Endo2/SA3: Endometriosis and Microvascular Dysfunction; Simvastatin and Duavee

Sponsor

Penn State University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05059626

Collaborator

The John B. Pierce Laboratory (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

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

Anticipated Enrollment :

55 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.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

Actual Study Start Date :

Jan 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 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.

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

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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