee fat pad.  


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We will repeatedly apply an amount of pressure (0.5 kg/cm2/s ramp rate; ITI = 5-15 seconds) equal 
to the average of the participant’s two pressure pain thresholds assessed during the first task. After 
each press, the participant will be asked to rate their pain on a NRS 0-10 scale. The pressure will be 
applied ten times or until the participant rates their pain as a 6, whichever comes first.   
EEG Testing: Subjects will be instrumented with a standard EEG cap.  Encephalography (EEG) 
recordings will be obtained using a standard montage and equipment. A trained research assistant or 
nurse will place the EEG cap and electrodes. All participants will undergo a resting state EEG task 
in order to analyze brain activity patterns associated with pain behavior. Participants will be asked to 
focus on a fixation cross on a computer monitor with their eyes open and sitting with their eyes 
closed for one minute each. In total, the task is expected to take 10 minutes. All participants will 
complete a handedness questionnaire,33 consisting of a series of questions asking which hand they 
use for different activities, in REDCap, which will help us interpret our EEG results.  
Sensory Amplification Tests: To evaluate whether sensitivity extends to other modalities we will use 
a software application that measures self-reported unpleasantness to increasingly loud and bright 
stimuli (safe and well below thresholds that could cause auditory or visual damage).  
Auditory stimuli will be provided by waveforms generated by a PC and transmitted through 
headphones calibrated by an audio monitor34 . Each stimulus will be a two-tone combination of 
1200 and 1350 Hz. Sounds will ranged in 5 dB steps from 35 to 90 dB SPL (A-weighted). After 
receiving instructions, the subject will be presented with a series of sounds, in random order of 
intensity. After each 2 s stimulus, the participant will be asked to rate its unpleasantness from 0 (“not 
at all unpleasant”) to 20 (“the most unpleasant sound imaginable”). 
Visual stimuli will be displayed on a computer monitor capable of providing up to 300 lux. In this 3 
min task, two visual stimuli will be presented in an alternating block design.  The control stimulus is 
a fixed crosshair centered in the middle of a solid background; the experimental stimulus will be a 
flashing (12.5 Hz) blue/yellow checkerboard presented at varying levels of brightness (luminance) in 
both an ascending and random manner.  Each subject will be presented with 6 test patterns 
alternated with 6 blanks patterns. Subjects will use a 0 (“not at all unpleasant”) to 20 (“the most 
unpleasant pattern imaginable”) numerical descriptor scale to rate the unpleasantness of each visual 
stimulus and the entire task. 
The visual task may be annoying or elicit a headache or nausea in sensitive individuals. Participants 
may stop at any time.  The sensory testing will take in total about 20 minutes and will be performed 
while the participant is connected to EEG. 
Additional quality controls: We may need to repeat a task, modify electrode positions, reconfigure 
equipment, or adjust features in the environment to evaluate the quality of our data acquisition 
scheme. For example, if a PPT measurement was not obtained or an electrode does not stay put, we 
may ask the subject to allow us to repeat additional measurements.  All embedded quality controls 
with permission from the subject will be documented in the subject record. 
Hormone Measurements: We will ascertain that subjects have not had more than 100 ml of blood 
drawn over the past 24 hours or 200 ml over the past 30 days. After completion of the 
pressure/pain testing, a trained nurse, physician, or phlebotomist will draw up to 60 mL of blood 
into vacutainers. Separation of serum and plasma will be performed using centrifugation and 
samples will be aliquoted and banked appropriately to allow for hormone measurements and 
analyses.  To control for the potential influence of reproductive hormones on pain sensitivity, and 
test our hypothesis about the role of hormonal influences on neurophysiological pain assessments, 
we will measure serum samples for E2, P4 and testosterone using methods that do not cross-react to 
contraceptives (some participants may be taking contraceptives) from the UVA or Emory Assay 
core.35  If the participant gives permission in the consent form, blood samples may also be analyzed 
for genetics. If the participant gives permission in the consent form, blood samples will continue to 


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9 
be stored after the study is completed for possible future analyses by our lab on women’s health 
conditions. If the participant does not give permission in the consent form for analyses beyond the 
current study, their sample will be destroyed upon study completion. 
 
Naproxen:  
Participants will be instructed on usage of prophylactic and recommended dosage of naproxen. 
Participants will be instructed to take one Naproxen (500 mg) pill in the morning and one again 12 
hours later the first day before their anticipated first day of menses. The research coordinators will 
help interpret the menstrual pain calendars for the participants to predict their next menstrual cycle. 
Participants will continue to take a pill twice daily for the first 3 days of their menstrual period. If 
participants still have menstrual pain the following day, they will be instructed to continue taking 2 
pills a day until their pain stops. Any unrelieved pain can be treated with acetaminophen (according 
to directions listed on the package). Participants will continue taking pills before and during their 
period for 6-8 months until the follow up visit is performed. In the event that a participant has been 
taking Naproxen for 3 consecutive days and has been asymptomatic (i.e., not started their menses) 
we will have them stop taking the study medication. The research staff will instruct them to start 
taking it again as soon as they start their period. 
 
The dosage does not exceed the maximal daily recommended over the counter dose for Naproxen (1500 
mg first day, 1000 mg subsequent days).   
Between visit measurements: 
Diaries: On each day of menstrual bleeding and/or pain, participants will complete a daily diary. The 
daily diary will be completed using REDCap and asks them to rate their menstrual, bladder, and 
bowel pain (using a numeric rating scale where 0-no pain, 10-worst pain imaginable), describe any 
bleeding, and what time the study medication wastaken. They will be asked to record any other pain 
reliever/medication they tried that day (heat pads, muscle relaxers, herbal teas, etc) in the notes 
section. They will be instructed to not take any additional painkillers except acetaminophen during 
their menses or while taking the study medication. Outside of their menses, they can treat their pain 
however they normally would (flu, headache). To protect confidentiality, subjects will not enter 
identifying information and only use their assigned subject ID #.  
Urine:  Participants will be told that urine samples will allow us to verify they are taking the study 
medication as directed. Participants will be asked to freeze urine collected from the evening of day 2 
of their menses for each cycle. 6 storage vials will be provided. The urine samples will allow us to 
verify if participants are taking the provided pills.   
Blood: Participants will be instructed to arrive at Evanston Hospital for a scheduled blood draw1.5-3 
hours after ingesting naproxen pills. This will allow us to verify naproxen is sufficiently absorbed to 
provide therapeutic effects. Only one naproxen absorption blood draw will be performed per 
participant. Participants will be allowed to choose the most convenient period day for testing, but 
cannot come on the first day. 
 
Follow up visit:  
Six to eight months later, participants will be invited to return for a follow-up visit. Participants will 
perform the same measurements obtained in the original baseline visit.  In the event participants are 
unable to return for a complete baseline visit, participants will receive a prorated stipend for partial 


N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
10 
completion of items (including questionnaires). Participants will bring in any unused study 
medication to this visit. 
 
Power Analysis/Data Analysis: 
The primary outcomes are menstrual pain and bladder pain. Menstrual pain will be evaluated by 
comparing diary data and questionnaire data from baseline to 6-8 months after treatment.  We 
estimated the needed sample size with a power analysis. Historically, the effects of NSAIDS are 
known to have a large effect size (dz>.7).  A power analysis (α=.05,1-β=.80) suggests that to detect a 
more moderate effect of dz=.7 sample size of 20 would be needed. To account for a ~20-30% drop 
out rate, we will recruit 30 participants.    
 
 
An additional primary outcome is bladder pain as measured by the experimental bladder pain test 
and the GUPI questionnaire.  We estimated the needed sample size with a power analysis. The 
effects of oral contraceptives on bladder pain had enormous effect size (dz=2.9). Unfortunately, too 
few participants were willing to take oral contraceptives. A power analysis (α=.05,1-β=.80) suggests 
that to detect a more moderate effect of dz=1 sample size of 10 would be needed. We will attempt 
to attain a sample size of n=20 to allow detection of and even lower effect size dz=0.7 (per the 
primary outcome for menstrual pain).  
 
Secondary outcomes include predicting NSAID effectiveness via the investigated mechanisms. We 
predict impaired conditioned pain modulation and reduced pain pressure thresholds will predict 
NSAID effectiveness for dysmenorrhea. With n=20, we can detect relationships between treatment 
response and conditioned pain modulation or pain pressure threshold testing with a correlation 
coefficient (Pearson’s r) exceeding 0.38.     
Bibliography 
1.  
Duggan KC, Walters MJ, Musee J, et al. Molecular Basis for Cyclooxygenase Inhibition by the 
Non-steroidal Anti-inflammatory Drug Naproxen. J Biol Chem. 2010;285(45):34950–34959. 
2.  
Chan WY, Dawood MY, Fuchs F. Prostaglandins in primary dysmenorrhea. Comparison of 
prophylactic and nonprophylactic treatment with ibuprofen and use of oral contraceptives. Am 
J Med. 1981;70(3):535-541. 
3.  
Chiou M-H, Wang H-H, Yang Y-H. Effect of systematic menstrual health education on 
dysmenorrheic female adolescents’ knowledge, attitudes, and self-care behavior. Kaohsiung J Med 
Sci. 2007;23(4):183-190. doi:10.1016/S1607-551X(09)70395-X 
4.  
Wesselmann U. Neurogenic inflammation and chronic pelvic pain. World J Urol. 
2001;19(3):180-185. 
5.  
Rudick CN, Berry RE, Johnson JR, et al. Uropathogenic Escherichia coli induces chronic 
pelvic pain. Infect Immun. 2011;79(2):628-635. doi:10.1128/IAI.00910-10 


N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
11 
6.  
Winnard KP, Dmitrieva N, Berkley KJ. Cross-organ interactions between reproductive, 
gastrointestinal, and urinary tracts: modulation by estrous stage and involvement of the 
hypogastric nerve. Am J Physiol Regul Integr Comp Physiol. 2006;291(6):R1592-1601. 
doi:10.1152/ajpregu.00455.2006 
7.  
Tu F, Epstein A, Pozolo K, Sexton D, Melnyk A, Hellman K. A  Non-Invasive Bladder 
Sensory Test Supports a Role for Dysmenorrhea Increasing Bladder Noxious 
Mechanosensitivity. Clin J Pain. in press. 
8.  
Westling AM, Tu F, Griffith JW, Hellman KM. The association of dysmenorrhea with 
noncyclic pelvic pain accounting for psychological factors. Am J Obstet Gynecol. August 2013. 
doi:10.1016/j.ajog.2013.08.020 
9.  
Vincent K, Warnaby C, Stagg CJ, Moore J, Kennedy S, Tracey I. Dysmenorrhoea is associated 
with central changes in otherwise healthy women. Pain. 2011;152(9):1966-1975. 
doi:10.1016/j.pain.2011.03.029 
10.  Costantini R, Affaitati G, Wesselmann U, Czakanski P, Giamberardino MA. Visceral pain as a 
triggering factor for fibromyalgia symptoms in comorbid patients. Pain. 2017;158(10):1925-
1937. doi:10.1097/j.pain.0000000000000992 
11.  Tu C-H, Niddam DM, Chao H-T, et al. Abnormal cerebral metabolism during menstrual pain 
in primary dysmenorrhea. NeuroImage. 2009;47(1):28-35. doi:10.1016/j.neuroimage.2009.03.080 
12.  Clemens JQ, Link CL, Eggers PW, et al. Prevalence of painful bladder symptoms and effect on 
quality of life in black, Hispanic and white men and women. J Urol. 2007;177(4):1390-1394. 
doi:10.1016/j.juro.2006.11.084 
13.  Nickel JC, Herschorn S, Whitmore KE, et al. Pentosan polysulfate sodium for treatment of 
interstitial cystitis/bladder pain syndrome: insights from a randomized, double-blind, placebo 
controlled study. J Urol. 2015;193(3):857-862. doi:10.1016/j.juro.2014.09.036 
14.  Foster HE, Hanno PM, Nickel JC, et al. Effect of amitriptyline on symptoms in treatment 
naïve patients with interstitial cystitis/painful bladder syndrome. J Urol. 2010;183(5):1853-1858. 
doi:10.1016/j.juro.2009.12.106 
15.  Glemain P, Rivière C, Lenormand L, Karam G, Bouchot O, Buzelin J-M. Prolonged 
hydrodistention of the bladder for symptomatic treatment of interstitial cystitis: efficacy at 6 
months and 1 year. Eur Urol. 2002;41(1):79-84. 
16.  Nickel JC, Shoskes D, Irvine-Bird K. Clinical phenotyping of women with interstitial 
cystitis/painful bladder syndrome: a key to classification and potentially improved 
management. J Urol. 2009;182(1):155-160. doi:10.1016/j.juro.2009.02.122 
17.  Giamberardino MA, Costantini R, Affaitati G, et al. Viscero-visceral hyperalgesia: 
characterization in different clinical models. Pain. 2010;151(2):307-322. 
doi:10.1016/j.pain.2010.06.023 


N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
12 
18.  Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): 
its relevance for acute and chronic pain states. Curr Opin Anesthesiol. 2010;23(5):611–615. 
19.  Harte SE, Ichesco E, Hampson JP, et al. Pharmacologic attenuation of cross-modal sensory 
augmentation within the chronic pain insula. Pain. 2016;157(9):1933-1945. 
doi:10.1097/j.pain.0000000000000593 
20.  Cella D, Yount S, Rothrock N, et al. The Patient-Reported Outcomes Measurement 
Information System (PROMIS): progress of an NIH Roadmap cooperative group during its 
first two years. Med Care. 2007;45(5 Suppl 1):S3-S11. doi:10.1097/01.mlr.0000258615.42478.55 
21.  O’Leary MP, Sant GR, Fowler FJ Jr, Whitmore KE, Spolarich-Kroll J. The interstitial cystitis 
symptom index and problem index. Urology. 1997;49(5A Suppl):58-63. 
22.  Tripp DA, Nickel JC, Fitzgerald MP, Mayer R, Stechyson N, Hsieh A. Sexual functioning, 
catastrophizing, depression, and pain, as predictors of quality of life in women with interstitial 
cystitis/painful bladder syndrome. Urology. 2009;73(5):987-992. 
doi:10.1016/j.urology.2008.11.049 
23.  Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30(2):191-197. 
24.  Sullivan MJL, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and validation. 
Psychol Assess. 1995;7(4):524-532. doi:10.1037/1040-3590.7.4.524 
25.  Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Müller-Lissner SA. 
Functional bowel disorders and functional abdominal pain. Gut. 1999;45 Suppl 2:II43-47. 
26.  Clemens JQ, Calhoun EA, Litwin MS, 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):983-987, quiz 987.e1-3. doi:10.1016/j.urology.2009.06.078 
27.  Tu FF, Fitzgerald CM, Kuiken T, Farrell T, Harden RN. Vaginal pressure-pain thresholds: 
initial validation and reliability assessment in healthy women. Clin J Pain. 2008;24(1):45-50. 
doi:10.1097/AJP.0b013e318156db13 
28.  Tu FF, Fitzgerald CM, Kuiken T, Farrell T, Harden RN. Comparative measurement of pelvic 
floor pain sensitivity in chronic pelvic pain. Obstet Gynecol. 2007;110(6):1244-1248. 
doi:10.1097/01.AOG.0000289228.23903.cc 
29.  Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria 
for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis 
Rheum. 1990;33(2):160-172. 
30.  Lee YC, Lu B, Edwards RR, et al. The role of sleep problems in central pain processing in 
rheumatoid arthritis. Arthritis Rheum. 2013;65(1):59-68. doi:10.1002/art.37733 
31.  Hellman K, Mason P. Opioids disrupt pro-nociceptive modulation mediated by raphe magnus. 
J Neurosci. In press. 


N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
13 
32.  Hellman KM, Brink TS, Mason P. Activity of murine raphe magnus cells predicts tachypnea 
and on-going nociceptive responsiveness. J Neurophysiol. 2007;98(6):3121-3133. 
doi:10.1152/jn.00904.2007 
33.  Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. 
Neuropsychologia. 1971;9(1):97-113. 
34.  Hollins M, Harper D, Gallagher S, et al. Perceived intensity and unpleasantness of cutaneous 
and auditory stimuli: An evaluation of the generalized hypervigilance hypothesis. PAIN. 
2009;141(3):215-221. doi:10.1016/j.pain.2008.10.003 
35.  Dmitrovic R, Kunselman AR, Legro RS. Continuous compared with cyclic oral contraceptives 
for the treatment of primary dysmenorrhea: a randomized controlled trial. Obstet Gynecol. 
2012;119(6):1143-1150. doi:10.1097/AOG.0b013e318257217a 
 
 
 
 
 
 

ICF_001.pdf: 
 
EH18-128 
EXAMINING THE ROLE 
OF IMPROVED NSAID 
MANAGEMENT IN 
TREATING 
DYSMENORRHEA AND 
BLADDER PAIN 
NCT03697720 
 
 
 
MAY 31, 2018 
WWW.CUREPERIODPAIN.ORG 
      


 
EH18-128 
Page 1/12 
Consent Version 2 dtd 5/4/18 
Consent valid through 3/1/2019 
 
CONSENT FORM 
 
Examining the Role of Improved NSAID Management in Treating Dysmenorrhea 
 
Principal Investigator: Frank Tu, MD MPH 
Principal Investigator telephone number: 847-570-2521   
Sponsor: NorthShore University HealthSystem 
 
EXPLANATION OF STUDY: 
 
Introduction:  You are being asked to volunteer for this clinical research study because you 
have painful periods. 
 
This Consent Form gives information about the study that you can talk about with your doctor 
and/or family.  You are being given this information to help your decision.  If you have any 
questions, you can ask the study doctor or staff. 
 
Why is this Study Being Done?  
 
Naproxen, a common pain medication known as a non-steroidal anti-inflammatory drug 
(NSAID), is approved by the Food and Drug Administration for the treatment of pain including 
menstrual cramps.  Not all women get relief of menstrual pain adequately from naproxen 
however, and this study will look at a women’s individual sensory sensitivity measures to see 
if those might predict how well naproxen works.   
 
This study will include a total of 30 subjects.  Of those subjects, all will be from NorthShore 
University HealthSystem (NorthShore).   
 
What Will Happen During the Study? 
 
If you decide to participate in this research study, you will be asked to sign this Consent Form.   
 
Screening Visit: You will be asked to sign this consent form before any study procedures are 
performed. This visit takes approximately 2- 2 ½ hours. During the screening visit, the following 
will be performed:  
 
Questionnaires: The questionnaires in this study ask about any past and current pain 
symptoms and any medication you have taken for pain.  We will also ask about your medical 
history, contraception history, and sexual functioning. There are also questions about your 
mental well-being. Some or all of these will be administered on the computer. You may 
choose not to answer questions that make you uncomfortable. We may also ask you to sign 
a records release to obtain records that are related to prior testing or treatments for any 
pelvic pain issues from other doctors. 
 
Rapid Bladder Sensation Test: Participants will be asked to take the rapid bladder sensation 
test, which involves drinking water and rating how your bladder feels throughout the visit.  
 
Urine sample: we will collect your urine to store for analysis (e.g., proteins, hormones).  


 
 
    
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Pelvic Floor Exam: If you have never had a gynecological exam before, a basic 
gynecological exam of the pelvic floor may be performed to introduce you to the internal 
testing procedures that will be performed at the assessment visit.  
 
Creatinine Test: A creatinine test will be conducted to check for kidney function via blood 
draw. 
 
After Screening Visit :  
 
Daily Pain Diaries: After the screening visit, you will be asked to complete daily diaries to 
assess your pelvic pain, days you experience menstrual bleeding, and any use of painkillers. 
These will be completed online using any device connected to the internet. You will be given 
instructions during your screening visit.   
 
If you previously participated in the CRAMPP study within the past 12 months:  You 
will be provided the study medication at the screening visit.  You will be asked to start 
the study medication on your second menstrual cycle after the screen visit 
 
 
If you have NOT participated in the CRAMPP study within the past 12 months: Contact 
Study Staff to schedule Baseline Visit: It is extremely important that you contact study 
staff on the day you start your first menstrual flow after the screen visit in order to 
schedule your baseline visit. In some cases, staff may advise you wait more than one 
menstrual cycle in which case we will advise accordingly.  
 
Baseline Visit: will be performed after one to four menstrual cycles and during your luteal 
Phase, which in most women takes place about 15-21days after you start your period (after 
ovulation and before your next menstrual period). This visit will take approximately 4-5 hours. 
The following will be performed:  
 
Bladder Testing: After a bathroom break, an abdominal ultrasound will be performed by a 
trained clinician to measure your bladder volume. You will be asked to lie down on an exam 
table and have your pants removed slightly below your hip bones. A small amount of gel, 
safe for use on the skin, will be applied and removed after the scan is completed. The 
ultrasound wand against your abdomen may cause some pressure symptoms, although it 
should not be uncomfortable.  
 
After drinking 20 ounces of water, you will be asked to report one by one a) first sensation 
of need to urinate b) first urge and c) maximum bladder capacity (defined as “when riding in 
a car, you would urinate on the side of the road in bumper-to-bumper traffic”). At each of 
these time points, the clinician will perform an ultrasound. Additionally, every fifteen minutes, 
you will rate your bladder urgency and bladder pain. After you reach maximum bladder 
capacity, you will be asked to go to the bathroom and urinate in a container. You may be 
asked to drink more water if you do not reach maximum tolerance after 45 or 60 minutes. 
 
 
Pressure Tests 
 
Pressure/Pain Threshold (PPT) Test: A doctor or nurse trained in this procedure will perform 
this test.  This test uses two specially designed pressure measuring devices (algometers) to 
measure the amount of pressure at which you first report pain. At the point which you begin 


 
 
    
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Consent Version 1 
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to feel pain, we will stop applying pressure. You will be asked to rate the intensity of pain on 
a 0-10 scale. The algometers are investigational and have not been approved by the Food 
and Drug Administration (FDA).  We will test the pressure at which you first report pain at 
several standard spots of your body using these algometers. We will measure at your right 
shoulder, right hip, right knee, and forehead using a handheld algometer. The tip of the 
handheld external algometer is made of rubber and about the same size as a pencil eraser. 
Then you will be helped into the stirrups and asked to lie down on the exam table.  Using a 
small amount of lubricant, the clinician will use an internal vaginal algometer to press on the 
muscles near the entrance of your vagina. The vaginal algometer fits on the pad of the 
examiner’s index finger under a glove.  
 
Cold Water Test (also known as conditioned pain modulation (CPM) test): For this test, you 
will be asked to put your hand up to your wrist in a bucket of cold water (0-6° C) for about 
20 seconds. The pressure measurement test will be performed on your left knee and left 
shoulder before you put your hand in cold water, after your hand is in the cold water for 20 
seconds and five and ten minutes after you remove your hand from the cold water. After 
each of the pressure measurement tests, we will ask you to rate your pain on a 0-10 scale. 
 
Repeated Pressure Measurement Test-Knee (also known as temporal summation): Using 
the handheld algometer, we will press on your knee up to ten times. You will be asked to 
rate how much pain you feel on a 0-10 scale after each press. 
 
Sensory Testing: We will ask you to watch brief videos of colorful moving patterns and listen to 
sounds using headphones and tell us what you think of them. 
 
Blood Draw: A trained doctor, nurse, or phlebotomist will collect 12 teaspoons (60 ml) of blood 
at the baseline visit, menses visit, and follow-up visit (total up to 36 teaspoons/180 ml) to 
examine factors (hormones, genes-if you give consent, proteins) that affect women’s health 
conditions. If you give your permission at the bottom of this consent form, we may also store 
your blood for future research in our lab on women’s health conditions beyond the current 
study. 
 
Monitoring During Visit: During each assessment visit, electroencephalography (EEG), 
electromyography (EMG), electrocardiogram (ECG) and respiratory belt devices will be used.  
An EEG test allows us to measure changes in your brain’s electrical activity, using an array of 
measuring wires placed under a cap that will fit over your scalp. An EMG test measures the 
electrical activity produced by your skeletal muscles, using stick-on wires applied to the skin 
overlying the muscle. An ECG is a test that measures the electrical activity of your heart by 
attaching stick-on wires to your chest and records your heart rate.  The respiratory belt goes 
around your ribcage and monitors your rate of breathing. 
 
 
After Baseline Visit (or After Screen Visit for 12 month CRAMPP participants):  You will 
be provided study medication at the end of your visit. You will be instructed to take one 500 
mg pill in the morning and one again 12 hours later the day before your anticipated first day 
of your period. You will continue to take a pill twice daily for the first 3 days of your menstrual 
period. If you still have menstrual pain the following day, you will be instructed to continue 
taking 2 pills a day (one in the morning and one 12 hours later) until your pain stops. You will 
be asked to continue taking the study medication before and during your period for 6-8 
months. In the event that you have been taking the study medication for 3 consecutive days 


 
 
    
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Consent Version 1 
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and do not have any symptoms of starting your menses, you will be instructed to stop taking 
the study medication. We will instruct you to start taking it again as soon as you start your 
period.   
 
 
You will be allowed to take acetaminophen (also known as Tylenol, according to directions 
listed on the package) as needed to manage any additional unrelieved pain. Do not take any 
other form of NSAID while you are taking the study medication. 
 
Monthly Menstrual Diaries: Starting approximately one day before the start of your menses 
and up until you have stopped bleeding, you will be asked to complete daily symptom diaries. 
These are to assess your period pain and to log your study medication usage. They can be 
completed online using any device connected to the internet. Please complete the diary close 
to the end of the day to have the most accurate representation of that day. 
 
Blood draw/Urine Collections: You will be asked to come in for a blood draw during your 
menses to measure hormones and the absorption of Naproxen. This can be done during any 
month after the baseline visit, but before the follow-up visit, on day 2 or later of your menses. 
You will be asked to collect a urine sample, in the collection containers we will provide you with, 
on the third day of your menstrual cycle for each period. Urine samples can be frozen and 
brought in at study visits or at a time agreed upon the participant and research staff.  
 
Follow-Up Visit (month 6-8) for all participants: You will be asked to come back in for a 
follow-up visit after 6-8 menses. This visit takes about 4 ½ hours. You will be asked to repeat 
the same tasks as the baseline visit (questionnaires, bladder test, pressure tests, blood draw, 
and sensory test).  
 
Does this study involve Genetic testing?  
Your blood may be used for genetic testing if you give permission at the bottom of this consent 
form. You may still participate in this study even if you do not give permission for genetic testing 
of your blood. Because there are no presently established genetic markers for pelvic pain, you 
will not be told the results of the testing. The scientists studying the DNA genetic information 
at NorthShore will never receive any information that could link your name to your clinical DNA 
data. Likewise, scientists at NorthShore will never receive any DNA data that could be linked 
to your name. DNA data will be kept under lock and key, and will be accessible only to 
authorized personnel.  
 
A federal law called the Genetic Information Nondiscrimination Act (GINA) generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information.  
 
This law will generally protect you in the following ways: 
  
• Health insurance companies and group health plans may not request your genetic 
information from this research.  
• If health insurance companies and group health plans do somehow receive your genetic 
information from this research, they may not use it to make decisions about your eligibility 
or premiums.  
 


 
 
    
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Employers with 15 or more employees may not use your genetic information from this research 
when making a decision to hire, promote or fire you or when setting the terms of your 
employment. 


 
 
    
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How Long Will I Be In the Study?  
 
You will be in this research study for approximately 32 weeks. The figure below outlines 
procedures across the 6-8 months and what to expect at each visit. 
 
 
 
Screen 
Visit  
Baseline 
Visit* 
Follow-Up Visit 
Schedule of 
Events 
Time to complete 
 
 
 
Consent 
30 min 
X 
 
 
Questionnaires 
30 min 
X 
X 
X 
Pelvic floor exam 
10 min 
X** 
 
 
Rapid Bladder Test 
 
X 
 
 
Creatinine Test 
10 min 
X 
 
 
Bladder test 
120 min 
 
X 
X 
Pressure tests 
45 min 
 
X 
X 
EEG 
60 min 
 
X 
X 
Urine Samples 
10 min 
 
 
Urine samples on 
the third day of 
your menses 
Blood draw 
10 min 
 
X 
Done any time 
and during your 
menses  
Participant incentive  
X 
X 
X 
Menstrual Diaries, 
Home checks  
Variable  
X 
 
Done once a 
month for 6-8 
months during 
your menstrual 
cycle 
*Baseline Visit is only completed if you have not completed an assessment visit in EH13-094 (CRAMPP 
Study) in the past 12 months.  
**Pelvic Floor Exam is only for those participants who have never had a gynecological exam before 
 
Final Visit/Early Termination Procedures: At the Follow-Up Visit, you will be asked to return 
any unused study medication. 
 
What Other Choices Do I Have? 
 
You do not have to take part in this study for treatment of your painful periods.  You may use 
naproxen even if you decide to not participate in the study. Other commonly used treatments 
include oral contraceptives, other pain relievers, heat pads, herbal teas, etc.  You may also 
choose no further treatment.  Your doctor can explain your disease/condition and the good and 
bad things about each of the options.  You are free to talk about your disease/condition and 
your health with your doctor. 
 


 
 
    
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Are There Benefits to Taking Part in the Study? 
 
This study may allow doctors to learn more about why naproxen works better for some women 
in the treatment of painful periods and whether that may explain why some women with period 
pain develop other pelvic pain problems.   
 
Taking part in this study may or may not make your health better. However, there is no proof 
of this.  There is the possibility that your health may become worse while you are in this study. 
 
What Side Effects or Risks Can I Expect? 
 
The drug used in this study might have undesired effects.  However, doctors do not know all 
the effects that may happen.  Side effects may be mild or very serious. Sometimes they can 
be life-threatening.  Some effects may go away soon after you stop taking the study drug.  The 
effects can be serious, long lasting or may never go away.  The study doctor will watch you 
carefully and will provide treatment for any effects.  This may include taking you off the study 
or giving you other medications. 
 
Side effects of naproxen: According to the FDA, short term use of naproxen, especially at low 
dosages, does not appear to be associated with increased risk of serious cardiovascular 
events. Less than 1 in 10 using naproxen experience side effects such as upset stomach, 
nausea, heartburn, headache, drowsiness, or dizziness. In the event these side effects persist, 
we will help you find a follow-up physician.   
 
Questionnaires: Some of the questions you will be asked may be upsetting to you since they 
reflect issues that are difficult to talk about.  If you become upset after answering the questions, 
you will have the option of talking to a trained mental health professional.  If at any time you 
are concerned that you are in immediate danger or harm, you may also call (847) 570-2500 to 
talk with a crisis counselor at NorthShore. 
 
Cessation of Painkillers: Subjects are asked to refrain from taking over-the-counter NSAIDs 
(such as naproxen, ibuprofen) or short-acting opioids (ex. hydrocodone or oxycodone) during 
their menses for the duration of the study. The most common risk associated with this is 
inadequate pain relief.  
 
Pressure Tests: Pressure testing may cause temporary muscle soreness. The discomfort is 
expected to be limited to the testing site and self-limited in time (we will stop applying pressure 
after you report the first sensation of pain). Over-the-counter pain medications will be 
recommended after evaluation as needed.  Occasionally, pain or soreness caused by the 
measurements may be delayed or of longer duration; it could also be severe enough to require 
additional pain medications. 
 
Blood Draws: Possible side effects from blood drawing include faintness, inflammation 
(redness and/or warmth) of the vein, pain, bruising, bleeding at the site of puncture, or (rarely) 
infection. 
 
Bladder Testing: Drinking the amount of water needed to complete the bladder testing may 
cause mild abdominal discomfort in certain individuals, but it is not dangerous.  The discomfort 
is expected to be temporary, but may need to be treated in the usual way a woman does when 
she has worsened pain.  
 


 
 
    
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EEG, EMG, and ECG recording: The EEG cap and/or ECG/EMG electrodes may also be 
slightly uncomfortable. We can adjust the position of the EEG, EMG and ECG to make them 
more comfortable. Our equipment is certified to prevent any risk of electric shock. 
 
Ultrasound: Ultrasound of the abdomen is safe. In rare cases, you may be allergic to the 
transmission gel and develop a mild rash of the skin.  The gel will be washed off when the scan 
is complete, so the degree of irritation should be limited even in that situation.  However, you 
may need to seek additional treatment for relief if a rash or skin problem were to develop. 
 
Sensory Testing: The sounds and videos of moving patterns involve flashing lights and may be 
annoying or elicit a headache or nausea in sensitive individuals. Participants may stop at any 
time.  
 
Reproductive Risks:  
 
NSAIDs do not pose significant risks to a developing fetus, but in some studies have been 
associated with a potentially higher risk of miscarriage.  A woman in this study, using NSAIDs 
for presumed menstrual pain, is at very low risk of actually exposing an early pregnancy to 
NSAIDs. 
 
You should use effective birth control methods if you or your partner can become pregnant and 
you wish to be in this study.  If you become pregnant during this study, you should notify the 
study doctor right away. If you become pregnant you may have to go off the study.  
 
Will My Medical Information Be Kept Private? 
 
Information from this study could be published in journals or presented at meetings. If either of 
these happens, your name and other personal information will not be used.  The researchers 
running this study will try to keep your personal information private.  Your study related 
information may be looked at by other doctors in this study]. Your research file can also be 
looked at by the NorthShore Institutional Review Board, other medical personnel at NorthShore 
who are involved in your care, or by the Food and Drug Administration (FDA).  
 
Protected Health Information (PHI) 
During this research, identifiable information about your health will be collected. In the rest of 
this section, we refer to this information simply as “protected health information (PHI).” In 
general, under federal law, PHI is private. However, there are exceptions to this rule, and you 
should know who may be able to see, use and share your PHI for research and why they may 
need to do so.  
 
Your PHI will only be used for the purposes described in this Consent Form. Your authorization 
for activities described in this section does not have an expiration date.  
 
What protected health information (PHI) will be used?  
• Past, present and future medical records, including information housed in the Electronic 
Medical Record called “Epic,” which is maintained by NorthShore University 
HealthSystem 
• Information about research procedures, including research office visits, medical tests, 
procedures, interviews and questionnaires 


 
 
    
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Who may see, use and share my PHI and why may they need to do so?  
• NorthShore research staff involved in this study 
• Non-research staff within NorthShore who need this information to do their jobs (such as 
for treatment, payment (billing) or health care operations) 
• The NorthShore IRB board that oversees the research and the NorthShore research 
quality improvement program 
• Federal and state agencies (such as the Food and Drug Administration, the Department 
of Health and Human Services, the National Institutes of Health and other US [] 
government bodies that oversee or review research) 
Some people or groups who get your PHI might not have to follow the same privacy rules that 
we follow. We share your PHI only when we must and we ask anyone who receives it from us 
to protect your privacy. However, if your information is shared outside NorthShore, we cannot 
promise that it will remain private. 
 
Do I have the right to withdraw permission for the use of my PHI? 
You have the right to withdraw your permission for us to use or share your PHI for this research 
study. If you want to withdraw your permission, you must notify the person in charge of this 
research study in writing.  
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others. 
 
Once permission is withdrawn, you cannot continue to take part in this study. However, you will 
not be penalized or lose any benefits to which you are entitled. 
 
Do I have access to my health information? 
You have the right to see and get a copy of your PHI that is used or shared for treatment or for 
payment. To ask for this information, please contact the person in charge of this research study. 
However, to protect the study, you will not be able to see some of the study information until 
after the study is completed. The researchers are not required to release to you research 
information that is not part of your medical record. 
 
You have the right not to sign this form that allows us to use and share your PHI for research; 
however, if you do not sign it, you cannot take part in this research study. 
 


 
 
    
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Consent Version 1 
Consent valid through 3/1/2019 
 
Will I Be Paid for Participating? 
 
You will be paid a sum of $255-$405 for being in this research study.  You will be paid at the 
screen visit, blood draw, urine samples, and follow-up visit.  You will be paid by check or, if you 
are an employee, paid through payroll. For payments under $20, you may be given a gift card 
instead depending on availability. If you do not complete the research study, you will only be 
paid for the length of time that you were a subject. You will be paid at the time you withdraw 
from the study. 
Screen Visit: $25 
Baseline Visit (for those who have not completed an assessment with the CRAMPP study in 
the past 12 months): $150 
Urine samples: $60 ($10/each)  
Blood draw Visit: $20 
Follow-Up Visit: $150 
 
Will There Be Additional Costs? 
 
There is expected to be no additional cost to you from being in this research study.  You will 
still be responsible for all costs that you would normally incur as part of routine care.   
 
Study medication (naproxen) will be provided to you at no cost. We will also provide you with 
parking validation. 
 
What If I Am Injured During the Study? 
 
If you become hurt or sick because of being in this research study, you can get medical 
treatment at NorthShore.  You or your health insurance plan will be billed. No money has been 
set aside to pay the costs of this treatment.  You can ask for more information from the 
Research Institute of NorthShore. 
 
Health insurance plans (including Medicare) may or may not cover costs of research-related 
injury or illness.  You should check with your insurance company before deciding to participate 
in this research study.  Costs not covered by insurance could be substantial. 
 
Can I Withdraw From the Study? 
 
Your participation in this research study is voluntary.  If you decide not to be in this study, you 
can still get medical care as usual.  If you decide to participate now, you may leave the study 
at any time.  No matter what decision you make, there will be no penalty to you and you will 
not lose any of your regular benefits. 
 
Your doctor/the sponsor may stop this study or take you out of the study without your 
permission.  If this happens, it might be the result of a bad reaction you have. There could also 
be new information that your doctor learns about the safety or helpfulness of this treatment. 
 


 
 
    
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Consent Version 1 
Consent valid through 3/1/2019 
 
What Are My Rights as a Research Subject? 
 
You may get more information about your rights from the Chairperson of the Institutional 
Review Board (IRB). You can also call the IRB Coordinators at 224/364-7100.  These are the 
people you should contact about any problems or research-related injuries that happen during 
the research study. 
 
By participating in this research study you do not waive any rights to which you would normally 
be entitled. 
 
Will I Be Informed of New Information About the Study? 
 
Any significant new information that may affect your participation will be given to you as soon 
as it becomes available. 
 
Who Can I Call With Questions? 
 
The study doctor and staff will answer any questions you have. If you have additional questions 
at any time during the study, you may contact the Principal Investigator, Frank Tu, MD, MPH, 
at telephone: 8475702521.   
 
Permission for Genetic Testing  
May we use your blood for genetic testing? You may still participate in this study even if you 
do not give permission for genetic testing of your blood.  
□ Yes     □ No 
 
Permission for Future Storage of Blood and Urine Samples 
May we store your blood and urine for additional testing in our lab on women’s health conditions 
after the study is completed? You may still participate in this study even if you do not give 
permission for future storage of blood and urine samples. If you do not give future permission, 
your blood and urine samples will be destroyed when the study is completed. 
□ Yes     □ No 
 
Permission to Link Your Information Between Studies 
May we link your data from the present study with data from any future studies you may 
participate in within our lab?  
□ Yes     □ No 
 
 
 
 
 
******************************************************************************** 
 
 


 
 
    
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Consent Version 1 
Consent valid through 3/1/2019 
 
INDIVIDUAL PROVIDING EXPLANATION: 
 
The procedures and/or investigations described in the above paragraphs have been explained 
to you by:  
 
Name of Person Explaining Study 
(Please PRINT) 
 
Signature of Person Explaining Study 
 
Date Study Was Explained 
 
 
CONSENT TO PARTICIPATE: 
 
I understand that the Principal Investigator and study staff will supervise the study. I have read 
this consent form or have had it read to me.  I understand what will happen if I enroll in this 
research study. I understand the possible benefits and risks of the study. I have been told about 
all of my treatment options. I give permission for the research study procedures described in 
this consent form. 
 
I have reviewed this information with the study doctor and/or staff. I have had enough time to 
talk about all of my questions and concerns.  I willingly consent to be a part of this study.  I will 
receive a signed and dated copy of this Consent Form. 
 
Subject’s Name (Please PRINT) 
 
Subject's  Signature 
 
Date Subject Signed