Simvastatin for Uterine Fibroids

Overseen By Mostafa Borahay, MD, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: Johns Hopkins University

Must not be taking: Statins, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Cancer, Menopausal, others

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: 6

Duration: 12 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing if simvastatin, a cholesterol-lowering drug, can reduce the size of uterine fibroids in women who are planning to undergo surgery. The study will see if simvastatin helps shrink the fibroids. Simvastatin is a well-known cholesterol-lowering drug that has been extensively studied for its effects on lipid profiles and cardiovascular health.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, especially those that interact with simvastatin, like strong CYP3A4 inhibitors and some other specific drugs. If you're on any of these, you may need to stop them before joining the trial.

What data supports the effectiveness of the drug Simvastatin for treating uterine fibroids?

Research shows that simvastatin can affect the growth of uterine fibroids by interfering with cholesterol production, which is linked to hormones like estrogen and progesterone that influence fibroid growth. ^{1 2 3 4 5}

Is simvastatin safe for use in humans, particularly concerning ovary and uterus health?

Simvastatin has been associated with some adverse effects related to the ovary and uterus, such as ovarian cysts and uterine disorders, according to data from the FDA Adverse Event Reporting System. However, in general, simvastatin has been shown to be effective with few adverse events reported in postmarketing studies. ^{1 2 6 7 8}

How is the drug simvastatin unique in treating uterine fibroids?

Simvastatin is unique in treating uterine fibroids because it targets the Wnt/β-catenin pathway, which is overactive in these tumors, potentially reducing their growth. This mechanism is different from other treatments, as simvastatin is primarily known as a cholesterol-lowering drug. ^{1 5 8 9 10}

Research Team

Mostafa Borahay, MD, PhD

Principal Investigator

Johsn Hopkins School Of Medicine

Eligibility Criteria

Women aged 18-55 with uterine fibroids causing heavy bleeding and pelvic pain are eligible for this trial. They must have at least one fibroid larger than 3cm, be using contraception, and not be pregnant or breastfeeding. Exclusions include allergies to simvastatin, liver disease, other cancers, menopause status, or currently in another study.

Inclusion Criteria

Signed informed written consent

I experience heavy menstrual bleeding and use contraception.

Uterine fibroids diagnosed by ultrasound (MRI will be used only if ultrasound is inconclusive)

Exclusion Criteria

I am currently taking simvastatin or a similar medication.

I am not taking strong medications that affect liver enzymes.

I need surgery within 3 months for health or personal reasons.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Simvastatin or placebo for 12 weeks prior to surgery

12 weeks

3 visits (in-person) at start, 6 weeks, and 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

2 visits (in-person) at 2 and 6 weeks post-surgery

Treatment Details

Interventions

• Placebo
• Simvastatin

Trial Overview The trial is testing whether Simvastatin (40mg), a medication typically used to lower cholesterol, can reduce the size of uterine fibroids compared to a placebo. Participants will randomly receive either the drug or an inactive substance.

Participant Groups

Group I: Treatment Group Experimental Treatment 1 Intervention

The 30 participants randomized in this group will intake Simvastatin 40mg / day of orally at the same time in the evening, every day for the study duration of 12 weeks prior to undergoing hysterectomy/ myomectomy. The fibroid samples will be collected after the surgery to evaluate the effects of the study medication on the fibroid tissue.

Group II: Placebo Group Placebo Group 1 Intervention

The 30 participants randomized in this group will intake Placebo 40mg / day orally at the same time in the evening every day for the study duration of 12 weeks prior to undergoing hysterectomy/ myomectomy. The fibroid samples will be collected after the surgery to evaluate the effects of the study medication on the fibroid tissue.

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

Approved in European Union as Zocor for:

• Hypercholesterolemia
• Cardiovascular disease

Approved in United States as Zocor for:

• Hypercholesterolemia
• Cardiovascular disease

Approved in Canada as Zocor for:

• Hypercholesterolemia
• Cardiovascular disease

Approved in Japan as Zocor for:

• Hypercholesterolemia
• Cardiovascular disease

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

Simvastatin induced dose-dependent apoptosis and inhibited proliferation in uterine leiomyoma cells in vitro, showing significant effects at concentrations of 5 and 10 μM.

In vivo studies demonstrated that simvastatin treatment for 28 days significantly inhibited tumor growth in mice with human leiomyoma tissue, as evidenced by reduced tumor size and decreased expression of the proliferation marker Ki67.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel effects of simvastatin on uterine fibroid tumors: in vitro and patient-derived xenograft mouse model study. Borahay, MA., Vincent, K., Motamedi, M., et al.[2018]

Simvastatin shows a concentration-dependent ability to reduce the growth of uterine leiomyoma cells, with a stronger effect observed at lower concentrations compared to patient-matched myometrium cells.

The drug induces apoptosis in leiomyoma cells by increasing caspase-3 activity and significantly inhibits the production of key extracellular matrix proteins, suggesting it could be a promising new treatment for uterine fibroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simvastatin, at clinically relevant concentrations, affects human uterine leiomyoma growth and extracellular matrix production. Malik, M., Britten, J., Borahay, M., et al.[2019]

Simvastatin significantly inhibited the growth of endometrial cancer cell lines and primary cultures, showing a dose-dependent effect and inducing apoptosis and cell cycle arrest.

The drug reduced cell adhesion and invasion, suggesting its potential as a treatment for endometrial cancer by modulating key signaling pathways like MAPK and AKT/mTOR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer. Schointuch, MN., Gilliam, TP., Stine, JE., et al.[2022]

A case of fatal rhabdomyolysis occurred in an 80-year-old male after he was treated with both simvastatin and danazol, highlighting the risk of severe muscle damage when these medications are used together.

The study emphasizes the need for careful monitoring of patients on statins, especially when they are also taking drugs that can inhibit statin metabolism, as early signs of muscle issues should prompt immediate discontinuation of the statin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concomitant administration of simvastatin and danazol associated with fatal rhabdomyolysis. Stankovic, I., Vlahovic-Stipac, A., Putnikovic, B., et al.[2022]

In a study of 29 patients with familial hypercholesterolemia, simvastatin (10 and 20 mg/day) significantly reduced total cholesterol by 20% and 26%, respectively, and LDL-cholesterol by 24% and 34%, demonstrating its efficacy as a hypolipidemic treatment.

Simvastatin was well tolerated with no significant adverse effects reported, making it a safe option for managing cholesterol levels in patients resistant to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Simvastatin in the treatment of familial hypercholesterolemia]. Ceska, R., Sobra, J., Procházková, R., et al.[2013]

Statin use may be linked to various adverse events related to the ovary and uterus, including ovarian cysts, neoplasms, and menstrual cycle disorders, based on an analysis of data from the FDA Adverse Event Reporting System involving multiple statins.

There are differences in the types and severity of these adverse events depending on the specific statin used, indicating the need for careful monitoring of these potential side effects in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ovary and uterus related adverse events associated with statin use: an analysis of the FDA Adverse Event Reporting System. Jiao, XF., Li, HL., Jiao, XY., et al.[2021]

In a study involving 438 patients and 100 healthcare providers in South Africa, simvastatin demonstrated significant effectiveness in lowering total cholesterol levels, with a 20.5% reduction for those on 10 mg daily and a 27.6% reduction for those who increased to 20 mg daily.

The safety profile of simvastatin was consistent with premarketing data, indicating it is a safe option for patients, and the study's methodology proved effective for monitoring drug safety and efficacy in the postmarketing phase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zocor, the postmarketing experience. Smart, AJ., Walters, L., Marais, AD., et al.[2014]

Simvastatin significantly reduces the expression of Wnt4 and its co-receptor LRP5 in uterine leiomyoma cells, which are linked to the overactive Wnt/β-catenin signaling pathway associated with these tumors.

In a randomized controlled trial involving women with symptomatic leiomyoma, simvastatin treatment led to decreased levels of total and nonphosphorylated β-catenin, suggesting it may effectively suppress the Wnt/β-catenin pathway and potentially provide therapeutic benefits for treating uterine leiomyomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simvastatin Inhibits Wnt/β-Catenin Pathway in Uterine Leiomyoma. El Sabeh, M., Saha, SK., Afrin, S., et al.[2022]

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]

Simvastatin effectively inhibited the growth of endometriotic stromal cells, suggesting its potential as a treatment for endometriosis-related issues.

The drug also reduced collagen gel contraction and cell attachment to collagen fibers, indicating its role in addressing fibrosis associated with endometriosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simvastatin inhibits the proliferation and the contractility of human endometriotic stromal cells: a promising agent for the treatment of endometriosis. Nasu, K., Yuge, A., Tsuno, A., et al.[2014]

References

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

Novel effects of simvastatin on uterine fibroid tumors: in vitro and patient-derived xenograft mouse model study. [2018]

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

Simvastatin, at clinically relevant concentrations, affects human uterine leiomyoma growth and extracellular matrix production. [2019]

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

Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer. [2022]

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

Concomitant administration of simvastatin and danazol associated with fatal rhabdomyolysis. [2022]

5. Czech Republic pubmed.ncbi.nlm.nih.gov

[Simvastatin in the treatment of familial hypercholesterolemia]. [2013]

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

Ovary and uterus related adverse events associated with statin use: an analysis of the FDA Adverse Event Reporting System. [2021]

7. South Africa pubmed.ncbi.nlm.nih.gov

Zocor, the postmarketing experience. [2014]

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

Simvastatin Inhibits Wnt/β-Catenin Pathway in Uterine Leiomyoma. [2022]

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

Effect of simvastatin on monocyte chemoattractant protein-1 expression in endometriosis patients: a randomized controlled trial. [2018]

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

Simvastatin inhibits the proliferation and the contractility of human endometriotic stromal cells: a promising agent for the treatment of endometriosis. [2014]