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

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ClinicalTrials.gov Identifier: NCT05059626
Recruitment Status : Recruiting
First Posted : September 28, 2021
Last Update Posted : April 15, 2022
Sponsor:
Collaborator:
The John B. Pierce Laboratory
Information provided by (Responsible Party):
Lacy Alexander, Penn State University

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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.
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 : January 1, 2022
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Endometriosis

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.




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



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05059626


Contacts
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Contact: Lacy M Alexander, PhD 814-867-1781 lma191@psu.edu
Contact: Susan K Slimak, RN 814-863-8556 sks31@psu.edu

Locations
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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
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Responsible Party: Lacy Alexander, Professor of Kinesiology, Penn State University
ClinicalTrials.gov Identifier: NCT05059626    
Other Study ID Numbers: 18347
First Posted: September 28, 2021    Key Record Dates
Last Update Posted: April 15, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Endometriosis
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