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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

Tracking Information
First Submitted Date  ICMJE September 10, 2021
First Posted Date  ICMJE September 28, 2021
Last Update Posted Date April 15, 2022
Actual Study Start Date  ICMJE January 1, 2022
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Endometriosis and Microvascular Dysfunction; Simvastatin and Duavee
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE 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  ICMJE Endometriosis
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 20, 2021)
55
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2026
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05059626
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Current Responsible Party Lacy Alexander, Penn State University
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Penn State University
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE The John B. Pierce Laboratory
Investigators  ICMJE Not Provided
PRS Account Penn State University
Verification Date April 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP