Simvastatin + Duavee for Endometriosis

(Endo2/SA3 Trial)

Overseen By Susan K Slimak, RN

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: Penn State University

Must not be taking: Cardiovascular medications

Disqualifiers: Diabetes, Hypertension, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 30 days

28 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications that could affect blood vessel function, such as those for heart or blood sugar issues. If you're on such medications, you would need to stop them to participate.

What data supports the effectiveness of the drug Simvastatin + Duavee for treating endometriosis?

Research shows that bazedoxifene with conjugated estrogens, components of Duavee, can cause regression of endometriosis in animal studies and may be a potential treatment option. Simvastatin, another component, has been shown to reduce pain and inflammation in endometriosis patients. ^{1 2 3 4 5}

Is the combination of Simvastatin and Duavee safe for humans?

Bazedoxifene with conjugated estrogens (Duavee) has been shown to be safe for treating menopausal symptoms and osteoporosis in postmenopausal women, with no significant stimulation of breast or uterine tissues. However, specific safety data for the combination of Simvastatin and Duavee for endometriosis is not available. ^{1 6 7 8 9}

How is the drug Simvastatin + Duavee unique for treating endometriosis?

Simvastatin + Duavee is unique for treating endometriosis because it combines a cholesterol-lowering drug, simvastatin, which reduces inflammation, with bazedoxifene/conjugated estrogens, which can help shrink endometriotic lesions without the side effects of traditional hormone therapies. This combination offers a novel approach by targeting both inflammation and estrogen-driven growth of endometriosis. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for women aged 18-45 with a prior diagnosis of endometriosis confirmed by laparoscopy within the last 5 years. Participants must not use nicotine, have diabetes, high blood pressure, abnormal liver function, cardiovascular disease, skin conditions or allergies relevant to the study drugs, and cannot be pregnant or breastfeeding.

Inclusion Criteria

I can take Tylenol for acute pain.

IUD contraceptive use (copper or levonogestrel) is allowed

Exclusion Criteria

Known allergy to latex or investigative substances

I have or might have a metabolic or heart-related condition.

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Participants undergo baseline assessments including cutaneous microdialysis and flow mediated dilation experiments

30 days

1 visit (in-person)

Washout

A 60-day washout period to minimize potential carryover effects

60 days

Treatment

Participants receive either Simvastatin or SERM (bazedoxifene + conjugated estrogen) for 30 days

30 days

1 visit (in-person)

Follow-up

Participants are monitored for changes in reproductive hormones, microRNA activity, inflammation, LOX-1 activity, skin blood flow, and peripheral blood flow

30 days post-intervention

Treatment Details

Interventions

• Bazedoxifene/Estrogens,Conjugated
• Placebo
• Simvastatin

Trial Overview The trial is testing whether simvastatin (10mg) and SERM (bazedoxifene + conjugated estrogens) can reduce inflammation and improve cardiovascular function in women with endometriosis. The focus is on how these treatments affect endothelium-dependent vasodilation—a marker of vascular health.

Participant Groups

Group I: bazedoxifene + conjugated estrogen Experimental Treatment 1 Intervention

30 days of bazedoxifene + conjugated estrogen (0.45mg/20mg/day)

Group II: Simvastatin Experimental Treatment 1 Intervention

30 days of Simvastatin (10mg/day)

Bazedoxifene/Estrogens,Conjugated is already approved in United States, European Union for the following indications:

Approved in United States as Duavee for:

• Moderate to severe vasomotor symptoms associated with menopause
• Prevention of postmenopausal osteoporosis

Approved in European Union as Duavive for:

• Treatment of oestrogen deficiency symptoms in postmenopausal women with an intact uterus with at least 12 months since last menses
• Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis

Who Is Running the Clinical Trial?

Penn State University

Lead Sponsor

Trials

380

Recruited

131,000+

The John B. Pierce Laboratory

Collaborator

Trials

3

Recruited

50+

Findings from Research

A case study of a patient with stage III endometriosis treated with bazedoxifene and conjugated estrogens for over 6 months showed complete resolution of pelvic pain, suggesting its potential efficacy as a treatment option.

The treatment did not result in any abnormal hormonal, uterine, or ovarian effects, indicating a favorable safety profile compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene-Conjugated Estrogens for Treating Endometriosis. Flores, VA., Stachenfeld, NS., Taylor, HS.[2021]

In a study involving 40 women with endometriosis, a 2-week treatment with 20 mg/day of simvastatin did not significantly reduce the expression of the MCP-1 gene or related macrophage-specific genes, suggesting limited efficacy for this dosage in treating endometriosis.

Although serum levels of MCP-1 increased after simvastatin treatment, the findings indicate that higher doses (40-100 mg/day) may be necessary for effectiveness, which could raise the risk of side effects like myopathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of simvastatin on monocyte chemoattractant protein-1 expression in endometriosis patients: a randomized controlled trial. Waiyaput, W., Pumipichet, S., Weerakiet, S., et al.[2018]

In a study involving 60 women with pelvic endometriosis, both simvastatin and GnRHa (Decapeptyl) significantly reduced endometriosis-related pain after surgery, with improvements measured over 16 weeks.

The effectiveness of simvastatin was comparable to that of Decapeptyl, indicating that both treatments can be viable options for managing pain associated with endometriosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of simvastatin in prevention of pain recurrences after surgery for endometriosis. Almassinokiani, F., Mehdizadeh, A., Sariri, E., et al.[2022]

In a study using CD-1 mice with experimental endometriosis, treatment with the selective estrogen receptor modulator bazedoxifene (BZA) significantly reduced the size of endometrial implants from an average of 60 mm² in the control group to 21 mm² in the BZA group, indicating its potential efficacy in treating endometriosis.

BZA treatment led to decreased expression of key markers associated with cell proliferation and estrogen activity in the endometrium, without causing ovarian enlargement or cyst formation, suggesting a safer profile compared to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model. Kulak, J., Fischer, C., Komm, B., et al.[2021]

Bazedoxifene/conjugated estrogens, when used with leuprolide, provide effective add-back therapy for premenopausal women with endometriosis without causing unwanted stimulation of the breasts, central nervous system, or endometrium.

This combination may serve as a progestin-free alternative to traditional add-back therapies, offering a safer option for managing symptoms associated with endometriosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene/conjugated estrogens in combination with leuprolide for the treatment of endometriosis. Hill, AM., Lessey, B., Flores, VA., et al.[2020]

Duavive, a combination of conjugated oestrogens and bazedoxifene acetate, is effective for treating estrogen deficiency symptoms in postmenopausal women who cannot use progestogen therapy, highlighting its targeted approach for this specific patient group.

Since its approval by the European Medicines Agency in 2014 and launch in the UK in 2016, Duavive has been reviewed for both efficacy and safety, establishing its role in managing menopausal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene for HRT? [2017]

Bazedoxifene demonstrated linear pharmacokinetics in healthy postmenopausal women, with steady-state achieved in one week and no unexpected accumulation across doses of 5 to 40 mg.

The drug was found to be safe and well tolerated, with an estimated oral bioavailability of approximately 6%, indicating that it is effectively absorbed in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women. McKeand, W.[2018]

In a 1-year study involving 1061 non-hysterectomized postmenopausal women, Bazedoxifene/conjugated estrogens (BZA/CE) demonstrated no cases of endometrial hyperplasia at the lower dose and only a small incidence at the higher dose, indicating strong endometrial safety.

BZA/CE significantly improved bone mineral density (BMD) in the lumbar spine and total hip compared to placebo, while also showing a favorable safety profile with low rates of bleeding and breast tenderness, making it a promising option for managing menopausal symptoms and preventing osteoporosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women. Mirkin, S., Komm, BS., Pan, K., et al.[2013]

Bazedoxifene acetate is an effective oral treatment for preventing and treating osteoporosis in postmenopausal women, showing positive effects on bone health without stimulating breast or uterine tissue.

In combination with conjugated estrogens, bazedoxifene improves bone mineral density and reduces fracture risk while also alleviating menopausal symptoms, making it a promising option for women at high risk of osteoporosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis. Kung, AW., Chu, EY., Xu, L.[2012]

References

1. United States pubmed.ncbi.nlm.nih.gov

Bazedoxifene-Conjugated Estrogens for Treating Endometriosis. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Effect of simvastatin on monocyte chemoattractant protein-1 expression in endometriosis patients: a randomized controlled trial. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Effects of simvastatin in prevention of pain recurrences after surgery for endometriosis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Bazedoxifene/conjugated estrogens in combination with leuprolide for the treatment of endometriosis. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Bazedoxifene for HRT? [2017]

7. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis. [2012]