Bazedoxifene + Estrogens for Atherosclerosis

(APPT Trial)

Overseen By Lora Maxwell, RN

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: University of Southern California

Must not be taking: Hormone replacement therapy

Disqualifiers: Cardiovascular disease, Diabetes, Hypertension, Breast cancer, others

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

Compensation: Varies

Number of Visits: 6

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of bazedoxifene and estrogens (taken orally) can slow the progression of early-stage atherosclerosis (a condition where arteries narrow) and cognitive decline in healthy postmenopausal women. Participants will receive either the actual treatment or a placebo (a harmless pill that resembles the treatment). It suits women who have stopped having regular periods for over six months but less than six years and have not had hysterectomies or heart issues. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

The trial requires that you stop using postmenopausal hormone replacement therapy (HRT) at least 1 month before joining. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that the combination of bazedoxifene and conjugated estrogens, used in the treatment under study, is generally well-tolerated. Studies indicate that this combination does not consistently harm blood vessels in the brain. It also appears safe for the heart, with stroke and heart disease rates similar to those seen with a placebo, suggesting it doesn't increase these risks. Additionally, some studies suggest it can improve cholesterol levels, benefiting heart health. Overall, based on the available data, this treatment seems safe for use in postmenopausal women. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for atherosclerosis?

Unlike the standard treatments for atherosclerosis, which typically include medications like statins that lower cholesterol, bazedoxifene combined with conjugated estrogens offers a novel approach by potentially addressing the condition through hormone therapy. Researchers are excited because bazedoxifene has selective estrogen receptor modulator (SERM) properties, which might help improve cardiovascular health without some of the risks associated with traditional hormone replacement therapies. This combination could provide an innovative way to manage atherosclerosis, especially for postmenopausal women, by leveraging its unique mechanism targeting estrogen receptors to influence vascular health.

What evidence suggests that this treatment might be an effective treatment for atherosclerosis?

Research has shown that the combination of bazedoxifene and conjugated estrogens (BZA/CE), which participants in this trial may receive, is safe for the heart and blood vessels. Studies indicate it does not worsen arterial hardening and may even offer benefits. Specifically, after 12 months, BZA/CE improved cholesterol levels by significantly reducing LDL, often called "bad cholesterol," compared to a placebo. This combination also supports overall metabolic health, which is important for preventing heart disease. While more research is needed, these findings suggest BZA/CE could help manage artery health in postmenopausal women. ^{1 2 3 4 6}

Who Is on the Research Team?

Howard N. Hodis, MD

Principal Investigator

University of Southern California Atherosclerosis Research Unit

Are You a Good Fit for This Trial?

This trial is for healthy postmenopausal women aged 45-59, within six years of menopause and with low estrogen levels. It's not for those who've had a hysterectomy, cardiovascular disease, diabetes, severe illness with short prognosis, liver disease, blood clots in veins or lungs, breast cancer history or recent hormone therapy.

Inclusion Criteria

I am a woman aged 45-59, less than 6 years postmenopausal, with low estrogen levels.

Exclusion Criteria

I have a history of heart problems.

Your blood test shows that you have high levels of creatinine, which is a waste product in the blood.

I have been using hormone replacement therapy for the past month.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Bazedoxifene/Conjugated Equine Estrogen or placebo for up to 3 years

Up to 3 years

Visits at baseline, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, and 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Oral bazedoxifene 20 mg / conjugated estrogens 0.45 mg
• Placebo

Trial Overview The APPT study tests if a combo pill (bazedoxifene and conjugated estrogens) can slow down heart artery hardening and mental decline compared to a placebo. The trial randomly assigns participants to either the treatment or placebo group in secret.

How Is the Trial Designed?

Group I: BZA/CE Experimental Treatment 1 Intervention

Oral bazedoxifene 20 mg / conjugated estrogens 0.45 mg

Group II: Placebo Placebo Group 1 Intervention

Oral matching placebo

Who Is Running the Clinical Trial?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

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 pooled analysis of five phase-3 trials involving 4868 healthy, non-hysterectomized postmenopausal women showed that conjugated estrogens/bazedoxifene (CE/BZA) has an acceptable cardiovascular safety profile, with low rates of venous thromboembolic events (VTEs) and comparable rates of stroke and coronary heart disease (CHD) to placebo.

The incidence of VTEs was very low across different doses of CE/BZA, with rates of 0.3 to 0.7 per 1000 woman-years, indicating that CE/BZA is a safe option for managing menopausal symptoms without significantly increasing cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. Komm, BS., Thompson, JR., Mirkin, S.[2015]

Bazedoxifene acetate is an investigational oral drug that effectively prevents bone loss and reduces vertebral fracture risk in postmenopausal women, without affecting the endometrium or breast tissue.

When combined with conjugated estrogens, bazedoxifene shows promise in improving menopausal symptoms while providing skeletal benefits, making it a potential treatment for postmenopausal osteoporosis and related symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene and bazedoxifene combined with conjugated estrogens for the management of postmenopausal osteoporosis. Lewiecki, EM.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3760976/

The Effects of Bazedoxifene, Conjugated Equine Estrogens ... BZA had no consistent adverse effect on cerebral artery atherosclerosis and did not attenuate the modest beneficial effect of CEE on common carotid arteries.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23435024/

Effects of bazedoxifene alone and with conjugated equine ... BZA had no adverse effects on the extent or severity of coronary or common iliac artery atherosclerosis when compared with no treatment. CEE, administered soon ...

3. tandfonline.com tandfonline.com/doi/full/10.3109/13697137.2014.992011

Full article: Cardiovascular safety of conjugated estrogens ... Up to 2 years of CE 0.45 or CE 0.625 mg with BZA 20 mg had an acceptable cardiovascular safety profile, with rates of stroke and CHD comparable to placebo.

4. insight.jci.org insight.jci.org/articles/view/182694

Metabolic and transcriptional effects of bazedoxifene ... These data support the use of BZA/CE to improve metabolic health and reduce breast cancer risk in individuals with obesity.

5. academic.oup.com academic.oup.com/jcem/article/100/6/2329/2829631

Pooled Analysis of the Effects of Conjugated Estrogens ... At 12 months, CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg produced significant (P < .001) improvements vs PBO in TC (−4.20% and −4.37% vs −0.88%), LDL-C (− ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0039128X14001433

Development of conjugated estrogens/bazedoxifene, the ... Therefore, CE 0.45 mg/BZA 20 mg is an effective, well-tolerated alternative to EPT for menopausal symptom relief and osteoporosis prevention for postmenopausal ...