Duavive for Menopausal Depression

(DOMA Trial)

Overseen By Leticia Hernandez Galan, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 1

Sponsor: St. Joseph's Healthcare Hamilton

Must not be taking: Antidepressants, Psychoactive medications

Disqualifiers: Cancer, Thromboembolic disease, Liver disease, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This study evaluates the impact of conjugated estrogens/ bazedoxifene (CE/ BZA) on the mood (depression and anxiety) in peri- and early menopausal women.

Will I have to stop taking my current medications?

If you are taking antidepressants or other psychoactive medications, you will need to stop them at least 2 weeks before the study starts.

What data supports the effectiveness of the drug Duavive for menopausal depression?

There is evidence that estrogen therapy, a component of Duavive, has antidepressant effects in perimenopausal women, especially those with hot flashes and other menopause symptoms. However, data on estrogen combined with other components like progestin are limited and not conclusive. ^{1 2 3 4 5}

Is Duavive safe for humans?

Duavive (also known as bazedoxifene/conjugated estrogens) has been shown to be generally safe in humans, with studies indicating no significant differences in serious health events like heart or stroke issues compared to other treatments. However, some side effects like hot flashes and leg cramps were more common than with a placebo. ^{6 7 8 9 10}

How is the drug Duavive unique for treating menopausal depression?

Duavive is unique because it combines conjugated estrogens with bazedoxifene, which acts as a selective estrogen receptor modulator (SERM) to help manage menopausal symptoms and potentially improve mood. This combination may offer a novel approach compared to traditional antidepressants or hormone therapies used separately. ^{1 3 5 11 12}

Research Team

Alison Shea, MD

Principal Investigator

St. Joseph's Healthcare, McMaster University

Eligibility Criteria

This trial is for English-speaking women aged 45-60 who are in perimenopause or early menopause (within 10 years of their last period) and experiencing depression (scoring 16+ on CES-D) or anxiety symptoms (scoring 10+ on GAD-7).

Inclusion Criteria

Able to communicate in English

I am a woman aged between 45 and 60.

I am in perimenopause or within 10 years of my last menstrual period.

Exclusion Criteria

Known or suspected pregnancy, women who may become pregnant, and nursing mothers

Known hypersensitivity to either CE or BZA

Uncontrolled hypertension (Systolic blood pressure >160mm Hg and/ or diastolic blood pressure >95 mm Hg)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CE/BZA treatment for mood and anxiety symptoms

16 weeks

Daily medication intake

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Duavive

Trial Overview The study tests the effects of Duavive, a tablet combining conjugated estrogens with bazedoxifene, on mood swings related to depression and anxiety in peri- and early postmenopausal women.

Participant Groups

Group I: Intervention group Experimental Treatment 1 Intervention

Patient will be provided with study medication. To be taken once a day for 16 weeks (112 days). Active drug brand name - Duavive/Duavee. Dose consisting of 1 pill of 0.45mg conjugated estrogens and 20mg bazedoxifene as bazedoxifene acetate.

Duavive is already approved in European Union, United States for the following indications:

Approved in European Union as Duavive for:

• Treatment of moderate to severe vasomotor symptoms associated with menopause in women with a uterus

Approved in United States as Duavee for:

• Treatment of moderate to severe vasomotor symptoms associated with menopause in women with a uterus

Who Is Running the Clinical Trial?

St. Joseph's Healthcare Hamilton

Lead Sponsor

Trials

203

Recruited

26,900+

McMaster University

Collaborator

Trials

936

Recruited

2,630,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

In a randomized, double-blind, placebo-controlled trial involving 387 perimenopausal and postmenopausal women, desvenlafaxine significantly reduced depression scores compared to placebo over 8 weeks, with a notable effect seen as early as week 1.

Desvenlafaxine treatment resulted in higher response (58.6%) and remission (38.2%) rates compared to placebo (31.6% and 22.4%, respectively), indicating its efficacy in treating major depressive disorder in this population, while it was generally well tolerated despite a higher rate of treatment-emergent adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term efficacy and safety of desvenlafaxine in a randomized, placebo-controlled study of perimenopausal and postmenopausal women with major depressive disorder. Kornstein, SG., Jiang, Q., Reddy, S., et al.[2015]

In a study of menopausal women receiving hormone replacement therapy with conjugated oestrogens (Premarin) over four weeks, non-depressed women showed improved depression scores and increased feelings of well-being.

However, the depressed group did not experience any improvement in their depression levels, suggesting that hormone replacement therapy may not be effective for alleviating depression in women who are already depressed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of exogenous oestrogens on depression in menopausal women. Schneider, MA., Brotherton, PL., Hailes, J.[2021]

Desvenlafaxine significantly reduced depression scores in both perimenopausal and postmenopausal women with major depressive disorder, showing a notable improvement compared to placebo after 8 weeks of treatment.

The study included 798 women, and desvenlafaxine also led to significant improvements in disability and menopause-related symptoms, indicating its efficacy beyond just mood enhancement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pooled analysis of the efficacy of desvenlafaxine for the treatment of major depressive disorder in perimenopausal and postmenopausal women. Kornstein, SG., Clayton, AH., Bao, W., et al.[2015]

Perimenopause is recognized as a critical period for the onset of depressive symptoms, with many women experiencing major depressive episodes during this time, often linked to prior depression episodes.

Front-line treatments for perimenopausal depression include antidepressants and psychotherapy, while estrogen therapy may provide additional benefits, especially for women with menopause-related symptoms, despite not being officially approved for this use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations. Maki, PM., Kornstein, SG., Joffe, H., et al.[2019]

Chronic intramuscular injections of tamoxifen led to significant depression-like symptoms in female rats, indicating its potential negative impact on mood.

In contrast, both klimadynon (Cimicifuga extract) and genistein demonstrated strong antidepressant effects in both intact and ovariectomized female rats, suggesting they may be beneficial for mood regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of synthetic and plant-derived selective modulators of estrogen receptors on depression-like behavior of female rats. Sapronov, NS., Kasakova, SB.[2019]

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]

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 is a selective estrogen receptor modulator designed specifically for preventing and treating osteoporosis in postmenopausal women, indicating its targeted approach to bone health.

It is also being studied in combination with Premarin to address menopausal symptoms, showing its potential dual role in women's health management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene (Wyeth). Gruber, C., Gruber, D.[2022]

In a study of 459 nonhysterectomized postmenopausal women, treatment with bazedoxifene (BZA) and conjugated estrogens (CE) for one year significantly improved sleep quality and health-related quality of life (HRQoL) compared to placebo.

Both BZA/CE and CE/medroxyprogesterone acetate (MPA) showed notable improvements in sleep parameters and MENQOL scores at 12 months, indicating their effectiveness in managing symptoms related to menopause.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens: a randomized trial. Pinkerton, JV., Pan, K., Abraham, L., et al.[2022]

Bazedoxifene has been shown to significantly reduce the incidence of new vertebral fractures by 42% in a phase III trial, demonstrating efficacy comparable to bisphosphonates and raloxifene.

The drug also appears to be more effective than raloxifene in reducing non-vertebral fractures, while maintaining a favorable safety profile with no significant increase in serious cardiovascular events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bazedoxifene as a new-generation SERM]. Ohta, H.[2012]

Women experience depression at higher rates than men, especially during the menopausal transition, where the risk of developing depression can increase by 1.5 to 4 times, particularly in those with vasomotor symptoms.

Estrogen therapy may be effective in improving mood and alleviating depressive symptoms in peri- and early postmenopausal women, making it a potential first-line treatment, while SSRIs and SNRIs are recommended for elderly postmenopausal women without hot flashes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Climacteric depression and anxiety]. Birkhäuser, M.[2021]

Tamoxifen administration in ovariectomized female rats resulted in anxiety and depression-like behaviors similar to those caused by the removal of ovarian hormones, indicating that tamoxifen may antagonize the effects of these hormones.

Interestingly, tamoxifen also showed anxiolytic effects in ovariectomized rats, suggesting it could help alleviate anxiety in this specific group despite its overall negative impact on mood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen antagonizes the effects of ovarian hormones to induce anxiety and depression-like behavior in rats. Azizi-Malekabadi, H., Pourganji, M., Zabihi, H., et al.[2015]

References

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

Short-term efficacy and safety of desvenlafaxine in a randomized, placebo-controlled study of perimenopausal and postmenopausal women with major depressive disorder. [2015]

2. Australia pubmed.ncbi.nlm.nih.gov

The effect of exogenous oestrogens on depression in menopausal women. [2021]

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

A pooled analysis of the efficacy of desvenlafaxine for the treatment of major depressive disorder in perimenopausal and postmenopausal women. [2015]

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

Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations. [2019]

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

Effects of synthetic and plant-derived selective modulators of estrogen receptors on depression-like behavior of female rats. [2019]

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

Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. [2015]

7. England pubmed.ncbi.nlm.nih.gov

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

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

Bazedoxifene (Wyeth). [2022]

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

Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens: a randomized trial. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

[Bazedoxifene as a new-generation SERM]. [2012]

11. Switzerland pubmed.ncbi.nlm.nih.gov

[Climacteric depression and anxiety]. [2021]

12. Germany pubmed.ncbi.nlm.nih.gov

Tamoxifen antagonizes the effects of ovarian hormones to induce anxiety and depression-like behavior in rats. [2015]