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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two treatments—a combination of bazedoxifene and conjugated estrogen (marketed as Duavee) and simvastatin—can help women with endometriosis. The researchers aim to determine if these treatments can reduce inflammation and improve heart health by enhancing blood vessel function. Women diagnosed with endometriosis in the last ten years who do not use nicotine or certain medications might be suitable candidates. The trial involves taking the treatments for 30 days. As a Phase 4 trial, this research focuses on understanding how these FDA-approved treatments can benefit more patients.

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 is the safety track record for these treatments?

Research has shown that the combination of bazedoxifene and conjugated estrogens has been tested for safety in various studies. These studies indicate some risks, such as a slight increase in the chance of developing cancer of the uterine lining and thickening of the uterine lining. However, users might have a lower risk of breast cancer compared to other hormone treatments. These treatments are not suitable for pregnant women due to potential risks to the developing baby.

For simvastatin, research suggests it is generally safe but can have some side effects. It is usually well-tolerated at lower doses, such as the 10 mg used in this trial. However, higher doses of simvastatin have been linked to muscle injury, so doctors recommend staying with lower doses unless a patient has been on a higher dose without problems. Some studies also suggest a possible link between statin use and issues related to the ovaries or uterus, but more research is needed to understand this fully.

Overall, both treatments have been tested in people before, and their safety profiles are well known, but they do come with some risks that participants should consider. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about the combination of Simvastatin and Duavee (bazedoxifene with conjugated estrogens) for endometriosis because it offers a novel approach compared to traditional treatments like hormone therapy or surgery. Simvastatin, primarily known for lowering cholesterol, may also reduce inflammation and slow the growth of endometrial tissue, which is different from how most current options work. Meanwhile, Duavee combines estrogen with a selective estrogen receptor modulator, which may provide hormonal balance with potentially fewer side effects. Together, this duo might offer a new, effective way to manage endometriosis symptoms with additional health benefits.

What evidence suggests that this trial's treatments could be effective for endometriosis?

This trial will compare the effects of two treatments for endometriosis. One treatment arm involves a combination of bazedoxifene and conjugated estrogens. Research has shown that this combination effectively treats endometriosis in animals and is expected to be safe for humans. It also reduces hot flashes and strengthens bones in postmenopausal women, though this is not directly related to endometriosis.

The other treatment arm involves simvastatin. Studies have found that simvastatin can lower the risk of endometriosis in animals by reducing the size and number of endometrial growths. Simvastatin may also make endometrial tissue less aggressive. However, some research suggests that higher doses than usual might be necessary for it to work effectively in humans. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10389232/

Comparative safety of conjugated estrogens/bazedoxifene ... CE/BZA users might experience slightly higher rates of endometrial cancer and endometrial hyperplasia, and a lower rate of breast cancer, than EP users in the ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4093999/

Treatment with Bazedoxifene and Conjugated Estrogens ... BZA/CE is an effective treatment for murine experimental endometriosis and is expected to yield a superior side effect profile in humans due to estrogenic ...

3. duavee.pfizerpro.com duavee.pfizerpro.com/efficacy

Efficacy & Safety Info View clinical studies to see how DUAVEE® helped to reduce moderate to severe hot flashes & increased bone mineral density (BMD) in postmenopausal patients.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0378512215000171

Perspective on prescribing conjugated estrogens ... In a 12-week study, CE 0.45 mg/BZA 20 mg significantly reduced the number and severity of hot flushes compared with placebo at weeks 4 and 12. Unlike estrogen- ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05059626

Endometriosis and Microvascular Dysfunction; Simvastatin ... Hypothesis: Treatment with the SERM (bazedoxifene + conjugated estrogen) or with simvastatin will decrease systemic inflammation and improve specific measures ...

6. duavee.pfizerpro.com duavee.pfizerpro.com/safety-and-tolerability

Safety & Tolerability Women who are pregnant should not use Duavee. Estrogen agonist/‌antagonists, including bazedoxifene, and estrogens individually are known to increase the risk ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/022247s007lbl.pdf

This label may not be the latest approved by FDA. For current ... The safety of conjugated estrogens/bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling ...

8. duavee.pfizerpro.com duavee.pfizerpro.com/

DUAVEE® (conjugated estrogens/bazedoxifene) | Safety Info There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Duavee contains bazedoxifene, an estrogen agonist ...

9. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK585122/

Bazedoxifene - StatPearls - NCBI Bookshelf - NIH In addition, bazedoxifene/conjugated estrogens pose significant risks due to their teratogenic effects on fetal development, leading to their ...