Endometriosis and Microvascular Dysfunction; Simvastatin and Duavee (Endo2/SA3)

• ClinicalTrials.gov Identifier: NCT05059626
• Recruitment Status: Recruiting
• First Posted: September 28, 2021
• Last Update Posted: March 28, 2023
• Sponsor: Penn State University
• Collaborator: The John B. Pierce Laboratory
• Information provided by (Responsible Party): Lacy Alexander, Penn State University

Tracking Information

• First Submitted Date: September 10, 2021
• First Posted Date: September 28, 2021
• Last Update Posted Date: March 28, 2023
• Estimated Study Start Date: April 30, 2023
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 20, 2021)

• Change in skin blood flow [ Time Frame: before intervention and 30 days post-intervention ]
  cutaneous vascular conductance (units = red cell flux/mean arterial pressure)
• Change in peripheral blood flow [ Time Frame: before intervention and 30 days post-intervention ]
  brachial artery flow mediated dilation

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 20, 2021)

• Change in LOX-1 activity [ Time Frame: before intervention and 30 days post-intervention ]
  LOX-1 receptor expression
• Change in reproductive hormones [ Time Frame: before intervention and 30 days post-intervention ]
  blood hormone concentrations
• Change in inflammation [ Time Frame: before intervention and 30 days post-intervention ]
  inflammatory cytokine concentration
• Change in microRNA activity [ Time Frame: before intervention and 30 days post-intervention ]
  microRNA expression

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Endometriosis and Microvascular Dysfunction; Simvastatin and Duavee
• Official Title: Mechanisms and Interventions Addressing Accelerated Cardiovascular Disease Risk in Women With Endometriosis

Brief Summary

Purpose: To determine the effects of SERM and simvastatin interventions on endothelial dysfunction in women with endometriosis.

Hypothesis: Treatment with the SERM (bazedoxifene + conjugated estrogen) or with simvastatin will decrease systemic inflammation and improve specific measures of cardiovascular function including endothelium-dependent vasodilation.

Detailed Description

Endometriosis is an estrogen dependent gynecological disorder associated with considerable chronic pelvic pain, pain during intercourse and is a major cause of infertility. While endometriosis is a local inflammatory syndrome, the inflammatory process is systemic and underlies many of the co-morbidities associated with this devastating disease. Endometriosis and atherosclerotic cardiovascular disease (CVD) are both inflammation-induced diseases. Robust epidemiologic data demonstrate a clear association between endometriosis, reproductive risk factors, inflammation and CVD risk, the leading cause of death in women worldwide. Estrogen exposure is beneficial for women from a CVD standpoint, but the standard of treatment for endometriosis includes estrogen suppression. This creates a conundrum for the long-term management of CVD risk in women with endometriosis. Moreover, there is a significant gap in prior research into the role of inflammatory signaling, CVD risk and effective interventions to mitigate cardiovascular comorbidities.

Endometriosis and Endothelial Dysfunction: Circulating LDL and oxidized (ox)LDL are two of many biomarkers of cardiovascular and inflammatory disease elevated in women with endometriosis. These circulating factors and inflammatory cytokines stimulate the ubiquitously expressed scavenger lectin-like oxidized LDL receptor (LOX-1) on the vasculature resulting in increased oxidant production and reduced nitric oxide (NO) metabolism, resulting in pronounced endothelial dysfunction, one of the earliest detectable indicators of increased CVD risk. Interestingly, estrogen directly inhibits LOX-1-dependent endothelial dysfunction. Our working model is that endometriosis-associated systemic inflammatory mediators increase LOX-1 receptor activity and result in endothelial dysfunction.

Therapies approved in 2018 for the treatment of endometriosis reduce endogenous estrogen production (elagolix) or selectively modulate estrogen receptors (SERM, bazedoxifene). Additionally, in preclinical models, therapies that modulate vascular function (statins) are also efficacious for reducing endometriosis proliferation. However, to date no studies have evaluated outcomes specific to systemic inflammation and cardiovascular function with these emerging endometriosis therapies.

This is a single blind placebo control randomized crossover study. Only women with endometriosis will complete this study. Women will be between the ages of 18 and 45 years and previously diagnosed (within the past 5 years) with endometriosis. Once consented and screened, each subject is block randomized to either 30 days of a treatment (Simvastatin or 30 days of SERM (bazedoxifene + conjugated estrogen; BZE+CE)) and , statin, or placebo. This will be done in a counterbalanced fashion. Subjects will only complete one of the treatments and the placebo with a 30 day washout to minimize potential carryover effects. On day 30 of pretreatment or placebo, each subject participates in a cutaneous microdialysis (MD) and flow mediated dilation (FMD) experiment. After a 30-day washout, the participant will start either the treatment or placebo and returns to repeat the study with the other pre-treatments (SERM/Statin/Placebo)undergo the MD and FMD experiments. These treatments/placebo are blinded to the investigators.

• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

This is a single blind placebo control randomized crossover study. Only women with endometriosis will complete this study. Once consented and screened, each subject is block randomized to either 30 days of a treatment (Simvastatin or 30 days of SERM (bazedoxifene + conjugated estrogen; BZE+CE)) and placebo. This will be done in a counterbalanced fashion. Subjects will only complete one of the treatments and the placebo with a 30 day washout to minimize potential carryover effects. We will use Research Randomizer software. These treatments/placebo are blinded to the investigators.

Masking: Single (Investigator)
Masking Description:

These treatments/placebo are blinded to the investigators. The subjects, physician, and the nurse on staff knows which treatment the subject is taking if there are any questions or safety concerns.

Primary Purpose: Basic Science

• Condition: Endometriosis

Intervention

• Drug: simvastatin 10mg
  Simvastation acts as a systemic LOX inhibitor.
• Drug: Bazedoxifene 20/Estrogens,Con 0.45Mg Tb
  Duavee is a selective estrogen receptor modulator.
• Drug: Placebo
  Placebo for statin and SERM pretreatments.

Study Arms

• Experimental: Simvastatin
  30 days of Simvastatin (10mg/day)
  Intervention: Drug: simvastatin 10mg
• Experimental: bazedoxifene + conjugated estrogen
  30 days of bazedoxifene + conjugated estrogen (0.45mg/20mg/day)
  Intervention: Drug: Bazedoxifene 20/Estrogens,Con 0.45Mg Tb
• Placebo Comparator: Placebo
  30 days of placebo (microcrystalline cellulose filler capsule; 1 pill/day)
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 8, 2022): 28
• Original Estimated Enrollment (submitted: September 20, 2021): 55
• Estimated Study Completion Date: December 2026
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Women between the ages of 18 and 45 years with endometriosis (diagnosis by prior laparoscopy by subject's own physician <5 years prior, and reported by the subject to the researchers)
• Tylenol if the subject has acute pain is allowed
• Contraceptive use is allowed

Exclusion Criteria:

• Use of nicotine-containing products (e.g. smoking, chewing tobacco, etc.)
• Diabetes (HbA1C .6.5%)
• BP>140/90
• Taking pharmacotherapy that could alter peripheral vascular control (e.g. insulin sensitizing, cardiovascular medications)
• Pregnancy
• Breastfeeding
• Taking illicit and/or recreational drugs
• Abnormal liver function
• Rash, skin disease, disorders of pigmentation, known skin allergies
• Diagnosed or suspected metabolic or cardiovascular disease
• Persistent unexplained elevations of serum transaminases
• Known allergy to latex or investigative substances

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Lacy M Alexander, PhD; 814-867-1781; lma191@psu.edu

Contact: Susan K Slimak, RN; 814-863-8556; sks31@psu.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05059626
• Other Study ID Numbers: 18347
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Lacy Alexander, Penn State University
• Original Responsible Party: Same as current
• Current Study Sponsor: Penn State University
• Original Study Sponsor: Same as current
• Collaborators: The John B. Pierce Laboratory
• Investigators: Not Provided
• PRS Account: Penn State University
• Verification Date: March 2023