Hormonal Influences on Inflammatory Bowel Diseases

Study Overview
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Brief Summary
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Of the 1.8 million U.S. women with inflammatory bowel diseases (IBD), over half of those who are premenopausal suffer from cyclical menstrual-related IBD symptoms, regardless of how well their disease is controlled. Despite the significant impact that cyclical IBD symptoms have on quality of life, evidence about how to alleviate these symptoms is lacking. In other chronic conditions which are hormonally influenced, such as epilepsy, hormonal contraception may be used to favorably impact disease-related symptoms associated with menses and improve quality of life. Long acting reversible contraception, including the etonogestrel (ENG) contraceptive implant and levonorgestrel (LNG) intrauterine device (IUD), are the most effective contraceptive options with excellent safety profiles and are highly desired if access barriers are removed, thus ideal for study in this population. In our previous cross-sectional study, 47% of the levonorgestrel (LNG) IUD users reported improvement in their cyclical IBD symptoms, but ENG implant use was uncommon and prospective data on the effect of either the IUD or implant on symptoms remain lacking. In order to design a future comparative effectiveness trial on the effect of the ENG implant and LNG IUD on menstrual-related IBD symptoms, the investigators propose this pilot randomized controlled trial with a participant-preference arm to define a feasible study design and recruitment plan, determine metrics to differentiate between non-menstrual and menstrual-related IBD symptoms, and explore the potential role of use of inflammatory markers in future trials. The investigators will recruit participants from the University of Utah IBD Center and clinics and through social media ads. Total study commitment will be  8 months which includes two spontaneous menstrual cycles prior to contraceptive initiation and then six months of follow-up. Study activities will include daily and weekly text message surveys, as well as blood draws and fecal samples for inflammatory markers commonly used for IBD management. Our aims include: (1) To determine acceptability of randomization to the ENG contraceptive implant or 52mg-LNG IUD and in those who decline, acceptability of participation in a participant-preference arm, (2) To obtain estimates of means and standard deviations in established IBD symptom scales (Harvey Bradshaw and partial Mayo) and IBD quality of life measures across the phases of two menstrual cycles and then for 6 months after contraceptive method initiation, and (3) To obtain preliminary estimates of inflammatory marker variation across menstrual phases and pre- and post- contraceptive initiation. This pilot will inform a future trial design and this line of inquiry will allow for an adjuvant approach for IBD symptom management that is sex-specific and addresses both concerns for hormonal triggers and the need for highly-effective contraception for those who desire it.

Detailed Description
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Aim 1. To determine acceptability of randomization to the ENG contraceptive implant or 52mg-LNG IUD and in those who decline, acceptability of participation in a participant-preference arm. Hypothesis: The majority of participants will accept randomization if they may switch methods if not satisfied. Aim 2. To obtain estimates of means and standard deviations in established IBD symptom scales (Harvey Bradshaw and partial Mayo) and IBD quality of life measures across the phases of two menstrual cycles and then for 6 months after contraceptive method initiation. Hypothesis: IBD symptom scale domains and total scores as well as quality of life measures will reliably reflect IBD symptom changes after contraceptive method initiation. Aim 3. To obtain preliminary estimates of inflammatory marker (fecal calprotectin and high sensitivity C-reactive protein) variation across menstrual phases and pre- and post- contraceptive initiation. Hypothesis: Variations that occur as a result of menstrual phase and IBD activity will decrease after contraceptive initiation. Study Design: A pilot prospective randomized trial with a patient-preference arm for those who decline randomization to assess acceptability of randomization to the ENG implant or LNG IUD in people with IBD and menstrual-related IBD symptoms. Participant recruitment: The investigators will recruit via four different sources: 1. The investigators will send recruitment emails to the University of Utah IBD Center patients who meet inclusion criteria via the Epic patient portal (MyChart). 2. The investigators will post fliers regarding the study in the gastroenterology, primary care, and women's health clinics across University of Utah sites. 3. The investigators will send recruitment materials to other non-university gastroenterology sites in Utah and request flier use in their clinics. 4. The investigators will advertise via targeted social media within the University of Utah catchment area with a link to a University of Utah Research Enterprise Data Capture (REDCap) survey to assess eligibility and provide contact information for study coordinators to connect for a phone screen. Sample Size: This pilot study is designed to collect baseline data to inform future trials and not powered to assess statistical differences between study groups. The investigators plan to recruit 40 participants to assess recruitment feasibility, while allowing for a large enough sample to assess acceptability of randomization, adherence to the protocol and survey completion requirements. Our sample size takes into consideration feasibility for recruitment given our recruitment timeline, as well as sample size recommendations for pilot clinical trials. The investigators anticipate at least 30 participants will find randomization acceptable with up to 10 in a participant-preference arm. Randomization scheme and concealment: The REDCap system will generate the randomization sequence with varied blocks (four and six): 1. ENG implant and 2. LNG IUD. No treatment concealment will occur for participants or providers due to differences in devices and inability to conceal either those inserting them, but statisticians not will be aware of treatment assignment, only study arm 1 or 2. Participant procedures: Total study engagement is  8 months with  2 months of natural menstrual cycles followed by contraceptive method placement and 6 months of follow-up. Phone screening visit: Subjects will be screened for eligibility and interest in the study followed by review of clinical documentation confirming IBD diagnosis. In-person screening visit: Each subject will have the study explained and, if participation is desired, informed consent documents will be signed prior to any study procedures. The screening visit will include urine pregnancy testing, physical examination, lab testing (complete blood count, hsCRP, ferritin, and they will receive kit to collect fecal calprotectin from home stool sample and return at 1 week blood draw). Participants will complete an enrollment survey to assess sociodemographic and reproductive characteristics, IBD history including current and prior treatments, menstrual cycle timing and symptoms including bleeding characteristics and pain scores, sexual satisfaction surveys, baseline IBD symptom surveys and quality of life measures, menstrual-related IBD symptoms, acceptability of randomization, method desired and reasoning if not willing to be randomized, and prior contraceptive experiences. Daily surveys. These short surveys will begin the day following the screening visit and continue through 6 months following LARC method insertion ( 8 months total study engagement). They will query the patient-reported questions for the IBD symptom scale depending on diagnosis (Harvey Bradshaw Index for Crohn's vs. partial Mayo Score) which assess stool pattern, rectal bleeding, abdominal pain, and well-being. The investigators will also query chronic pelvic pain severity, vaginal bleeding and amount, and if bleeding, menstrual-related pain and severity. Weekly Surveys. These longer surveys will include the daily questions plus the Short Form IBD QOL index, a Likert scale on how bothersome IBD symptoms have been in the past week, sexual activity with assessment of dyspareunia and the Contraceptive Sexual Acceptability survey, additional treatments for IBD or menstrual symptoms, and any changes to health history. Lab assessments of inflammatory markers will occur at varying intervals. WBC, ferritin and albumin will be assessed at baseline screening visit and again at the exit visit 6 months post-method insertion. The hsCRP will be measured at baseline and then occur weekly until contraceptive device insertion and then monthly until the 6-month exit visit. Fecal calprotectin (from 1st morning stool) will be measured at baseline (sample collected at 1-week blood draw after enrollment), at LARC initiation, then monthly for 6 months. The hsCRP and fecal calprotectin assessments that occur outside of scheduled clinic visits can be drawn/dropped off at local University labs throughout the region. In-person contraceptive placement visit: The participant will notify the research staff when their 2nd menstrual cycle after screening visits begins and they will be scheduled for an in-person enrollment visit within 7 days. Changes in health history will be assessed. The REDCap system will generate the randomization sequence with varied blocks (four and six): 1. ENG implant and 2. LNG IUD. No treatment concealment will occur for participants or providers due to differences in devices and inability to conceal either those inserting them, but statisticians not will be aware of treatment assignment, only study arm 1 or 2. Devices will be inserted via standard practice. Participant-preference arm- those who opt out of randomization will select their method at the same cycle timing as those randomized. An additional survey will query reasoning for declining randomization and decision-making regarding device selection. All other study procedures will remain the same as those randomized. In-person follow-up visit: The participant will have a follow-up visit  2mo after contraceptive method placement. Changes in health history will be assessed and for those with an IUD, a string check performed. In-person Exit visit: The participant will have an exit visit  6mo after contraceptive method placement. Changes in health history will be assessed and for those with an IUD, a string check performed. Those who desire contraceptive method continuation may keep their devices and continue use based on method approval. Analyses. The goal of Aim 1 is to calculate a point estimate of the proportion of participants willing to be randomized to either an ENG implant or LNG IUD. A 95% confidence interval around this estimate will describe its variability. Secondary outcomes include the proportion of participants that agree to participation in the patient preference arm, and of these, reasoning for method selection and unacceptability of randomization. The investigators will use descriptive statistics, as well as thematic findings from free text response options. Aim 2 will assess changes in IBD symptom scores and QOL measures after contraceptive initiation. Cycle timing will be calculate based on reported cycle length and on bleeding intervals in the 2 months prior to LARC insertion and other metrics analyzed for changes by ovulation timing and menses. The investigators will calculate proportion of participants who change IBD treatment during the study timeframe, as this may inform sampling in future trial. The investigators will also calculate the proportion enrolled who had reported cyclical symptoms in 4 or more of their pre-enrollment cycles but then do not have cyclical changes in their 2 spontaneous cycles in the study, as this impacts future sample size calculations. The Harvey Bradshaw Index, partial Mayo Score, IBD-Q Short Form, and the Contraceptive Sexual Acceptability Scale will all be scored as appropriate. Report of bothersome IBD symptoms, chronic pelvic pain, dysmenorrhea, and dyspareunia will be on a Likert scale from 0-10. Any other reported changes in health, treatments or concerns will be reported by frequency and cycle timing. The investigators will compare means in symptom scores and QOL before and after contraceptive initiation using paired t-tests, and will compare variations in these means across menstrual cycle phases using linear regression, controlling for contraceptive initiation as a dichotomous variable. An Autoregressive Integrated Moving Average (ARIMA) l will be examined if data collection exceeds 100 observations. This approach will be utilized in future studies to better understand changes in patient reported outcomes overtime. Aim 3 will assess the proportion of participants with hsCRP and fecal calprotectin levels within a 'normal' range before and after contraceptive initiation through chi-square tests. Additionally, The investigators will compare mean hsCRP and fecal calprotectin levels before and after contraceptive initiation using paired t-tests. The investigators will compare variations means across menstrual cycle phases using linear regression, controlling for contraceptive initiation as a dichotomous variable. The investigators will look for difference in inflammatory marker levels across levels of IBD symptom scores to determine whether to include these symptom scores as covariates in our regression models. No comparisons will be made between participants, as baseline levels may vary and never be in a normal range for some markers.

Official Title
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Targeting the Knowledge Gap for Sex-specific Hormonal Influences on Inflammatory Bowel Disease Symptoms and Management

Conditions
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Inflammatory Bowel Diseases, Contraception, Menstrual Problem

Intervention / Treatment
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* Device: ENG Implant
* Device: LNG IUD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 18-45 years old Fluent in English and/or Spanish Have biopsy-proven IBD Have a regular menstrual cycle (21-35 days) Report recurrent cyclical IBD symptoms in >50% of menstrual cycles in past 6 months (e.g. change in bowel habits, abdominal pain, etc.) Intend to use a LNG IUD or ENG implant and willing to consider randomization Not at risk for pregnancy (e.g. sterilization, same-sex partner, abstinence) or willing to use condoms until 7 days after LARC device initiation Exclusion Criteria: Current pregnancy (+urine pregnancy test in clinic) Breastfeeding without resumption of 2 normal menses Contraindication to ENG implant or LNG IUD (U.S. Medical Eligibility Criteria for Contraceptive Use13 category 3 or 4) History of intolerance/ side effects with ENG Implant/LNG IUD Vaginal bleeding of unknown etiology Use of contraceptive steroids in past 30d without resumptions of menses Active, steroid-requiring IBD flare in past 30 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The REDCap system will generate the randomization sequence with varied blocks (four and six): 1. ENG implant and 2. LNG IUD.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Etonogestrel contraceptive implant<br>Participants who randomize to the implant or choose it in the participant preference arm will have it inserted during their 2nd menses after their screening visit. | Device: ENG Implant<br>* This is an FDA approved contraceptive device<br>* Other names: Nexplanon;|
| Active Comparator: 52mg levonorgestrel intrauterine device<br>Participants who randomize to the hormonal IUD or choose it in the participant preference arm will have it inserted during their 2nd menses after their screening visit. | Device: LNG IUD<br>* This is an FDA approved contraceptive device<br>* Other names: Liletta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptability of randomization | Proportion of participants willing to be randomized to an LNG IUD or ENG implant | 2 months after screening visit | 
| Change in IBD symptom scores in participants with Crohn's disease by menstrual timing and contraceptive | Variation in mean Harvey Bradshaw Index by menstrual phase prior to contraceptive initiation and changes from pre to post-method initiation. Scores of 5-7, 8-15 and >16 indicate mild, moderate and severe disease. A score of ≤4 denotes clinical remission and a drop ≥3 clinical response. | Measured daily on follow-up surveys for up to 8 months | 
| Change in IBD symptom scores in participants with ulcerative colitis by menstrual timing and contraceptive | Variation in mean Partial Mayo Score (pMS) both by menstrual phase prior to contraceptive initiation and changes from pre to post-method initiation. The pMS pMS (without endoscopic subscore) varies from 0 to 9. Lower scores are correlated with clinical response or remission. | Measured daily on follow-up surveys for up to 8 months | 
| Change in IBD quality of life score by menstrual timing and contraceptive | Variation in mean mean Inflammatory Bowel Disease Short Form Score (SIBDQ) both by menstrual phase prior to contraceptive initiation and changes from pre to post-method initiation. The SIBDQ is a shortened (10-item) version of a QOL survey with range 10-70. A 9-point change is generally considered a response amd higher scores indicate improved QOL. | Measured daily on follow-up surveys for up to 8 months | 
| Effect of contraceptive initiation on C Reactive Protein level | Proportion of participants with 'Normal' range (based on reference lab values or participant known baseline) at 1st study visit and compared to exit visit | Measured at baseline and exit visit | 
| Effect of contraceptive initiation and menstrual phase on C Reactive Protein level | Trend in mean of participant values over study timeframe of 8 months | Measured at baseline and weekly for 2 months until contraceptive initiation, then monthly for 6 months | 
| Effect of contraceptive initiation on fecal calprotectin level | Proportion of participants with 'Normal' range (based on reference lab values or participant known baseline) at 1st study visit and compared to exit visit | Measured at baseline and monthly for 8 months with contraceptive initiation at the 2 month timepoint | 
| Effect of contraceptive initiation and menstrual phase on fecal calprotectin level | Trend in mean of participant values over study timeframe of 8 months | Measured at baseline and monthly for 8 months with contraceptive initiation at the 2 month timepoint | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intrauterine device, subdermal contraceptive implant