Estrogen Therapy for NASH in Postmenopausal Women

Overseen by Karen K Miller, MD

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Massachusetts General Hospital

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

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

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic in the United States. Despite this, the treatment options remain limited. Preclinical and preliminary clinical data suggest that estrogen deficiency plays an important role in the pathology of steatosis, inflammation and fibrosis in non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Post-menopausal women are a growing population with particularly high risk of NASH due to their lack of estrogen. This study will examine the effect of estradiol on hepatic fibrosis and fat in post-menopausal women with NASH.

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.

What data supports the effectiveness of the drug Estradiol patch for treating NASH in postmenopausal women?

Research shows that transdermal estradiol patches, like Estraderm and Climara, are effective in reducing menopausal symptoms and may decrease the risk of osteoporosis. They also avoid some risks associated with oral estrogen, such as increased blood pressure, by bypassing the liver. ^{1 2 3 4 5}

Is estrogen therapy using transdermal patches safe for postmenopausal women?

Estrogen therapy using transdermal patches like Estraderm and Climara is generally safe for postmenopausal women, with the most common side effect being mild skin irritation at the patch site. Some studies suggest a potential increased risk of breast cancer with long-term use, so more research is needed. The patches do not adversely affect liver proteins or lipid levels, and they avoid some risks associated with oral estrogen therapy. ^{2 3 4 6 7}

How is the Estradiol patch treatment for NASH in postmenopausal women different from other treatments?

The Estradiol patch is unique for NASH treatment as it involves hormone therapy using estrogen, which is not a standard approach for this condition. Unlike other treatments that target liver-specific pathways, this therapy may offer benefits related to hormone replacement, particularly in postmenopausal women. ^{8 9 10 11 12}

Research Team

Karen K Miller, MD

Principal Investigator

Massachsuetts General Hospital

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Estradiol patch (Hormone Therapy)
• Placebo (Drug)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. William Curry

Massachusetts General Hospital

Chief Medical Officer

MD from Harvard Medical School

Dr. Anne Klibanski

Massachusetts General Hospital

Chief Executive Officer since 2019

MD from Harvard Medical School

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

References

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

Safety and efficacy of transdermal estradiol replacement therapy in postmenopausal liver transplanted women. A preliminary report. [2019]

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

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

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

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

4. United States 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). [2019]

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

A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms. [2013]

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

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

7. Italy pubmed.ncbi.nlm.nih.gov

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

8. Korea (South) pubmed.ncbi.nlm.nih.gov

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

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

Emerging drugs for non-alcoholic steatohepatitis. [2014]

10. Australia pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of nonalcoholic steatohepatitis: Reflections on the existing evidence. [2018]

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

The therapeutic landscape of non-alcoholic steatohepatitis. [2022]

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

New drugs for NASH. [2021]