Fibroids & Infertility

(FRIEND Trial)

Recruiting at 3 trial locations

Overseen By Heping Zhang, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: Yale University

Must not be taking: Depo-progestins, Hormonal implants

Disqualifiers: Pregnancy, Diabetes, Heart disease, 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 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 4 cycles

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether green tea extract can help women with fibroids improve their chances of pregnancy and having a healthy baby. It focuses on women with fibroids (non-cancerous growths in the uterus) who have experienced infertility for at least six months. Participants will take green tea extract (also known as Epigallocatechin Gallate or EGCG) or a placebo alongside fertility treatments to determine if it improves pregnancy rates. Women with fibroids who are trying to conceive and have at least one open fallopian tube might be suitable for the trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking fertility treatments.

Will I have to stop taking my current medications?

The trial requires that participants not take any medications that could interfere with the study. If you are on depo-progestins or hormonal implants, a two-month period without these medications is needed before screening. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

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

Research has shown that taking green tea extract, specifically 800 mg of EGCG daily, is generally safe for women. It does not harm the liver or affect folate levels, both crucial for health. In studies, participants who used green tea extract experienced a noticeable decrease in the size of uterine fibroids, indicating that the treatment is well-tolerated.

The current trial will use a higher daily dose of 1650 mg. However, the previous findings of safety at 800 mg suggest that the treatment might still be safe at this higher dose. Participants should always consult a healthcare provider before joining a trial to discuss any possible risks. ^{1 2 3 4 5}

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

Most treatments for uterine fibroids and infertility typically involve hormonal therapies or surgical options. However, green tea extract, which is under investigation, is unique because it harnesses the power of epigallocatechin gallate (EGCG), a potent antioxidant. Researchers are excited about this treatment because EGCG may help shrink fibroids and improve fertility with fewer side effects compared to traditional hormone therapies. Additionally, this extract is taken orally in a convenient capsule form, potentially offering a more natural and accessible option for those seeking alternatives to standard care.

What evidence suggests that green tea extract might be an effective treatment for uterine fibroids and infertility?

Research has shown that Epigallocatechin Gallate (EGCG), a key component of green tea extract, can help shrink uterine fibroids. In this trial, participants will receive either green tea extract containing EGCG or a placebo. Studies suggest that EGCG might also improve the health of the uterine lining, which is crucial for women trying to conceive, as a healthy lining can increase the chance of pregnancy. Green tea's ability to reduce fibrous tissue, prevent new blood vessels from forming, and promote the natural death of cells further aids in managing symptoms of non-cancerous conditions like fibroids. Although more research is needed to confirm these effects, current evidence is promising for those with fibroids and fertility issues. ^{2 3 5 6 7}

Who Is on the Research Team?

David Weinberg, PhD

Principal Investigator

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

Are You a Good Fit for This Trial?

This trial is for women aged 18-40 with a desire to conceive, who have been infertile for at least six months and have certain types of uterine fibroids (FIGO types 2-6). They must be regularly ovulating, have at least one open fallopian tube, and their male partner should have a sufficient sperm count. Women can't join if they've had severe endometriosis, unexplained bleeding, alcohol abuse issues or a history of blood clots.

Inclusion Criteria

I have fibroids of specific types and sizes according to FIGO classifications.

At least one open fallopian tube confirmed by hysterosalpingography (HSG), sonohysterography, or laparoscopy/hysteroscopy in the last three years preceding enrollment into the study. An uncomplicated intrauterine non-IVF pregnancy and uncomplicated delivery and postpartum course resulting in live birth within the last three years will also serve as sufficient evidence of a patent tube and normal uterine cavity as long as the participant did not have, during the pregnancy or subsequently, risk factors for Asherman's syndrome or tubal disease or other disorder leading to an increased suspicion for intrauterine abnormality or tubal occlusion.

At least one open fallopian tube confirmed by hysterosalpingography (HSG), sonohysterography, or laparoscopy/hysteroscopy in the last three years preceding enrollment into the study. An uncomplicated intrauterine non-IVF pregnancy and uncomplicated delivery and postpartum course resulting in live birth within the last three years will also serve as sufficient evidence of a patent tube and normal uterine cavity as long as the participant did not have, during the pregnancy or subsequently, risk factors for Asherman's syndrome or tubal disease or other disorder leading to an increased suspicion for intrauterine abnormality or tubal occlusion.

Exclusion Criteria

I have been diagnosed with Cushing's disease.

You regularly drink too much alcohol or have a history of binge drinking.

I have had a blood clot in my veins, lungs, or a stroke.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either low caffeine green tea extract or placebo along with Clomiphene citrate-intrauterine insemination (CC-IUI) cycle, up to 4 cycles if no pregnancy is achieved

Up to 4 cycles

Regular visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of conception and live birth outcomes

Up to 15 months

What Are the Treatments Tested in This Trial?

Interventions

• Green Tea Extract
• Placebo

Trial Overview The study aims to see if taking green tea extract containing epigallocatechin gallate (EGCG) affects the size of fibroids in the uterus and improves chances of pregnancy and live births compared to those taking a placebo. The trial involves 200 women seeking fertility treatment.

How Is the Trial Designed?

Group I: Green tea extract containing 45% epigallocatechin gallate (EGCG) Experimental Treatment 1 Intervention

Low caffeine green tea extract (1650mg in 6 capsules) taken orally on a daily basis (QD) along with Clomiphene citrate-intrauterine insemination (CC\_IUI) cycle, up to 4 cycles if no pregnancy is achieved, participant will stop green tea if she becomes pregnant

Group II: Placebo Placebo Group 1 Intervention

Placebo (1650mg in 6 capsules) matched (smell, taste, color, texture) capsules taken orally on a daily basis (QD) along with Clomiphene citrate-intrauterine insemination (CC\_IUI) cycle, up to 4 cycles if no pregnancy is achieved, participant will stop placebo if she becomes pregnant

Green Tea Extract is already approved in United States for the following indications:

Approved in United States as Epigallocatechin Gallate for:

• None approved; currently in clinical trials for uterine fibroids and infertility

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

University of Illinois at Chicago

Collaborator

Trials

653

Recruited

1,574,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

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

Collaborator

Trials

2,103

Recruited

2,760,000+

University of Chicago

Collaborator

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

Green tea extract, specifically epigallocatechin gallate (EGCG), significantly inhibits the growth of wild-type human leiomyoma (WT-HuLM) cells by reducing the expression and activity of the enzyme catechol-o-methyltransferase (COMT).

The antiproliferative effects of EGCG are linked to its ability to modulate multiple signaling pathways, which are less effective in cells where COMT has been silenced, indicating that COMT plays a crucial role in the mechanism of action of EGCG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Green tea extract inhibition of human leiomyoma cell proliferation is mediated via catechol-O-methyltransferase. Zhang, D., Rajaratnam, V., Al-Hendy, O., et al.[2021]

The combination of Crila and the green tea extract EGCG showed synergistic effects in inhibiting the growth of human uterine fibroid cells, suggesting a more effective treatment than using either compound alone.

This growth inhibition was linked to reduced cell proliferation rather than increased cell death, indicating that these natural compounds could serve as a safe and cost-effective alternative to hormonal therapies for treating uterine fibroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of natural compounds Crila and epigallocatechin gallate showed enhanced antiproliferative effects on human uterine fibroid cells compared with single treatments. Bai, T., Ali, M., Somers, B., et al.[2023]

In a study involving 39 premenopausal women, a daily dose of 800 mg of EGCG was found to be safe, showing no signs of liver injury or abnormal folate levels, indicating good tolerability.

EGCG, when used alone or in combination with fertility medications like clomiphene citrate or letrozole, does not pose risks of liver toxicity or folate deficiency, supporting its potential use in treating unexplained infertility associated with uterine fibroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing the Hepatic Safety of Epigallocatechin Gallate (EGCG) in Reproductive-Aged Women. Siblini, H., Al-Hendy, A., Segars, J., et al.[2023]

The green tea polyphenol epigallocatechin gallate (EGCG) has shown promise in inhibiting the growth of uterine fibroids, but its clinical use is limited due to issues like low stability and poor bioavailability.

A newly developed prodrug of EGCG (Pro-EGCG) and its analogs (2a and 4a) demonstrate enhanced stability and biological activity, showing strong potential in reducing cell proliferation, angiogenesis, and fibrosis in uterine leiomyoma cells, suggesting a novel therapeutic approach for treating uterine fibroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological and Mechanistic Characterization of Novel Prodrugs of Green Tea Polyphenol Epigallocatechin Gallate Analogs in Human Leiomyoma Cell Lines. Ahmed, RS., Liu, G., Renzetti, A., et al.[2018]

Green tea, particularly its main component EGCG, has shown potential therapeutic benefits in treating benign gynecological disorders, such as alleviating symptoms of uterine fibroids and improving endometriosis through various cellular mechanisms.

EGCG can also help reduce pain associated with dysmenorrhea and adenomyosis, and while its role in infertility is debated, it may provide symptomatic relief during menopause and for conditions like polycystic ovary syndrome (PCOS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Green Tea and Benign Gynecologic Disorders: A New Trick for An Old Beverage? Hazimeh, D., Massoud, G., Parish, M., et al.[2023]

Epigallocatechin gallate (EGCG) from green tea significantly inhibits the growth of cultured human leiomyoma cells (HuLM) in a dose- and time-dependent manner, suggesting its potential as a treatment for uterine fibroids.

EGCG treatment not only induces apoptosis in HuLM cells but also alters gene expression related to key signaling pathways, including up-regulating TGF-β and stress pathways while inhibiting survival and inflammatory pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Zhang, D., Al-Hendy, M., Richard-Davis, G., et al.[2021]

In a study of 25 women with uterine myomas, daily ingestion of green tea extract (GTE) capsules for 6 months significantly improved physical quality of life scores, as measured by the SF-12 questionnaire.

Despite the improvement in physical health, there were no significant changes in mental health scores, myoma size, or other symptoms, and no relevant side effects were reported, indicating GTE may be safe but its efficacy on myoma-related issues is limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of epigallocatechin gallate-enriched green tea extract capsules in uterine myomas: results of an observational study. Biro, R., Richter, R., Ortiz, M., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10806662/

Fibroids and unexplained infertility treatment with ... We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05364008

Study Details | NCT05364008 | FRIEND: Fibroids and ... The investigators hypothesize that EGCG in low caffeine green tea extract will reduce the fibroid size, improve the quality of endometrium, and increase the ...

3. trialx.com trialx.com/clinical-trials/listings/274227/friend-fibroids-and-unexplained-infertility-treatment-with-epigallocatechin-gallate-a-natural-compound-in-green-tea/

FRIEND: Fibroids and Unexplained Infertility Treatment ... The investigators hypothesize that EGCG in low caffeine green tea extract will reduce the fibroid size, improve the quality of endometrium, and ...

4. mdpi.com mdpi.com/2072-6643/15/6/1439

Green Tea and Benign Gynecologic Disorders Green tea alleviates symptom severity in uterine fibroids and improves endometriosis through anti-fibrotic, anti-angiogenic, and pro-apoptotic mechanisms.

5. withpower.com withpower.com/trial/phase-3-myofibroma-5-2022-c4862

Green Tea Extract for Uterine Fibroids and Infertility Research shows that Epigallocatechin Gallate (EGCG), a component of green tea extract, can shrink uterine fibroids and improve symptoms of benign gynecological ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9861948/

Assessing the Hepatic Safety of Epigallocatechin Gallate ... The study showed a significant reduction in (32.6%, p = 0.0001) the total uterine fibroid volume in subjects randomized to the green tea extract ...

7. hopkinsmedicine.org hopkinsmedicine.org/news/newsroom/news-releases/2023/07/new-study-using-human-fibroid-cells-supports-use-of-green-tea-compound-as-treatment-for-uterine-fibroids

New Study Using Human Fibroid Cells Supports ... New study from @HopkinsGynob using human fibroid cells supports the use of green tea compound as a treatment for uterine fibroids. ›.