Mechanistic Characterization of Uterine Pain

NCT04145518 | Completed Phase 4 DMC FDA Drug

• 2 other identifiers: EH19-040R01HD098193-01A1
• Study Type: interventional
• Target: 183
• Locations: 1 country
• Sites: 1

Brief Summary

There are limited treatment options for management of dysmenorrhea, and the physiological processes they affect are not completely understood. For example, NSAIDs are effective in reducing menstrual pain in some women by inhibition of prostaglandin synthesis, but whether those effects are mediated by affecting contractility, perfusion, or hypoxemia is unknown. Understanding how these drugs relieve menstrual pain (and why they fail) would be of substantial clinical significance. Given the foregoing, Two Specific Aims are proposed: Aim #1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI scans of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. The investigators will include cohorts of women with imaging diagnosed leiomyoma and surgically-confirmed endometriosis to evaluate the contribution of structurally identifiable factors. Based on preliminary data, the investigators anticipate finding four phenotypes with menstrual pain related to: 1) myometrial activity, 2) inadequate perfusion and/or oxygenation, 3) a combination of phenotypes 1 \& 2, and 4) a non-uterine source. Aim #2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. In women with primary dysmenorrhea, the investigators will acquire pelvic MRI scans and evaluate self-reported menstrual cramping pain before and after administration of randomized naproxen or placebo. Naproxen could principally affect one or more potential sources of uterine pain such as myometrial activity, perfusion, and/or oxygenation. The investigators will corroborate preliminary data findings, which suggest menstrual phenotypes with myometrial activity will be more likely to respond. Conversely, Aim 2 will also elucidate the mechanisms responsible for inadequate pain relief from naproxen. Bioavailability of naproxen levels and other molecules associated with NSAID-resistance will be evaluated from the serum of participants after taking naproxen using HPLC-MS.

Conditions

Dysmenorrhea (Disorder); Dysmenorrhea Primary; Dysmenorrhea Secondary; Endometrial Diseases; Leiomyoma; Fibroid Uterus

Keywords

pain; NSAID; women's health; uterus; MRI

Outcome Measures

Primary Outcomes (3)

• Calculate response profiles of MRI signals for each menstrual pain phenotype

  The investigators will calculate the change in R2\*, ASL (arterial spin label), HASTE, and BOLD (Blood Oxygen Level Dependent) signal for each menstrual pain phenotype. Principal component analysis of derived MRI signal variables and subsequent scree plotting will be used to reduce the dataset to 4-6 representative parameters that meaningfully separate potential phenotypes via hierarchical cluster analysis (R cluster library). Cluster dissimilarity metrics will be used to establish the probable number of phenotypes. Thus, our analyses are not entirely dependent on hypothesized phenotypes. A post-hoc ANOVA will be performed on relevant signal intensity variables to validate differences between the phenotypes. A post-hoc ANOVA will also be performed to compare whether there are differences in R2\*, ASL, HASTE, and BOLD signals between primary dysmenorrhea, endometriosis and leiomyoma participants.

  Initial Scan (1 hour)

• Calculate response profiles of MRI signals associated with NSAID-resistance

  Data will be processed similarly to Outcome #1. The investigators will use a repeated measures ANOVA and ANCOVA to examine changes in mean R2\*, ASL, HASTE, or EPI-BOLD signal intensity (4 dependent variables) after naproxen and/or placebo administration in all women with primary dysmenorrhea-regardless of cluster identity or phenotype. The investigators will also use an ANCOVA to examine whether the 4 MRI metrics of uterine physiology are related to changes in pain, using the difference of VAS (Visual Analog Scale) after naproxen minus the VAS before naproxen as a covariate. The investigators will detect for ANCOVA assumptions (e.g., homogeneity of variance, normality) and utilize appropriate corrections (transformation, permutation analysis) when needed.

  through study completion, an average of 16 weeks

• Calculate phenotype consistency

  The investigators will also use a paired X2 (McNemar) test to establish reliability of the repeat scans and examine differences in cluster/phenotype categorization across visits. The combined use of principal component analysis, hierarchical testing, and validation by a repeatability test follows recommended guidelines

  through study completion, an average of 16 weeks

Secondary Outcomes (3)

• Anatomical effects

  through study completion, an average of 16 weeks

• Covariate analysis

  through study completion, an average of 16 weeks

• Calculate the relationship between Naproxen absorption and NSAID resistance.

  through study completion, an average of 16 weeks

Study Arms (2)

Naproxen/Placebo Crossover

ACTIVE COMPARATOR

Participants will be randomized to take either a placebo pill or a single 550 mg naproxen sodium pill. Randomization with a block size only known by the statistician, will be programmed to be allocated out of REDcap. Our clinical research pharmacy will provide naproxen and an identical looking placebo in containers with codes only known to the statistician to provide a double-blinded experimental design. On a subsequent episode of menstrual pain (1-2 months later), participants will receive the opposite treatment and undergo the exact same assessments.

Drug: Naproxen Sodium

Placebo/Naproxen Crossover

PLACEBO COMPARATOR

Participants will receive placebo first in this arm.

Drug: Naproxen Sodium

Interventions

Naproxen Sodium DRUG

Participants will be randomized to take either a placebo pill or a single 550 mg naproxen sodium pill.

Also known as: Placebo

Naproxen/Placebo Crossover; Placebo/Naproxen Crossover

Eligibility Criteria

• Age: 18 Years - 45 Years
• Gender Eligibility Details: Participants must have a uterus and must not be undergoing hormone therapy.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may not qualify if:

• Age restrictions for all study participants: Regularly menstruating women (age 18-45) will be identified using our well-tested community-wide recruitment strategy, including approaching our division's busy gynecological disorders clinic, and the departments of Ob/Gyn at NorthShore and the University of Chicago. Although women above the age of 45 can have menstrual pain, irregularities in perimenopause could cause confounding effects on uterine physiology and scheduling difficulty. Similarly, irregularities in menstruation, ovulation, and pain levels in participants under age 18 could potentially detract from meaningful interpretation of phenotypes (Seidman et al., 2018). Additionally, before age 18, the uterus is still developing and substantially increasing in size (Porcu et al., 1989; Verguts et al., 2013). Thus, to limit potential confounding effects, participants under the age of 18 will be investigated in a separate study.
• The investigators will exclude participants with criteria that would affect our ability to obtaining meaningful MRI data such as
• presence of an intrauterine device (IUD). The use of an IUD potentially affects interpretability of MRI because it creates an imaging artifact in the endometrium extending to the myometrium.
• inability to read or comprehend the informed consent written in English,
• history of metallic implants,
• history of metallic injury,
• any diagnosed condition that would preclude investigation with MRI (e.g., claustrophobia),
• BMI \>40,
• allergy or inability to tolerate naproxen
• thyroid dysfunction,
• adrenal dysfunction,
• renal disorders,
• liver disorders,
• coagulopathy,
• prolactinoma,

Sponsors & Collaborators

• Endeavor Health: lead
• National Institutes of Health (NIH): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

NorthShore University HealthSystem

Evanston, Illinois, 60201, United States

Location

MeSH Terms

Conditions

Dysmenorrhea; Uterine Diseases; Leiomyoma; Pain

Interventions

Naproxen

Condition Hierarchy (Ancestors)

Menstruation Disturbances; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Pelvic Pain; Neurologic Manifestations; Signs and Symptoms; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Naphthaleneacetic Acids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Kevin M Hellman, PhD

  Endeavor Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Associate Professor

Study Record Dates

• First Submitted: October 25, 2019
• First Posted: October 30, 2019
• Study Start: October 25, 2019
• Primary Completion: July 23, 2025
• Study Completion: July 23, 2025
• Last Updated: December 12, 2025

Record last verified: 2025-12

Locations

US (1)