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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Endometriosis	Drug: simvastatin 10mg; Drug: Bazedoxifene 20/Estrogens,Con 0.45Mg Tb; Drug: Placebo	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 28 participants
• 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
• Official Title: Mechanisms and Interventions Addressing Accelerated Cardiovascular Disease Risk in Women With Endometriosis
• Estimated Study Start Date: April 30, 2023
• Estimated Primary Completion Date: December 2025
• Estimated Study Completion Date: December 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Simvastatin; 30 days of Simvastatin (10mg/day)	Drug: simvastatin 10mg; Simvastation acts as a systemic LOX inhibitor.
Experimental: bazedoxifene + conjugated estrogen; 30 days of bazedoxifene + conjugated estrogen (0.45mg/20mg/day)	Drug: Bazedoxifene 20/Estrogens,Con 0.45Mg Tb; Duavee is a selective estrogen receptor modulator.
Placebo Comparator: Placebo; 30 days of placebo (microcrystalline cellulose filler capsule; 1 pill/day)	Drug: Placebo; Placebo for statin and SERM pretreatments.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

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

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

Locations

United States, Connecticut

The John B. Pierce Laboratory; Recruiting

New Haven, Connecticut, United States, 06519

Contact: Nina Stachenfeld, Ph.D. 203-562-9901 ext 219 nina.stachenfeld@yale.edu

Sponsors and Collaborators

Penn State University

The John B. Pierce Laboratory

More Information

• Responsible Party: Lacy Alexander, Professor of Kinesiology, Penn State University
• ClinicalTrials.gov Identifier: NCT05059626
• Other Study ID Numbers: 18347
• First Posted: September 28, 2021
• Last Update Posted: March 28, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Lacy Alexander, Penn State University:

Skin blood flow; Estrogen; Selective Estrogen Receptor Modulator; Intradermal Microdialysis

Additional relevant MeSH terms:

Endometriosis; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Bazedoxifene; Simvastatin; Estrogens; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Hormone Antagonists; Bone Density Conservation Agents