Clinical trial NCT02519231
Conditions: Menorrhagia
Keywords: IUD naproxen bleeding
Sponsor: University of Washington
Start date: 2016-02-01; Completion date: 2017-11-01
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Studies indicate that bleeding irregularities and dysmenorrhea are common reasons for copper IUD method discontinuation. Some evidence suggests that non-steroidal anti-inflammatory medications (NSAIDs) can help improve bleeding during Cu-IUD use. However, these studies did not examine NSAID use with the TCu380A specifically, nor did they evaluate readily available NSAIDs such as over-the-counter naproxen. For this reason, the investigators propose a pilot trial in which new TCu380A users complaining of heavy or prolonged menstrual bleeding or spotting after 1 month of use are randomized to naproxen or placebo to be taken the first 7 days of menstruation for three consecutive cycles, and then observed for one cycle without treatment.

Detailed description:
The Copper IUD (Cu-IUD) is the most widely used IUD in the world, and its use in the United States (US) is on the rise. The Cu-IUD is considered one of the most effective contraception methods, being as effective as permanent sterilization but having the convenience of being reversible should a woman decide to conceive.2 The Copper 380A (TCu380A) is the only Cu-IUD available in the US; of all Cu-IUDs, the TCu380A is considered the most effective. Despite its increasing popularity in the US, studies indicate that bleeding irregularities and dysmenorrhea are common reasons for method discontinuation. Some evidence suggests that non-steroidal anti-inflammatory medications (NSAIDs) can help improve bleeding during Cu-IUD use. However, these studies did not examine NSAID use with the TCu380A specifically, nor did they evaluate readily available NSAIDs such as over-the-counter naproxen. For this reason, the investigators propose a pilot trial in which new TCu380A users complaining of heavy or prolonged menstrual bleeding or spotting after 1 month of use are randomized to naproxen or placebo to be taken the first 7 days of menstruation for three consecutive cycles, and then observed for one cycle without treatment. The number of bleeding/spotting days will be compared using Student t-test. In addition to assessing how well naproxen reduces incidence and amount of bleeding, the investigators will also assess the use of naproxen and TCu380A on quality of life, sexual function, method satisfaction, menstrual pain, and adverse events. By measuring these variables, the investigators will assess both positive and negative consequences of TCu380A use, ensuring that harm does not outweigh benefits.

Arms: arm 1: This study arm includes naproxen as potential treatment for heavy or prolonged bleeding or dysmenorrhea may provide useful preliminary data for a larger, adequately powered placebo-controlled comparative trial testing additional promising treatments, such as tranexamic acid. arm 2: This study arm includes capsules that are exactly like the active treatment medication (naproxen), but there is no active treatment medication in these tablets.
Interventions: intervention 1: Naproxen intervention 2: Placebo
Intervention descriptions: intervention 1: Naproxen 440mg 1x pid intervention 2: Placebo tablet 440mg 1x pid

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Title: A multi-center, double-blinded, randomized, phase IV 6-month pilot study to 
compare bleeding patterns, satisfaction, and quality of life among new Copper 380A IUD 
users treated with naproxen sodium (440 mg twice daily) versus placebo  
 
 
Short title: Copper IUD Treatment Observation Study (CITROS) 
 
 
Study Protocol 
Trial registration: ClinicalTrials.gov: NCT02519231  
Version 9, 7/1/16 
 
 
 
 
 
Principal Investigator: Emily Godfrey, MD, MPH 
Department of Family Medicine 
University of Washington 
 
 
 
 
 
 
 
 
 
 
 
 
 


Note: this protocol was written in accordance with SPIRIT Guidelines 2013.1  
1.0. Summary 
The Copper IUD (Cu-IUD) is the most widely used IUD in the world, and its use in the United 
States (US) is on the rise. The Cu-IUD is considered one of the most effective contraception 
methods, being as effective as permanent sterilization but having the convenience of being 
reversible should a woman decide to conceive.2 The Copper 380A (TCu380A) is the only Cu-
IUD available in the US; of all Cu-IUDs, the TCu380A is considered the most effective. Despite 
its increasing popularity in the US, studies indicate that bleeding irregularities and 
dysmenorrhea are common reasons for method discontinuation. Some evidence suggests that 
non-steroidal anti-inflammatory medications (NSAIDs) can help improve bleeding during Cu-IUD 
use. However, these studies did not examine NSAID use with the TCu380A specifically, nor did 
they evaluate readily available NSAIDs such as over-the-counter naproxen. For this reason, we 
propose a pilot trial in which new TCu380A users complaining of heavy or prolonged menstrual 
bleeding or spotting after 1 month of use are randomized to naproxen or placebo to be taken the 
first 7 days of menstruation for three consecutive cycles, and then observed for one cycle 
without treatment. The number of bleeding/spotting days will be compared using Student t-test. 
In addition to assessing how well naproxen reduces incidence and amount of bleeding, we will 
also assess the use of naproxen and TCu380A on quality of life, sexual function, method 
satisfaction, menstrual pain, and adverse events. By measuring these variables, we will assess 
both positive and negative consequences of TCu380A use, ensuring that harm does not 
outweigh benefits.  
2.0. Background/Rationale 
Intrauterine devices (IUDs) are among the most widely used reversible contraceptive methods 
in the world.3 In the US, IUD use is on the rise, with more than 2 million women currently using 
the method.4 The IUD is considered one of the most effective methods (>99%); it is as effective 
as permanent sterilization but has the convenience of reversibility should a woman decide to 
conceive.2 Copper-containing IUDs (Cu-IUDs) were introduced into worldwide markets in the 
late 1960s and are available in a variety of types, most of which are named for their shape and 
amount of copper on the device. The Cu-IUD is considered non-hormonal, which is important 
especially for women with underlying medical conditions for which hormone-related 
contraceptives are contraindicated. Currently, the Copper 380A (TCu380A) is the sole Cu-IUD 
available in the US and is approved for use for 10 years, although effectiveness for up to 20 
years has been shown.5  
Despite its growth in popularity in the US, approximately 20% of women who have a TCu380A 
IUD inserted will discontinue the method within the first year of use. The most common reasons 
for Cu-IUD and TCu380A discontinuation are bleeding irregularities and dysmenorrhea.5-8 
TCu380A IUD users who report abnormal menstrual bleeding are 1.4 times more likely to 
prematurely discontinue their method than hormonal levonorgestrel IUD users.9  
Because of the commonality of perceived heavy or prolonged menstrual bleeding among Cu-
IUD users, a number of treatments have been studied. Few of these studies have included 
TCu380A. In a recent systematic review that evaluated 11 studies for acute treatment for Cu-
IUD users with underlying heavy or prolonged menstrual bleeding, none included TCu380A.10 
Among treatments, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely studied. 
Findings indicated that NSAIDs can reduce menstrual bleeding compared to baseline or 
placebo for a current heavy bleeding episode and may prevent heavy or prolonged menstrual 
bleeding.10 The applicability to US women of findings from this systematic review is limited, 
however, because most NSAIDs studied were either non-FDA-approved or available by 


prescription only. A study that includes an over-the-counter (OTC) NSAID medication, such as 
naproxen, as potential treatment for heavy or prolonged bleeding or spotting during TCu380A 
use could affect continuation among TCu380A users.  
2.1. NSAID Treatment among Cu-IUD Users 
NSAIDs are thought to help treat heavy and prolonged menstrual bleeding because they act as 
inhibitors of prostaglandin synthetase and decrease the endometrial prostaglandin release, 
thereby potentially reducing mean menstrual blood loss (MBL), even in the presence of Cu-
IUDs.11 A commonly used and readily available NSAID, such as naproxen, has never been 
evaluated for the treatment of heavy or prolonged menstruation during Cu-IUD use. Yet it has 
the potential to be a simple and accessible treatment for women who experience menstrual 
bleeding disturbances during TCu380A use because it currently is available over-the–counter 
(OTC) in the US. OTC naproxen sodium (Aleve) is often prescribed to patients between the 
ages of 12 and 65 for fever and minor aches. The approved dosage of Aleve is 220 mg (200 mg 
of naproxen and 20 mg of sodium). Patients are asked to take 220 mg (one tablet) every 8 to 12 
hours.  
A meta-analysis reviewed by the FDA that evaluated 8,404 patients, of which 4,138 had taken 
either naproxen (3,589 patients with doses 187.5-400 mg) or naproxen sodium (549 patients 
with doses 220-440 mg) found that OTC naproxen sodium was as safe as ibuprofen, 
acetaminophen, and placebo. The age of the patients ranged from 14 to 86 years. Across the 
48 studies, 83% of the patients reported no adverse effects. Among the patients that withdrew 
for adverse effects 0.62% were in the placebo group and 0.68% were in the naproxen/naproxen 
sodium group. The most commonly reported adverse effects included headache (6.4% placebo, 
4.8% naproxen/naproxen sodium), nausea (3.1% placebo, 3.4% naproxen/ naproxen sodium), 
and somnolence (1.9% placebo, 2.7% naproxen/naproxen sodium). This meta-analysis showed 
a low frequency of adverse events associated with OTC naproxen sodium when taken as 
directed.12 Between the years 1995 and 2000, there were no reports of a fatal overdose of 
naproxen/naproxen sodium, as reported by the American Association of Poison Control (AAPC). 
According to the most recent AAPC annual report (2012), naproxen had been mentioned in 
13,611 cases. Of these cases, only 11 had some major outcome due to the drug, and no deaths 
were reported. Safety profiles of both low-dose (220 mg) and high-dose (440 mg) naproxen 
sodium were not statistically significant.13 According to the FDA review of the safety and efficacy 
of naproxen sodium in the two meta-analyses conducted, there was no evidence of overall 
dose-related increase in adverse events.14  
A study that includes naproxen as potential treatment for heavy or prolonged bleeding or 
dysmenorrhea may provide useful preliminary data for a larger, adequately powered placebo-
controlled comparative trial testing additional promising treatments, such as tranexamic acid. 
We therefore are requesting funds to conduct a double-blind, randomized controlled pilot trial in 
which new TCu380A users who complain of increased menstrual flow 4 to 6 weeks after 
insertion are randomized to OTC (440 mg) naproxen or placebo. We will follow the participants 
for three treatment cycles and one cycle without treatment following the treatment cycles to 
compare number of bleeding and/or spotting days. A recent systematic review evaluating 
clinical outcomes in abnormal uterine bleeding trials recommended that additional outcomes 
other than reduction of bleeding by the treatment should include quality of life, pain related to 
bleeding, sexual health, patient satisfaction, additional treatments, and adverse events.15 By 
measuring these components, we assess both positive and negative consequences of 
TCu380A use, ensuring that harm does not outweigh benefits.  
 
 


3.0. Hypothesis 
TCu380A users who are randomized to the OTC (440 mg) naproxen group will have fewer 
bleeding and spotting days each month than users randomized to the placebo group.  
4.0. Study Objectives  
4.1. Primary Study Objective 
• 
To evaluate whether treatment during menstruation with OTC naproxen reduces excess 
bleeding and spotting in new TCu380A users complaining of increased menstrual flow or 
spotting.  
4.2. Secondary Study Objectives/End-Points 
• 
To assess feasibility of recruiting, enrolling, and maintaining new TCu380A users in a 
randomized, placebo-controlled clinical trial. 
• 
To describe the impact of TCu380A IUD use on satisfaction, menstruation, 
dysmenorrhea, sexual functioning, and quality of life (QOL) scores by treatment group.  
• 
To describe the safety of OTC naproxen compared to placebo.  
5.0. Trial Design 
The CITROS pilot study is a prospective, double-blind, two-arm randomized placebo-controlled, 
phase IV feasibility study to be conducted at several clinics in Seattle, WA, and Chicago, IL. The 
primary endpoint of this study is number of bleeding/spotting days over the 3-month (84-day) 
treatment period. Randomization will be performed as 4-block randomization with 1:1 allocation.  
6.0. Methods: Participants, Interventions, and Outcomes 
6.1. Study Setting  
This pilot trial will take place in two separate urban settings: the University of Washington in 
Seattle, WA, Stroger Hospital of Cook County in Chicago, IL. We chose these two settings to 
optimize the diversity in patient population and maximize our enrollment. Seattle is a large city, 
whose metro area makes up of approximately 600,000 residents. The average age of each 
resident is 36 years. The city is mostly White (70%), followed by Asian (14%) and African 
American (8%).16 The University of Washington enrolls more than 43,000 students annually. 
The average age on campus is 24 years, and the racial mix is primarily White (48%) and Asian 
(23%).17 The Hall Health, Roosevelt Women’s Health Clinic, and Northgate Family Medicine 
Center serve both UW students and Seattle residents. Hall Health, Roosevelt Women’s Health, 
and Northgate place approximately 300, 350, and 124 IUDs annually, respectively. It is 
estimated that at least 1/3 of these placements are TCu380A IUDs.  
Chicago, on the other hand, is a city of almost 3 million, and the median age is approximately 33 
years. Chicago city residents are largely White (45%), African American (33%), and Hispanic 
(29%; residents of Hispanic origin may be of any race).18 Stroger Hospital of Cook County in 
Chicago serves a primarily low-income, minority population. The Family Planning Clinic at 
Stroger Hospital is funded with Title X government funding and serves approximately 10,000 
patients annually. This clinic places approximately 20 TCu380A IUDs monthly. 
6.2. Eligibility Criteria  
Patients eligible for the trial must comply with all of the following at the first visit:: 
6.2.1. Inclusion Criteria – pre TCu380A Insertion 


• 
Age ≥ 18 and < 49 years. We are including a wide range of ages because women of 
all ages request TCu380A. While we recognize that some women approaching 
menopause (median age = 51.4 years) may have changes in their baseline 
menstruation, we trust that clinicians enrolling the patients into the study will ensure 
that these women meet all inclusion (i.e., regular cycles) and exclusion criteria (i.e., 
do not have diagnosis of menorrhagia).  
• 
Requesting to have TCu380A IUD inserted as contraceptive method. 
• 
English or Spanish speaking. 
• 
Regular menstrual cycles ranging 21-35 days apart (when not on hormonal 
contraception)  
• 
Generally healthy. 
• 
Willing to attend a 4- to 6-week follow-up visit and complete surveys.  
6.2.2. Inclusion Criteria – Post TCu380A Insertion at 4- to 6-Week Follow-Up Visit 
• 
Reports any change in volume and/or duration of blood loss or spotting at 4- to 6-
week follow-up compared to pre TCu380A IUD insertion. 
• 
Willing to avoid use of NSAIDs (except for study medication) for the remaining 
duration of the study.  
• 
Willing to comply with the study protocol by adhering to the medication regimen.  
• 
Has a cell phone that allows for texting.  
• 
Willing to keep a bleeding diary.  
6.2.3. Exclusion Criteria - Pre TCu380A Insertion 
• 
Known or suspected pregnancy.  
• 
Contraindications to NSAID use. This includes underlying heart failure, chronic renal 
disease, chronic liver disease, peptic ulcer disease, or history of upper 
gastrointestinal bleed, and allergy to NSAIDs.  
• 
Current regular use of a NSAID.  
• 
Unwilling to avoid use of NSAIDs (except for study medication) for the duration of the 
study.  
• 
Current diagnosis of menorrhagia, metrorrhagia, symptomatic uterine fibroids, or 
endometrial polyps.  
• 
Use of depot medroxyprogesterone acetate (DMPA) or levonorgestrel-releasing 
intrauterine device (LNG IUD) within the previous 3 months.  
• 
Postpartum in the past 4 weeks. The average day in which non-breastfeeding 
postpartum women ovulate is 25 days after birth, indicating that menstrual cycles can 
resume after the 4th postpartum week. Post medication abortion or surgical abortion 
does not count as post-partum- these patients are otherwise eligible for the study.  
• 
Currently breastfeeding.  
• 
Previous use of the TCu380A. 
6.2.4. Exclusion Criteria – Post TCu380A Insertion at 4- to 6-Week Follow-Up Visit 


• 
Lacks cell phone or has phone that does not allow texting.  
• 
Not willing to comply with completion of bleeding diary. 
• 
Not willing to comply with medication regimen. 
6.3. Interventions 
Eligible participants who meet inclusion criteria and informed consent will be asked to complete 
a baseline questionnaire regarding menstrual history, dysmenorrhea scale, quality of life, 
medical history, and demographics within 7 days of their TCu380A IUD insertion. Each woman 
will be asked to return for a follow-up research appointment within 4-6 weeks of their TCu380A 
insertion (Follow-Up Visit 1). All women will be asked to complete a brief health questionnaire to 
assess if the TCu380 is still in place. If a woman claims that the volume and/or duration of blood 
loss has changed in any way or if she mentions symptoms of spotting since TCu380A IUD 
insertion, she will be recruited into the randomized treatment arm of the study.  
Participants will be expected to take their assigned medication as directed for 7 days starting 
the first day of their menstrual period for a total of three consecutive cycles (cycle defined as 28 
days) following Follow-up Visit 1 (months 3, 4, and 5). We have chosen 7 consecutive days 
because this is consistent with current U.S. national contraceptive guidelines for NSAID 
treatment of unscheduled spotting or light bleeding or heavy or prolonged menstrual bleeding 
with Cu-IUD use.19 Also, by limiting the number of naproxen pills, we minimize potential harm of 
taking excessive or prolonged doses of NSAIDs, which can lead to adverse gastrointestinal and 
cardiovascular side effects.  
Participants will then be followed for one month after completion of the intervention (without 
treatment). During treatment and for the month following treatment, participants will complete a 
bleeding diary (described under Bleeding Diary heading below). The study team will make 
contact with each participant at the end of each study month to verify completion of bleeding 
diaries, assess the participants' perceptions of menstrual flow and for continued use of 
TCu380A. A second in-person follow-up visit will occur at approximately 6 months (Follow-up 
Visit 2) post device placement, in which participants will undergo assessment of satisfaction with 
TCu380A, menstruation, dysmenorrhea, quality of life, sexual functioning, and continuation.  
6.3.1. Treatment  
Women will take 1 capsule orally of 440 mg naproxen or placebo every 12 hours for heavy 
menstrual bleeding for 7 days, starting the first day of their menstrual period for 3 consecutive 
menstrual cycles. Women will be counseled that if they have pelvic pain, they may take regular 
strength OTC acetaminophen as directed on the bottle. The OTC 440 mg naproxen dose was 
chosen because of its accessibility to women in the US. Single-dose naproxen is dispensed as 
220 mg per tablet. This study, in essence, proposes a dose equivalent to two tablets of OTC 
naproxen every 12 hours.  
During this phase, we will track the number of people who called in or were approached by their 
provider, were screened, had CuT380A IUD inserted, and completed Follow-Up Visit 1. We will 
track the number of women who reported increase in blood loss or spotting at Follow-Up Visit 1 
and were enrolled and randomized to a treatment group. During treatment and one month 
following treatment, we will track the number of participants completing each scheduled follow-
up visit or phone call, and the number requiring interim visits.  
The study drug and placebo for the clinical sites at the University of Washington will be 
compounded by Kelley-Ross Pharmacy in Seattle. The study drug for Stroger Hospital will be 
compounded by Save-Rite Pharmacy & Compounding.  


6.4. Interventions: Modifications  
Gastrointestinal Effects: Ingestion of naproxen has the potential to cause gastrointestinal 
effects, including dyspepsia, peptic ulcer disease, and bleeding. Participants who experience 
dyspepsia can take OTC calcium carbonate (500 mg) 15 minutes prior to ingesting their 
treatment capsule. Should a participant experience an acute peptic ulcer or upper intestinal 
bleeding, we will withdraw the participant from the study and report this as an adverse event.  
Cardiovascular Effects: Naproxen, unlike other non-selective NSAIDs, does not appear to 
increase cardiovascular risks among otherwise healthy individuals.20 Although other non-
selective NSAIDs have been associated with increased risk of MI, stroke, heart failure, atrial 
fibrillation, and cardiovascular death for persons without underlying cardiovascular disease, the 
absolute risk is low (< 1-2 events per 1000 person-years).  
Hepatic Injury: Elevations of serum transaminases are associated with NSAID use; however, 
liver failure is quite rare.21 In a retrospective study of 625,000 patients, the incidence of acute 
liver injury was 3.7 per 100,000 NSAID users. NSAIDs that have shown a substantially greater 
risk of causing hepatic injury are sulindac and diclofenac, which will not be used in this study. 
Transaminase monitoring is thus not indicated for this study.  
Allergic Reactions: Allergic reactions have been observed in rare cases, presenting as urticarial, 
angioedema, generalized pruritus, tachycardia or bradycardia, hypotension, cardiac arrhythmia, 
nausea and vomiting, or light-headedness. If allergic reaction is suspected, we will withdraw the 
participant from trial. We will report this as an adverse event.  
6.5. Interventions: Adherence  
To help ensure adherence, we will ask participants for three contacts who will generally know 
the whereabouts of the participant enrolled. We will use texting to document daily bleeding. 
Monthly bleeding diaries will be assessed. Participants will be contacted by phone or email if 
any bleeding diaries are missing during a given a month. The participants will be asked to 
approve which method(s) of contact are acceptable and, for purposes of confidentiality, if it is 
acceptable for the research staff to identify themselves or state the reason for the call to another 
party, to leave a message, or to use a code name for a message. 
6.6. Interventions – Concomitant Care 
Women who experience pelvic pain during TCu380A IUD use may take regular strength OTC 
oral acetaminophen as directed on the bottle.  
6.7. Outcomes 
6.7.1. Primary Outcome Measures  
The primary outcome of this trial is the number of bleeding and/or spotting (B/S) days over the 
3-month (84-day) treatment period, based on diary data received from the participants. Based 
on standard criteria, bleeding will be defined as any bleeding that requires > 1 panty liner, 
tampon, or pad in a day. Spotting will be defined as minimal blood loss that requires one or no 
use of any protection including panty liners.22 Bleeding episodes will be defined as days of 
bleeding or spotting that are bounded by 2 days of no bleeding or spotting. In accordance with 
criteria described by Mishell et al., all bleeding in this study will be defined as unscheduled. One 
cycle will be defined as 28 days. 
 
Bleeding/spotting episodes will be classified by bleeding pattern: prolonged (i.e., length of a 
single B/S episode 14 days or more per 84-day reference period), frequent (more than 5 B/S 
episodes per 84-day reference period), infrequent (i.e., less than 3 B/S episodes per 84-day 


reference period) or amenorrhea (i.e., absence of B/S for at least 84 consecutive days). 
Subjects who report a 14-day episode and more than 5 episodes within a 84-day period will be 
classified as “both prolonged and frequent bleeding.” Subjects who report between 3-5 
bleeding/spotting episodes will be considered as having a “normal” bleeding pattern.  
 
6.7.2. Secondary Outcomes Measures  
• 
Compare mean number of days of bleeding and spotting for the last 28 days (post 3-
month treatment period) and total study period (120 days [13 x 84-day treatments + 
1 x 28 day no-treatment]) between treatment groups.  
• 
Improvement in menstrual bleeding symptoms assessed by standardized menstrual 
questionnaire. 
• 
Changes in satisfaction, sexual functioning, and QOL. 
• 
Medication-associated side effects. 
6.8. Participant Timeline  
All potential participants may be pre-screened over the phone for entry criteria prior to the initial 
screening visit. Participants who are recruited to the study will participate in an initial screening 
visit. The screening visit may occur the same day as the TCu380A IUD insertion visit or within 7 
days of Cu-IUD insertion. 
6.8.1. Visit 0: Screening 
1. Each participant will be screened to confirm study eligibility. 
2. Written informed consent: A research assistant will explain the study and its associated 
procedures, risks, and benefits prior to conducting any study procedures. The participant 
will be asked to sign an informed consent form if she wishes to participate. The consent 
form will be written to be understandable at a 6th-grade reading level. A copy of the 
consent form will be given to the study participant.  
3. A demographic questionnaire (Appendix B) will be obtained. Contact information will be 
obtained (phone and/or email). The participants will be asked to approve which 
method(s) of contact are acceptable and, for purposes of confidentiality, if it is 
acceptable for the research staff to identify themselves or state the reason for the call to 
another person, to leave a message, or to use a code name for a message.  
4. A short medical history will be obtained. Appendix C  
5. The participant will complete the Female Sexual Function Index (FSFI) questionnaire 
(Appendix D).23 This is a 19-item questionnaire that assesses six separate domains: (1) 
desire, (2) arousal, (3) lubrication, (4) orgasm, (5) satisfaction, and (6) sexual pain 
factors.  
7. The participant will complete the Q-LES-Q-SF quality of life questionnaire (Appendix 
E).24 This questionnaire is a 16-item questionnaire that has been shown to be valid and 
reliable among depressed patients undergoing treatment. This questionnaire is 
particularly sensitive to assess change, which is important to determine before and after 
TCu380A use.  
8. The participant will complete a menstruation and pelvic pain questionnaire. We will use a 
questionnaire adapted from the World Endometriosis Research Foundation (WERF 
EPHect Questionnaire – Standard [EPQ-S]).25 Questions assessed include menarche, a 


description of menstruation of the prior 3 months, and what a woman’s period is like 
when not using hormones. There are 8 questions related to pelvic pain which assess 
pain during last period, pain control, and how the pain might affect her ability to work or 
attend school. (Appendix F) 
6.8.2. Follow-Up Procedures 
Follow-Up Visit 1 (4-6 weeks post IUD insertion) 
The participant will return for a visit approximately 4 to 6 weeks (1 month) after TCU380A 
IUD insertion. The participant will fill out a brief health questionnaire to assess whether the 
Cu-IUD is still in place or if a new medical condition (newly diagnosed obesity, chlamydia or 
gonorrhea has been diagnosed since Cu-IUD placement). 
Women who state that they have had any changes in menstrual flow or complain of spotting 
will be recruited into the study. 
After randomization, the participant will receive: 
• 
An instruction sheet regarding when to take the medication and with a phone 
number to call if she has any questions or problems (Appendix A).  
• 
Instructions on daily texting or app usage regarding bleeding (Appendix B & C).  
• 
Bleeding diaries to complete for 4 months. The participant will be informed that 
these should be completed daily in case of technical difficulties with texting. 
• 
Assigned medication (3-month supply, or 42 capsules total), treatment or 
placebo, will be blinded to both provider and participant.  
• 
Compensation will be provided to the participant for this visit.  
Monthly Email or Phone Call 
The participant will be contacted approximately every 28-30 days after Follow-Up Visit 1 for a 
total of 4 monthly emails or phone calls. The research assistant will ask questions about the 
following: 
1. IUD.  
a. Presence of IUD.  
2. Menstruation (adapted from St. Louis CHOICE project questionnaire). 
a. Study medication taken as prescribed. 
b. How she experienced her period flow (light, moderate, or heavy) 
c. Number of days of bleeding during LMP.  
d. Frequency of pain during LMP.  
e. The monthly bleeding diary will be reviewed.  
3. Side Effects  
Participants will be asked about headaches, abdominal cramping, nausea, vomiting or 
diarrhea, somnolence, and dizziness. 
Follow-Up Visit 2 
The participant will return for a visit approximately 5 months (Month 6) after Follow-Up Visit 1.  


1) The participant will complete the Female Sexual Function Index (FSFI) questionnaire 
(Appendix D).  
2) The participant will complete the Q-LES-Q-SF quality of life questionnaire (Appendix 
E).24  
3) The participant will complete a further adapted dapted EPQ-S menstruation and 
pelvic pain questionnaire to collect information for the last 6 months, not historical 
information that was collected in Visit 0.  
4) A post-study questionnaire to assess satisfaction and plans to continue using the 
CuT380A IUD will be obtained from the participant. (Appendix G) 
5) The participant will be informed as to which type of medication she was randomized 
to. Any unused study medications will be returned to the research team.  
6) Compensation will be provided to the participant.  
Visit and contact schedule 
Visit 0 
Screening  
Visit 1 
4-6 week 
FU 
Monthly 
telephone or 
email contact 
Visit 2 
6-month 
FU 
Month 
0 
2 
3-6 
7 
Day(s) 
+/- 7 days 
of IUD 
insertion 
28-42 (±7) 
56-140 (±7) 
168 (±7) 
• Written informed consent 
x 
 
 
 
• Medical history questionnaire 
X 
X 
 
 
• Demographic questionnaire 
X 
 
 
 
• Female Sexual Function Index  
X 
 
 
X 
• QOL questionnaire  
X 
 
 
X 
• Menstruation and pelvic pain 
questionnaire (EPHect EPQ-S) 
X 
 
 
X 
• Cu-IUD Satisfaction 
 
 
 
 
• Evaluation of inclusion/exclusion 
criteria 
X 
X 
 
 
• Randomization to group 
assignment 
 
X 
 
 
• Dispense study drug 
 
X 
 
 
• Train participants to respond to 
daily texting 
 
X 
 
 
• Train participants to complete 
bleeding diaries 
 
X 
 
 
• Obtain three contacts for each 
participants  
X 
X 
 
 
• Review daily texting of bleeding 
diary  
 
 
X 
X 
• Review participant completion of 
diary 
 
 
X 
X 
• Return of study drug 
 
 
 
X 
• Completion of satisfaction 
questionnaire 
 
X 
 
X 
• Assessment of Paragard 
 
X 
X 
X 


 
Interim Visits  
1) Participants who call the study center will be interviewed by a research coordinator, 
and their concern will be assessed by a clinician.  
2) Participants will be encouraged to come to clinic if clinically necessary.  
3) Participants will be interviewed for medical issues/illnesses, issues with the 
TCU380A IUD (e.g., expulsions), occurrence of adverse events, use of concomitant 
medications, etc.  
4) Clinically relevant assessments will be performed. 
Early Discontinuation  
1) Participants who discontinue from the study early will undergo the Follow-Up Visit 2 
procedures described above. 
6.8.3. Criteria for Discontinuation 
• 
Participants may be discontinued before randomization as discussed in Section VI.b 
above (inclusion/exclusion criteria). 
• 
Participants will be discontinued from the study if they become pregnant. 
• 
Participants may withdraw from the study at any time. 
6.9. Sample Size 
We aim to enroll 60 women into the treatment phase of this study. Based on the study by 
Dietrich in which approximately 70% of women using TCu380A IUD reported “heavier” bleeding 
volume at 3 months, we anticipate that 86 women will need to agree to TCu380A IUD 
insertion26; approximately 24 of these women will not have any symptoms of increased blood 
loss or spotting at Follow-Up Visit 1 and therefore will not continue in the study . Based on the 
response rate of approximately 60% from a prior US-based IUD study evaluating treatments for 
the prevention of bleeding among new levonorgestrel users, we anticipate we will need to 
approach 144 women to recruit 86 women into the study, of which we anticipate 60 will 
experience symptoms of increased blood loss or spotting.  
 
6.10. Recruitment 
We aim to recruit 60 subjects within a 5-month period. Each site will be given a recruitment 
target; however, competitive enrollment will be implemented to ensure the study meets its 
recruitment targets. Participants will be recruited at each site using both active and passive 
techniques. Investigators plan to recruit directly from their clinical sites. The study coordinator 
will obtain names and contact information for every patient receiving a Cu-IUD at a University of 
Washington clinic in the last 7 days and contact them by email and phone. Flyers will be posted 
at clinical sites, across the site’s medical centers, and at off-site clinics to attract a broader 
patient population and to remind clinic staff about the study. The postings and advertisements 
will ask interested participants to contact our research staff. This study will enroll a convenience 
sample, but given selection of sites for this study the final sample will be representative of 
TCu380A IUD users in the US.  
expulsion 
• Adverse event monitoring 
 
X 
X 
X 


6.10.1. Participant Incentives  
Participants will be paid for the screening visit when they will complete questionnaires and enroll 
in the study ($25). They will be paid at Follow-Up Visit 1 ($40), as well as $1 each day for 
completion of bleeding data for the 3 treatment cycles plus the one non-treatment cycle (up to 4 
x $28, since each cycle=28 days). They will be paid at Follow-Up Visit 2 ($45). Thus, a 
participant who completes the study in full will be paid $222.  
7.0. Methods: Assignment of interventions 
7.1. Allocation  
Allocation to naproxen or placebo study group will be determined through computer block 
random number generator to define15 blocks of participants (each block is in 1:1 ratio for sets of 
4 sequentially numbered participants) by the University of Washington Investigational Drug 
Service (IDS). The UW IDS will provide each clinical site their own randomization list. Because 
we expect enrollment to be slightly faster at the UW clinical sites, we will assign one extra block 
at the UW clinical site: they will be assigned 8 blocks (32 participants) and Stroger Hospital will 
be assigned 7 blocks (28 participants).  
7.2. Blinding  
Study participants, UW, Stroger Hospital research teams, and the study statistician will be 
blinded to intervention assignment. Treatment and placebo capsules will be compounded in 
Seattle, WA and distributed to the UW IDS for the UW study participants. Stroger Hospital will 
have their own compounding pharmacy, but the randomization list will come from UW and be 
provided to Stroger Hospital pharmacy, who will be responsible for dispensing medications to 
study participants. The Stroger Hospital site in Chicago will receive their own randomization list, 
which will assign each sequential participant to a study group. After the study group is assigned, 
the study participant will receive a pill packet indicating the same numbered study group. A 
study group treatment log will be maintained at each study site. 
To maintain the overall quality and legitimacy of the clinical trial, code breaks should occur only 
in exceptional circumstances when knowledge of the actual treatment is absolutely essential for 
further management of the study participant. The Principal Investigator (PI) is to be informed by 
other investigators if a study participant is believed to have had an adverse event requiring un-
blinding. The PI will discuss with the IRB if un-blinding may be necessary. If un-blinding is 
necessary, the PI will use the system for emergency un-blinding as determined by the UW IDS.  
8.0. Methods: Data Collection, Management, and Analysis 
8.1. Data Collection Methods 
Data will be collected by each research center. Each participant will have a set of source 
documents (medical history, physical exam, surveys), which will be entered into an existing UW 
Web-based program (REDCap) that is a password-protected database managed by the UW. 
When a computer is available, participants will answer directly into the database, which leaves 
less room for transposing errors. In case of technical difficulty with computer access to the 
REDCap website, each clinical site will receive paper source documents. Each survey (online 
and paper) will be identified by the participant's study number.  
8.1.1. Bleeding Diaries 
Participants randomized to a treatment arm will complete both paper and electronic bleeding 
diaries. For the electronic bleeding diary, participants will start receiving a daily text or email 
message from a study-affiliated messaging service (developed with Mir3, San Diego, CA) 
prompting a response about their bleeding for the day. This approach uses the same service 


provider that has been previously studied by Westhoff’s Columbia University group with 
excellent real-time response rates (>90%).27 The digital message bleeding diary for this project 
will be uniquely designed by UW and Mir3 to fit the needs of this study. Subject ID numbers and 
their cell phone numbers or email addresses are entered into the system to allow subjects to 
receive messages and send responses to the study database. The company adheres to a strict 
privacy policy for phone numbers in the system. In the daily text message, subjects are asked to 
classify their bleeding using the terminology recommended by Mishell et al.22 This includes for a 
given 24-hour period whether the woman has experienced: 
1. Bleeding: any day during which bleeding requires the use of more than one panty liner, 
pad, or tampon.  
2. Spotting: Minimal blood loss that could be contained with one or no panty liner, pad, or 
tampon.  
3. No bleeding.  
 
Subjects will also be asked if they took their study medication each day for the 3 treatment 
months. Text responses will be 1: yes, and 2: no. 
If the subject does not respond to the text or email message, a second text or email will be sent 
the following evening. The subject has only these two chances to report their bleeding 
information for that day, and otherwise must use the paper diary.  
Responses to the messaging system will be compiled in a secured web database by Mir3, 
which can be accessed by research staff for data retrieval and entry onto research computers. 
Paper diaries will also be provided for use in case of technical difficulty in receiving or 
responding to text or email messages. Participants are encouraged to complete paper diaries in 
addition to the electronic diary. If there is a discrepancy between electronic and paper diaries, 
we take data from the electronic diary. If there are missing data, we will take information from 
the paper diaries to complete the electronic diaries. 
 
Subjects in Seattle will be given the choice , as their smart phone plan allows, to use one of two 
electronic methods of bleeding tracking, text messages, or the period tracking app Clue. Clue 
users will be able to track other side effects mentioned in the bleeding diary directly into the app. 
We are piloting the feasibility of using an app versus text message to collect this data.  
 
8.2. Data Management 
The University of Washington will have the overall responsibility of this project and will serve as 
the Data Coordinating Center. As the Data Coordinating Center, UW will create the source 
documents for the study and be responsible for creating and managing the web-based database 
for the study with feedback from Stroger Hospital. Data will be maintained in locked files in a 
locked room at both sites. Ideally, each site will have participants enter responses to the 
questionnaires directly into a UW Web-based program (REDCap). In case of technical difficulty 
with computer access to the REDCap website, each clinical site will receive paper source 
documents.  Other forms collected (i.e., medical history, physical exam, interim visits) will be de-
identified, with only the participant study number and entered into REDCap, a web-based, 
password-protected database managed by UW.  
To assure the accuracy and completeness of the data, the PI and research team at UW will 
periodically compare data reporting forms with source documents at both sites. As part of this 


study, we will also be setting up best practices for data collection and analyses for a larger, 
multicenter trial.  
8.3. Statistical Methods 
Computer Facilities: Appropriate computer facilities are readily available for data analysis. 
REDCap will be used for entry and preparation of data for statistical analysis. Statistical analysis 
will be performed using STATA 12. 
• Objective 1: To evaluate the number of days of bleeding and spotting for the treatment period 
of this study as reported by the participant bleeding text responses, and bleeding diaries (as a 
backup).  
For the 84-day period entailing episodes of bleeding and spotting, we will perform a sensitivity 
analysis to compare b/s during the days they were on treatment (or eligible for treatment) and 
days they were not on treatment, in order to elucidate whether treatment with naproxen was 
effective.  
 
We will also evaluate the number of days of bleeding and spotting according to each 28-day 
cycle using descriptive analysis. We will plan to show episodes of bleeding by cycle and by 
group using box plots. Because we anticipate skewed data, we will use the Wilcoxon rank-sum 
test to compare the distributions of the number of days of bleeding and spotting during the first 3 
cycles of treatment (84-day reference period) between the two treatment groups. Analysis will 
be performed based on intention to treat, meaning all subjects who are randomized and are 
dispensed treatment (naproxen or placebo) will be included in the full analysis.  
 
We will also calculate the proportion of bleeding episodes by bleeding pattern (prolonged, 
frequent, infrequent, or amenorrhea) by treatment group as defined in 6.7.1. Primary Outcome 
Measures. For each 28-day cycle, we will indicate whether each woman had any prolonged 
episodes and/or any frequent episodes during that cycle.  To evaluate the relationship between 
those who have prolonged episodes and those who report frequent episodes, for each 28-day 
cycle, we will report a 2x2 table of counts of patients by treatment group with neither, just 
prolonged, just frequent, or both prolonged and frequent episodes, and compare these by Chi-
Square test (or Fisher's Exact Test if any cell count is below 5 subjects).   We will use a 
multinomial model to determine whether treatment was associated with differences in these four 
separate bleeding pattern categories for each 28-day cycle, and use generalized estimating 
equations (GEE) repeated measures model to determine whether treatment was associated 
with differences in these four separate bleeding pattern categories for each 84-day reference 
period. 
 
Objective 2: To assess feasibility of recruiting, enrolling, and maintaining new TCu380A IUD 
users in a randomized, placebo-controlled clinical trial. 
We will report numbers of women inquiring about the study, screened, and enrolled into the 
study. The status of participants at the end of the study (e.g., completed study, lost to follow-up, 
discontinued, reasons for discontinuation) will be reported by treatment group.  
• Objective 3: To describe the impact of TCu380A IUD use on satisfaction, menstruation, 
dysmenorrhea, sexual functioning, and quality of life (QOL) scores by treatment group.  
o Satisfaction with the TCu380A IUD is measured by a 3-point Likert scale adapted from 
the St. Louis CHOICE project and will be compared using two sample t test. Open-
ended questions regarding the acceptability of the study will be reported descriptively 
and used to inform study procedures for a future clinical trial. Satisfaction will be asked 


at the end of each treatment cycle, non-treatment cycle and the follow up visit #2. We 
will adjust for multiple comparisons.  
o Menstruation and pelvic pain will be assessed using a global score calculated from the 
Adapted EPQ-S.25 Menstruation and pelvic pain will be assessed by this questionnaire at 
screening and after 3 consecutive months of treatment. We will compare means of 
menstruation and pelvic pain scores by treatment group using analysis of covariance 
(ANCOVA). We will adjust for baseline menstrual flow at the screening visit. We will also 
adjust for precision variables (significantly associated with outcome score with p<0.05) 
from the following list: age, contraceptive method type in the prior month prior to 
enrollment in study, baseline cycle length, baseline number of days of bleeding during 
menstruation, and baseline pain with period. If the outcome scores are found to be 
skewed, we will use Wilcoxon rank-sum test for comparisons. 
o The Female Sexual Function Index (FSFI) is a 19-question survey and will be 
administered at screening and 6-month follow-up. Scoring is done by adding the scores 
of the individual items that comprise each domain and multiplying the sum of the six 
scores by the domain factor.23 We will compare 6-month means adjusted for baseline 
using ANCOVA.  If the data are found to be skewed, we will use Wilcoxon rank-sum test 
for comparisons. 
o The Q-LES-Q-SF quality of life measure, administered at screening and the 6-month 
follow-up, will be compared. The scoring of the Q-LES-Q-SF involves summing only the 
first 14 items to yield a raw total score. The last two items are not included in the total 
score but are stand-alone items. The raw total score ranges from 14 to 70. The raw total 
score is transformed into a percentage maximum possible score using a prescribed 
formula.28 We will compare 6-month means adjusted for baseline using ANCOVA.  We 
will adjust for age and baseline depression/anxiety as reported in medical history 
questionnaire. If the data are found to be skewed, we will use Wilcoxon rank-sum test for 
comparisons. 
• 
Objective 4: To describe the safety of OTC naproxen compared to placebo. 
o Participants will be asked about headaches, abdominal cramping, nausea, vomiting, 
diarrhea and dizziness at each monthly email or phone call and at Follow-Up Visit 2. For 
each reported side effect, we will compare the treatment groups using Chi-square or 
Fisher exact test, depending on the prevalence of each side effect. 
o Subgroup analysis: We will plan to evaluate whether there is effect modification by age. 
 
9.0. Methods: Monitoring 
9.1. Disposition 
We will determine the proportion of participants needed to approach, enroll, and maintain to 
meet goal of 30 participants per treatment group. 
 
9.2. Safety Assessment Methods  
Subjects will be informed at the start of the study that they are to report all adverse events or 
concerns related to the treatment.. Monitoring of data will be performed by the PI and research 
team at the two sites to assure that the clinical staff adheres to the protocol, that data are 
entered completely and accurately on the data reporting forms, that regulatory requirement for 


conducting clinical research are followed, that facilities are adequate to conduct the clinical trial, 
and that IRB approval is obtained. They will monitor adverse events through biweekly phone 
meetings. 
9.3. Adverse Event Management and Reporting  
Each participant will be advised to contact the research site immediately if she has any 
significant medical problems or complaints during the course of this study. A designated study 
clinician will be available 24 hours a day and will evaluate all complaints and assure that 
appropriate health care or referral is provided for all study participants. Adverse events are 
defined by federal regulations (CFR, Title 21, Part 312.32) as follows: 
• 
“Associated with the use of the drug” means: “There is a reasonable possibility that 
the experience may have been caused by the drug.”  
• 
“Serious adverse drug experience” (SAE) means “Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: death, a life-
threatening adverse drug experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.”  
• 
“Unexpected adverse drug experience” means: “Any adverse drug experience, the 
specificity or severity of which is not consistent with the current investigator brochure; or, 
if an investigator brochure is not required or available, the specificity or severity of which 
is not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended.”  
All serious adverse events, including those that may appear to be unrelated to the study 
product, will be reported to the Institutional Review Board by the investigator (according to the 
local policies). If any serious adverse events or complications occur, the respective IRBs will be 
notified within 24 hours, and the investigators will meet with the IRBs to assess if the study can 
continue. No Data Safety Monitoring Board will be used for this study. The medication used for 
treatment (naproxen sodium) is FDA-approved and already used in a non-prescription, over-the-
counter context, and side effects will be monitored on a regular basis. The principal 
investigators at each site will be responsible for monitoring participant safety.  
Each center will maintain and track their study medications. Regular site monitoring will be done 
by UW to ensure that Stroger Hospital is following study procedure and to identify and rectify 
any problems that may be occurring. There will also be regular conference calls with the project 
team to discuss progress with recruitment, enrollment, retention, adverse events, etc.  
We will not perform an interim analysis for safety and efficacy because of proven safety of OTC 
naproxen and because of the short 3-month duration of treatment. 
9.4. Duration of Project 
• 
The duration of the project is expected to be about 18 months.  
• 
Recruitment is expected to take 5 months. 
• 
Creation of the web-based REDCap database for data entry will occur before enrollment 
begins, and data entry will be ongoing throughout the study. Data entry will be 
completed within one month of the completion of data collection. 


• 
All data collection will be done six month after enrollment of the last participant.  
 
 
10.0. Ethics and Dissemination Plan 
With assistance from Stroger Hospital the UW (as the Data Coordinating Center) will be 
responsible for preparing a summary report of the trial.  
This study is a critical first step to determining whether a larger definitive study comparing 
treatment of heavy or prolonged menstrual bleeding with naproxen and placebo is feasible 
among TCu380A IUD users. Though it is a feasibility study, it will be the first head-to-head study 
examining naproxen for menstrual bleeding in new TCu380A IUD users. If a larger-scale study 
is feasible, we anticipate adding additional promising treatments (e.g., tranexamic acid) and 
focusing on important clinical outcomes such as unscheduled bleeding, satisfaction, and quality 
of life among TCu380A IUD users. We plan to present our data at a national family planning 
conference, as well as a conference related to primary care research. We will develop a 
summary paper from this feasibility study consistent with CONSORT clinical trial guidelines.  
PROJECT ACTIVITIES Oct 15-
Dec 15 
Feb 16-
Aug 16 
Mar 16- 
Oct 16 
July 15-
feb 17 
Oct 16-
Nov 16 
Nov 16- 
Dec 16 
Jan 17-
Mar 17 
Mar 
17-
May17
M 
Jun 17-
Jul 17 
IRB submission, CRBB 
review, set up database 
X 
X 
 
 
 
 
 
 
 
• Recruitment  
 
X 
X 
X 
 
 
 
 
 
• Screening Visit 
 
X 
X 
X 
 
 
 
 
 
• Insertion Visit 
 
X 
X 
X 
X 
 
 
 
 
• Follow-up Visit #1 
 
 
X 
X 
X 
X 
 
 
 
• Monthly Contact 
 
 
X 
X 
X 
X 
X 
 
 
• Follow-up Visit #2 
 
 
 
X 
X 
X 
X 
 
 
• Clean database  
 
 
 
 
 
X 
X 
X 
 
• Analyze survey data  
 
 
 
 
 
 
X 
X 
X 
• Prepare and finalize 
manuscript  
 
 
 
 
 
 
 
 
X 
X 


LITERATURE 
 
1. 
Chan AW, Tetzlaff JM, Altman DG, Dickersin K, Moher D. SPIRIT 2013: new guidance 
for content of clinical trial protocols. Lancet. Jan 12 2013;381(9861):91-92. 
2. 
U.S. Selected Practice Recommendations for Contraceptive Use, 2013: adapted from 
the World Health Organization selected practice recommendations for contraceptive use, 
2nd edition. MMWR Recomm Rep. Jun 21 2013;62(RR-05):1-60. 
3. 
d'Arcangues C. Worldwide use of intrauterine devices for contraception. Contraception. 
Jun 2007;75(6 Suppl):S2-7. 
4. 
Mosher WD, Jones J. Use of contraception in the United States: 1982-2008. Vital and 
health statistics. Series 23, Data from the National Survey of Family Growth. 2010(29):1-
44. 
5. 
Sivin I. Utility and drawbacks of continuous use of a copper T IUD for 20 years. 
Contraception. Jun 2007;75(6 Suppl):S70-75. 
6. 
Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova 
T) IUDs during five years of use:< i> A randomized comparative trial</i>. Contraception. 
1994;49(1):56-72. 
7. 
Grunloh DS, Casner T, Secura GM, Peipert JF, Madden T. Characteristics associated 
with discontinuation of long-acting reversible contraception within the first 6 months of 
use. Obstet. Gynecol. Dec 2013;122(6):1214-1221. 
8. 
Rosenberg MJ, Foldesy R, Mishell DR, Jr., Speroff L, Waugh MS, Burkman R. 
Performance of the TCu380A and Cu-Fix IUDs in an international randomized trail. 
Contraception. 1996;53(4):197-203. 
9. 
Berenson AB, Tan A, Hirth JM, Wilkinson GS. Complications and continuation of 
intrauterine device use among commercially insured teenagers. Obstet. Gynecol. May 
2013;121(5):951-958. 
10. 
Godfrey EM, Folger SG, Jeng G, Jamieson DJ, Curtis KM. Treatment of bleeding 
irregularities in women with copper-containing IUDs: a systematic review. Contraception. 
May 2013;87(5):549-566. 
11. 
Grimes DA, Hubacher D, Lopez LM, Schulz KF. Non-steroidal anti-inflammatory drugs 
for heavy bleeding or pain associated with intrauterine-device use. Cochrane Database 
Syst Rev. 2006;4. 
12. 
DeArmond B, Francisco CA, Lin JS, et al. Safety profile of over-the-counter naproxen 
sodium. Clin. Ther. Jul-Aug 1995;17(4):587-601; discussion 586. 
13. 
Mowry JB, Spyker DA, Cantilena LR, Jr., Bailey JE, Ford M. 2012 Annual Report of the 
American Association of Poison Control Centers' National Poison Data System (NPDS): 
30th Annual Report. Clinical toxicology (Philadelphia, Pa.). Dec 2013;51(10):949-1229. 
14. 
Administration UFaD. NDAC Briefing Document: Review of Safety and Efficacy of OTC 
Naproxen Sodium. . Non-prescription drug advisory committee. 
15. 
Rahn DD, Abed H, Sung VW, et al. Systematic review highlights difficulty interpreting 
diverse clinical outcomes in abnormal uterine bleeding trials. J. Clin. Epidemiol. Mar 
2011;64(3):293-300. 
16. 
Seattle Demographics. 2010; 
http://data.spokesman.com/census/2010/washington/cities/seattle-wa/. 
17. 
Washington Uo. Academic Data Management Autumn 2013. 2013; 
https://depts.washington.edu/reptreq/wp-
content/uploads/2012/05/Quick_Stats_Aut2013_Seattle.pdf. Accessed September 30, 
2014. 
18. 
Census US. Chicago Demographics. 2012; 
http://factfinder2.census.gov/faces/nav/jsf/pages/community_facts.xhtml. Accessed 
September 30, 2014. 


19. 
Prevention CfDCa. U.S. Selected Practice Recommendations for Contraceptive Use, 
2013: Adapted from the World Health Organization Selected Practice Recommendations 
for Contraceptive Use, 2nd Edition. Vol 62. 2 ed2013:1-46. 
20. 
Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-
steroidal anti-inflammatory drugs: meta-analyses of individual participant data from 
randomised trials. Lancet. Aug 31 2013;382(9894):769-779. doi: 710.1016/S0140-
6736(1013)60900-60909. Epub 62013 May 60930. 
21. 
Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic 
toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin 
Gastroenterol Hepatol. May 2005;3(5):489-498. 
22. 
Mishell DR, Jr., Guillebaud J, Westhoff C, et al. Recommendations for standardization of 
data collection and analysis of bleeding in combined hormone contraceptive trials.[see 
comment]. Contraception. Jan 2007;75(1):11-15. 
23. 
Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): a 
multidimensional self-report instrument for the assessment of female sexual function. J. 
Sex Marital Ther. Apr-Jun 2000;26(2):191-208. 
24. 
Endicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction 
Questionnaire: a new measure. Psychopharmacol. Bull. 1993;29(2):321-326. 
25. 
Vitonis AF, Vincent K, Rahmioglu N, et al. World Endometriosis Research Foundation 
Endometriosis Phenome and biobanking harmonization project: II. Clinical and covariate 
phenotype data collection in endometriosis research. Fertil. Steril. Nov 
2014;102(5):1223-1232. 
26. 
Diedrich JT, Desai S, Zhao Q, Secura G, Madden T, Peipert JF. Association of short-
term bleeding and cramping patterns with long-acting reversible contraceptive method 
satisfaction. Am. J. Obstet. Gynecol. Jul 18 2014;18(14):025. 
27. 
Nippita S, Velasco MG, Oviedo JD, Westhoff CL, Davis AR, Castano PM. Text 
messages compared with monthly paper diaries: collecting bleeding data after 
intrauterine device insertion. Obstet. Gynecol. May 2014;123 Suppl 1:12S-13S. 
28. 
Endicott J. Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-
LES-Q-SF). 1993; https://outcometracker.org/library/Q-LES-Q-SF.pdf. Accessed 
December 5, 2014. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
CITROS ver. 1,07/29/2015 
 
1 of 6 
UNIVERSITY OF WASHINGTON 
CONSENT FORM 
COPPER IUD TREATMENT OBSERVATION STUDY (CITROS)  
 
Emily Godfrey, MD, MPH 
Associate Professor 
Dept. of Family Med 
 
Kelly Gilmore, MPH 
Research Coordinator 
Dept. of Obstetrics 
and Gynecology 
206-685-1855 
bcstudy@uw.edu 
24-hour Emergency Contact: Please call UWMC Paging Operator: (206) 598-6190 and ask to have Dr. 
Godfrey paged 
 
What is “informed consent”? 
We are asking you to be in a research study.  The purpose of this consent form is to give you the 
information you will need to help you decide if you want to be in the study.  We will go over this form 
with you out loud, you may also want to read this form carefully before deciding. You may ask 
questions about the research like, what we will ask you to do, the risks and benefits, your rights, and 
anything else. When we have answered all your questions, you can decide if you want to be in the 
study or not.  This process is called “informed consent.”  We will give you a copy of this form. 
What is this study about? 
We want to know if a medication you can buy at the drug store, like Aleve, can help Copper IUD users 
have less heavy bleeding when they first get their IUD. Most copper IUD users have bleeding changes 
for the first six months after getting their Copper IUD. We want to know if taking these medications 
can help women cope with these bleeding changes and increase women’s satisfaction with their 
copper IUD. We expect to enroll 86 women in this study in Seattle and Chicago. 
 
Why are you asking me to be in this study? 
You are being asked to participate in this study because you are considering having a Copper IUD 
inserted for birth control. 
How does this study work? 
In this study women who use the Copper IUD will be split into two different groups. You and the study 
doctor will not know which group you are in. Women in both groups will be asked to take a medication 
for the first seven days of their period for 3 months. One group of women will be taking a medication 
call sodium naproxen- this medication is known by the brand name Aleve. The other group of women 
will be taking a “placebo” pill. A placebo pill is a sugar pill that is made to look exactly like the sodium 
naproxen pill.  
This study will take place at the University of Washington and Stroger Hospital of Cook County, 
Chicago, IL. The study will take place over about 18 months, but we are only asking you to participate 
for 6 months.  
What will I have to do to be in the study? 
This study includes three doctors office visits over 6 months, answering online and in person 
questionnaires, and writing down your bleeding every day for 4 months. 


CITROS ver. 1,07/29/2015 
 
2 of 6 
 
1) Your IUD Consultation/Insertion Visit 
At your IUD insertion visit or birth control visit with your doctor, if you and your doctor decide that you 
will have a TCu380A IUD inserted, you may be eligible to enroll in this study. We will figure out if you 
are eligible to participate by asking you some questions about your medical history and contact 
preferences.  If you are eligible and you decide to participate you will complete several study 
questionnaires after your regular doctors’ visit. The study questionnaires will ask about: 
• Contact information and general demographic information. 
• Your sexual desire, arousal and satisfaction. 
• Your quality of life including your satisfaction with your relationships, work and other areas of 
life. 
• Your history and experience with menstrual cramping and bleeding. 
• A member of the research team will ask you about your medical history, just like the nurse at 
your doctor’s office would. 
We will also ask your permission to record the results of your most recent pelvic exam from your 
medical record.  The research portion of this visit (after you have seen your regular doctor) will take 
about 1.5 hours.  
2) Study Visit 1 
If you have chosen to participate in the study, we will ask you to answer some more questions after 
your regularly scheduled IUD “string check” follow up visit with your doctor. Your doctor typically asks 
you to come in for your “string check” visit about 4-6 weeks after you get your copper IUD.  After your 
visit with your doctor, we will ask you some questions to figure out if you are still eligible to continue in 
the study.  If you have not had certain bleeding changes, then your study participation will end. If you 
are no longer in the study, we will still keep the information you have given us so far. 
If you continue in the study at this point, you will be placed into one of two groups. You will not know 
which group you are in. The group you are placed in will be chosen randomly, like flipping a coin. One 
group will receive 440 mg of naproxen sodium (Aleve) in pill form and the other group will receive a 
placebo pill.  You will not know which tablet you are getting.  You will take one tablet twice a day (12 
hours apart) at the beginning of your monthly period, for no more than SEVEN consecutive days.  You 
will receive enough medication for three months.  You will also receive an instruction sheet and study 
contact information in case you have questions. This study visit can take up to one hour. 
3) Monthly Bleeding Diaries 
We will also ask you to keep a bleeding diary.  You will complete both a paper and electronic bleeding 
diary. The electronic bleeding diary will consist of daily text or email messages about your bleeding for 
the day.  
If you do not respond to the text/email message, a second text/email will be sent the following 
morning. You have only these two chances to report your bleeding information via text/email for that 
day, otherwise you will need to use the paper diary.  
You will be compensated $1 for each day you provide information about your bleeding. 
 
 


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4) Monthly Email or Phone Call 
You will receive a monthly phone call or email from the research coordinator for 4 months.  They will 
ask you questions about your IUD and your satisfaction with that method of birth control.  They will ask 
you questions about your monthly period such as date of your period, did you experience pain, and are 
there changes in your bleeding.  They will also review your monthly bleeding diary with you and ask 
about any other changes in your health.  These phone calls or email may take about 15 – 20 minutes of 
your time. 
 
5) Study Visit 2 
This visit will happen about 6 months after you had the Copper IUD inserted.  We will ask you to return 
to the clinic for a study visit.  You will be asked to bring back your bottle of study medication (even if it 
is empty) and we will ask you to complete several questionnaires.  This visit will take about 1.5 hours.   
The research coordinator will ask the same questions asked in the monthly phone call.  We will also ask 
you to complete questionnaires about: 
• Your sexual desire, arousal and satisfaction. 
• Your quality of life including your satisfaction with your relationships, work and other areas of 
life. 
• Your history and experience with menstrual cramping and bleeding. 
• Your satisfaction with the Copper IUD. 
 
Are there side-effects or health risks from taking this medication? 
There are possible side effects associated with taking the study medication, naproxen sodium (Aleve) 
even though it is a medication you can buy at the drugstore without a doctor’s prescription. Millions of 
women take Aleve, and side effects are very rare. It is possible you may experience the following side 
effects: 
• Heartburn 
• Nausea 
• Vomiting 
• Ringing in Ear 
• Bloating 
• Diarrhea 
• Constipation 
• Black Stools 
• Severe Abdominal Pain 
• Vision changes 
• Fluid Retention 
• Allergic Reaction to the study medication 
If you experience any of the above please be sure to let the research staff know.  As with any drug, 
there may also be other side effects that we don’t know about. 
 
 


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Are there other risks involved in this study? 
You may feel uncomfortable answering personal and private questions about your period and sex life.  
Research staff will do everything possible to help you feel more comfortable, but you never have to 
answer any questions you don’t want to. 
There is also a risk that someone who is not on the research team could find the private information 
you give us.  We make every effort to keep your personal information secure and private.  One way we 
keep your information is safe is by assigning you a “subject ID number. “ This number is used instead of 
your name on all study documents so no one can figure out which answers are yours. The research 
coordinator has a list of subject ID numbers that show which ID number was assigned to which person. 
This is the only document where your name is linked to the study ID number. This document, and all of 
the information you provide for this study, is kept on a password protected computer at the University 
of Washington.  
What if I decide I don’t want a Copper IUD? 
Depending on your birth control needs and medical history you may prefer to use another method of 
birth control. You do not need to participate in the study to have access to the Copper IUD. 
 
Will I benefit from being in this study? 
You will not directly benefit from participating in this study. Information from this study will help 
health care professionals establish better care for women who use a copper IUD.  
 
Who is paying for this study? 
Teva Pharmaceuticals, the company that makes the Copper IUD, is paying the University of 
Washington and the research team to conduct this study.  
 
Will my information be private? 
The data from this study will be confidential. Your information will be linked to your subject ID number. 
The research team will have access to the information you provide for this study.   
Who besides the research team might see my study information? 
Government or university staff sometimes review studies like this one to make sure they are being 
done safely and legally.  Teva Pharmaceuticals, the sponsor of this study may also review the study 
records to make sure the study was done safely and legally. Teva can review these records any time up 
to 5 years after the study is finished. If a review of this study takes place, someone from outside the 
research team may read your study records.  The reviewers will protect your privacy.  The study 
records will not be used to put you at legal risk of harm. 
This study will be registered with ClinicalTrials. 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.  
Who else will know that I was in this study? 


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Your healthcare providers at UW Medicine will know you have participated in this study because it will 
be noted in your health record at UW Medicine. They do not have access to the study information so 
they will not know your survey answers, only that you participated in the study. 
 
What if I don’t want to participate or change my mind? 
You may refuse to participate and you are free to withdraw from this study at any time without 
penalty. This means if you chose not to participate or to leave the study early your care at UW 
Medicine will not be affected in any way and you will still receive a gift card incentive for each study 
visit that you completed. 
 
Will I get paid to be in this study? 
You will receive a $25.00 gift card for the first study visit and a $40.00 gift card for the second visit. You 
will receive $1.00 a day for 4 months for responding to the daily texts and/or completing the diary 
about your bleeding.  You will receive a $45.00 gift card for the final visit.  If you complete all the study 
visits you will receive $222.00 in gift cards.  We will also pay for parking for subjects who return for the 
final study visit.  
 
Do these payments get taxes taken out? 
The US government requires us to have your name, address, and social security number in order to pay 
you for your time.  That information, your payment amount, and the name of the study will be kept 
secure and confidential in our department’s financial office and the University’s financial office. If you 
are paid a total of $600 or more as a research subject in a calendar year, the University is required to 
report the payment to the Internal Revenue Service (IRS). The University will send you a form (IRS form 
1099) in January documenting the payment total.   
 
Who pays for my doctor’s visits in this study? 
You or your insurance company will be responsible for the costs of the visits with your clinician to have 
IUD insertion and the 4-6 week follow-up visit.  These visits would occur even if you are not in the 
research study. The study will reimburse your for parking for the last study visit. Your health insurance 
will not be charged for this last study visit. 
 
What if I have a serious health emergency while I am in the study? 
For a life-threatening problem, call 911 right away or seek help immediately. Contact Dr. Godfrey at 
206-598-6190 (UWMC Paging) when the medical emergency is over or as soon as you can. For all other 
problems: contact Dr. Godfrey at 206-685-4895 right away. She will treat you or refer you for 
treatment. 
 
What if I get injured because of the study medications or procedures? 
If you are injured as a result of being in this study, necessary medical treatment will be offered at a UW 
Medicine facility. 
 
If you are harmed or injured as a result of your participation in this study, the costs of your medical 
treatment may be billed to you or your insurance just like other medical costs, or it may be covered by 
the UW’s discretionary Human Subjects Assistance Program (HSAP). The researcher may request HSAP 


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coverage.  If you wish to request HSAP coverage yourself, contact the researcher or the UW Human 
Subjects Division at hsdinfo@uw.edu or 206-543-0098.  Ask the researcher if you would like 
information about the limits and conditions of HSAP.  The UW does not normally provide any other 
form of compensation for injury.  However, the law may allow you to seek payment for injury-related 
expenses if they are caused by malpractice or the fault of the researchers.  You do not waive any right 
to seek payment by signing this consent form.   We will bill your health insurance for treating problems 
that result from your reproductive care or from standard clinical care.  If you have no health insurance 
or your insurance refuses to pay, we will bill you. 
 
 
 
Printed name of study staff obtaining consent 
Signature 
Date 
 
Subject’s statement 
This study has been explained to me.  I volunteer to take part in this research.  I have had a chance to 
ask questions.  If I have questions later about the research, or if I have been harmed by participating in 
this study, I can contact one of the researchers listed on the first page of this consent form.  If I have 
questions about my rights as a research subject, I can call the Human Subjects Division at (206) 543-
0098.  I give permission to the researchers to use my medical records as described in this consent form.  
I will receive a copy of this consent form. 
 
 
Printed name of subject 
 
Signature of subject  
 
 
Date 
 
I am willing to be contacted in the future about other studies related to female reproductive care. 
 
______  YES 
 
______  NO 
 
 
Copies to: 
Researcher 
 
 
Subject