Estrogen Therapy for NASH in Postmenopausal Women

Overseen By Caitlin Dobbie, NP

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: Massachusetts General Hospital

Must not be taking: Corticosteroids, Methotrexate, Amiodarone, Tamoxifen

Disqualifiers: Heavy alcohol use, Cirrhosis, Estrogen contraindications, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether an estradiol patch (a form of estrogen therapy) can reduce liver damage and fat in postmenopausal women with NASH, a severe form of non-alcoholic fatty liver disease. Researchers believe that the lack of estrogen after menopause may contribute to liver issues, and the trial aims to determine if adding estrogen can help. Participants will receive either the estradiol patch or a placebo patch. Women who are postmenopausal, have been diagnosed with NASH or NAFLD in the last six months, and have no history of heavy alcohol use may be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial requires that you have not used certain medications like NASH treatments, corticosteroids, methotrexate, amiodarone, tamoxifen, estrogen, or progesterone within specific time frames before joining. If you are on these medications, you may need to stop them to participate.

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

Research has shown that estradiol, a type of estrogen, is generally safe for postmenopausal women. One study on estradiol patches, which deliver the hormone through the skin, found them to be safe and effective for improving bone strength and metabolism in these women. This finding suggests that the estradiol patch might be safe for other uses as well.

Reports indicate that when progesterone is used with estradiol for women who still have their uterus, it might cause liver inflammation. However, studies have not found this issue with estrogen alone, meaning the estradiol patch itself is not linked to liver problems.

The current trial is in a later stage, which usually indicates that earlier studies did not reveal major safety concerns. Estradiol patches have also been approved by the FDA for other conditions, indicating they are generally safe. ^{1 2 3 4 5}

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

Unlike the standard care options for NASH, which typically include lifestyle changes and medications like vitamin E or pioglitazone, the estradiol patch offers a unique approach by using hormone therapy to address the condition. Researchers are excited about this treatment because it leverages estradiol, a form of estrogen, delivered through a transdermal patch, which might help reduce liver inflammation and fat buildup linked to NASH. Additionally, this method provides a convenient and non-invasive delivery system that could be particularly beneficial for postmenopausal women, a group often affected by this liver condition.

What evidence suggests that estradiol might be an effective treatment for NASH?

Research has shown that using an estrogen patch, such as the estradiol patch, can benefit individuals with non-alcoholic fatty liver disease (NAFLD). Studies have found that this treatment can slow liver problems associated with NAFLD. It appears to lower certain blood fat levels, potentially improving liver health. In this trial, some participants will receive the estradiol patch, which may be especially beneficial for postmenopausal women, who face a higher risk of these liver issues due to lower estrogen levels. Evidence suggests that using an estradiol patch may improve liver health and reduce related symptoms. ^{3 6 7 8 9}

Who Is on the Research Team?

Karen K Miller, MD

Principal Investigator

Massachsuetts General Hospital

Are You a Good Fit for This Trial?

This trial is for postmenopausal women aged 45-70 with NASH or NAFLD, who haven't used estrogen or progesterone in the past year. They must have a negative hepatitis test and mammogram. Women with severe chronic illness, known cirrhosis, active cancer, certain blood conditions, or heavy alcohol use are excluded.

Inclusion Criteria

Hepatitis C antibody and hepatitis B surface antigen negative

Negative mammogram within 1 year

I am a woman aged 45-70 and have gone through menopause.

Exclusion Criteria

I have used estrogen or progesterone in the past year.

I haven't taken corticosteroids, methotrexate, amiodarone, or tamoxifen in the last 6 months.

I cannot take estrogen therapy due to health risks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive estradiol or placebo via transdermal patch for 12 months

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Estradiol patch
• Placebo

Trial Overview

The study tests if an estradiol patch can help reduce liver fibrosis and fat in postmenopausal women with NASH. Participants will either receive the estradiol patch or a placebo to compare effects.

How Is the Trial Designed?

Group I: Estradiol Active Control 1 Intervention

Estradiol in the form of a transdermal patch 100 mcg daily (Vivelle-Dot generic). Women with an intact uterus will also receive progesterone (100 mg) in the form of a vaginal tablet (Endometrin, Ferring Pharmaceuticals, Inc.) inserted daily for endometrial protection

Group II: Placebo Placebo Group 1 Intervention

Placebo patch (containing no estradiol) Women with an intact uterus will also receive vaginal placebo capsules (containing no progesterone)

Estradiol patch is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Estraderm for:

• Menopausal symptoms
• Osteoporosis prevention
• Hypogonadism

Approved in European Union as Vivelle for:

• Hormone replacement therapy
• Osteoporosis prevention

Approved in Canada as Climara for:

• Menopausal symptoms
• Osteoporosis prevention

Approved in Japan as Estradiol Transdermal System for:

• Menopausal symptoms
• Osteoporosis prevention

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

The transdermal therapeutic system of estrogen (Estraderm) is effective in relieving hot flushes and vaginal atrophy, showing similar efficacy to oral estrogen treatments while maintaining bone health.

The patch is well tolerated with minimal side effects, such as low incidence of endometrial hyperplasia and breast tenderness, and patients generally prefer this method over oral administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with transdermal estradiol in the treatment of the climacteric. Utian, WH.[2013]

Currently, there are no FDA-approved pharmacotherapies for nonalcoholic fatty liver disease (NAFLD), despite extensive research into various treatment options over the past decade.

Numerous clinical studies have investigated the safety and efficacy of drugs targeting nonalcoholic steatohepatitis (NASH), leading to the development of guidelines for diagnosis and management, although no specific medication has been approved yet.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of nonalcoholic steatohepatitis: Reflections on the existing evidence. Tang, JT., Mao, YM.[2018]

NASH is a serious liver condition that often requires pharmacological treatment due to the difficulty many patients have in changing their diet and lifestyle; key features of the disease include insulin resistance and inflammation.

Recent clinical trials have shown promising results for new treatments like obeticholic acid and elafibranor, which target various pathways involved in NASH, and are currently being evaluated in phase III studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The therapeutic landscape of non-alcoholic steatohepatitis. Perazzo, H., Dufour, JF.[2022]

Non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure and transplantation in the U.S., linked to conditions like obesity and type 2 diabetes, highlighting the urgent need for effective treatments.

Current first-line treatments focus on weight loss and lifestyle changes, but these may not work for patients with advanced liver disease, emphasizing the importance of ongoing drug development targeting NASH's underlying mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New drugs for NASH. Albhaisi, SAM., Sanyal, AJ.[2021]

In a study of 104 postmenopausal women, the Systen estradiol patch was found to have better tolerability and adhesion compared to the Estraderm patch, with 79% of Systen users rating their treatment as 'good' or 'very good'.

Overall satisfaction with therapy was higher for Systen (53%) compared to Estraderm (46%), indicating that Systen may be a more effective option for estrogen replacement therapy in terms of patient acceptance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms. Van Leusden, HA., Albertyn, G., Verlaine, C., et al.[2013]

In a study involving a once-weekly transdermal estradiol patch applied to either the buttocks or abdomen, the buttock application resulted in significantly higher estradiol levels, with a 125.1% peak concentration compared to the abdomen.

The buttocks provided better bioavailability of estradiol, which may benefit women experiencing menopausal symptoms, as it maintained higher hormone levels throughout the week.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of site of application on the transcutaneous absorption of 17-beta estradiol from a transdermal delivery system (Climara). Taggart, W., Dandekar, K., Ellman, H., et al.[2019]

The new 7-day estrogen matrix patch (Climara) effectively alleviates climacteric symptoms in postmenopausal women, showing positive results in two 11-week placebo-controlled studies with good tolerance across different doses.

The 7-day patch demonstrated superior adhesion compared to the Estraderm patch, and absorption of estradiol was found to be higher and more consistent when applied to the buttock rather than the abdomen, indicating potential for optimized application sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with a 7-day estrogen patch: principles and practice. Notelovitz, M.[2013]

Transdermal estrogen replacement therapy in 32 menopausal women who had undergone liver transplantation was found to be safe, as it did not impair liver function or cause thrombotic effects over a 6-month follow-up period.

The treatment effectively achieved desired hormonal effects, as confirmed by biochemical markers and transvaginal ultrasound, indicating that transdermal estrogen can be safely combined with immunosuppressive drugs post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of transdermal estradiol replacement therapy in postmenopausal liver transplanted women. A preliminary report. Appelberg, J., Isoniemi, H., Nilsson, CG., et al.[2019]

The 7-day estradiol transdermal patch (Climara) effectively reduces hot flushes in women, with a mean decline of 74.6% for the higher dose compared to 64.5% for the lower dose, showing comparable efficacy to traditional hormone therapies.

The Climara patch is well tolerated, with a low withdrawal rate due to adverse events (8.9%), primarily related to skin reactions, and it demonstrated better adhesion compared to other patches, making it a practical option for estrogen replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with a seven-day estradiol transdermal system for estrogen replacement therapy. Gordon, SF.[2019]

The Estraderm Transdermal System, which delivers 17-beta estradiol, is an effective method for estrogen replacement therapy, providing relief from climacteric symptoms similar to oral estrogens, with localized skin irritation as the primary side effect in about 15% of users.

Transdermal estrogen therapy may have advantages over oral estrogen, such as bypassing the liver to reduce risks associated with blood pressure elevation, but there are concerns about an increased risk of breast cancer, highlighting the need for further long-term studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen replacement therapy and the estraderm transdermal system. Youngkin, EQ.[2013]

Non-alcoholic fatty liver disease affects about 25% of the global population, with nonalcoholic steatohepatitis (NASH) affecting 1.5% to 6.45%, and patients with NASH face higher risks of serious liver complications.

While there are no FDA-approved drugs specifically for NASH, several agents are currently in large phase 3 trials, and new effective treatments are expected within 2 to 4 years, with a focus on combination therapies and personalized medicine based on patient-specific factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming. Jeong, SW.[2021]

There is a growing prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) linked to obesity and metabolic syndrome, highlighting the need for effective treatments.

Current pharmacological therapies for NASH are varied and lack consensus on effectiveness, but ongoing clinical trials for new drugs may significantly impact treatment strategies, aiming not only to improve liver health but also to reduce cardiovascular risks and prevent diabetes and cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging drugs for non-alcoholic steatohepatitis. Tomeno, W., Yoneda, M., Imajo, K., et al.[2014]

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