Vaginal Hormonal Contraception for PCOS

(RING-PCOS Trial)

Overseen By Andrea Morley

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: Andrea Roe, MD, MPH

Must not be taking: Hormonal contraception, Lipid-lowering agents

Disqualifiers: Pregnancy, Metabolic syndrome, Diabetes, Hypertension, Cancer, others

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

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how a vaginal contraceptive ring (Etonogestrel/ethinyl estradiol vaginal ring) affects the metabolism of women with polycystic ovary syndrome (PCOS) who are overweight or obese. The ring releases hormones to help manage PCOS symptoms, and researchers aim to determine its impact on metabolic health. It suits women diagnosed with PCOS who do not wish to become pregnant during the study and experience infrequent periods or signs of high male hormones. As a Phase 4 trial, this study involves an FDA-approved treatment and aims to understand its benefits for more patients.

Will I have to stop taking my current medications?

The trial requires that you stop using hormonal contraception at least four weeks before starting the study. If you are using lipid-lowering or weight loss medications, you will also need to stop those. For other medications, the protocol does not specify, so it's best to discuss with the study team.

What is the safety track record for the Etonogestrel/ethinyl estradiol vaginal ring?

Research has shown that the etonogestrel/ethinyl estradiol vaginal ring, known as NuvaRing, is generally safe and well-tolerated. In studies involving 2,501 women, it was used for over 24,000 cycles without major safety issues. Some women experienced side effects like vaginal discomfort and headaches, but these were usually mild. Serious side effects, such as blood clots, are rare but important to note. Since this treatment is already approved as a contraceptive, strong evidence supports its safety in humans. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard treatments for PCOS, which often include oral contraceptive pills or anti-androgens, the Etonogestrel/ethinyl estradiol vaginal ring offers a unique delivery method. This ring provides consistent hormone release directly through vaginal absorption, which may enhance hormonal regulation and reduce systemic side effects. Researchers are excited because this method could offer a more convenient, potentially more effective option for women with PCOS who experience irregular periods or hormonal imbalances. Additionally, the ring's continuous, low-dose hormone delivery might improve user adherence compared to daily oral pills.

What evidence suggests that this treatment might be an effective treatment for PCOS?

Research has shown that the etonogestrel/ethinyl estradiol vaginal ring, which participants in this trial will use, effectively manages symptoms of polycystic ovary syndrome (PCOS). Studies have found that this contraceptive ring helps regulate menstrual cycles and ease symptoms in women with PCOS. Compared to birth control pills, the vaginal ring has a gentler effect on insulin levels, which benefits PCOS management. This is crucial because many women with PCOS experience insulin resistance. Overall, the ring offers a promising option for women seeking both birth control and relief from PCOS symptoms. ^{4 6 7 8 9}

Who Is on the Research Team?

Andrea Roe, MD MPH

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for overweight or obese women with PCOS who are in good health and not currently pregnant, breastfeeding, or wishing to become pregnant soon. They must have a BMI between 25 and 45 kg/m2 and meet two of three specific criteria related to PCOS. Women over 35 who smoke or have certain medical conditions like uncontrolled blood pressure, liver disease, or history of clotting disorders cannot participate.

Inclusion Criteria

Willing to avoid pregnancy for the duration of the study

I have PCOS with at least 2 symptoms: irregular periods, high androgen levels, or polycystic ovaries.

You weigh between 55 and 99 pounds and are not too underweight or overweight.

Exclusion Criteria

I have been diagnosed with metabolic syndrome.

Criterion: You cannot participate if you are over 35 years old and use tobacco, have a history of blood clots, certain heart conditions, certain types of headaches, liver tumors, undiagnosed abnormal uterine bleeding, certain types of cancer, or are allergic to any components of NuvaRing.

I do not have unmanaged health issues or recent major surgeries.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants use the contraceptive vaginal ring for a 4-month period to study its metabolic effects

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Etonogestrel/ethinyl estradiol vaginal ring

Trial Overview

The study is testing the effects of a contraceptive vaginal ring on metabolic factors in women with PCOS over four months. It aims to recruit 40 participants to see if this method affects their risk of developing metabolic syndrome.

How Is the Trial Designed?

Group I: Contraceptive Ring Experimental Treatment 1 Intervention

Etonogestrel/ethinyl estradiol vaginal ring (NuvaRing), which releases 120 mcg of etonogestrel and 15 mcg of ethinyl estradiol daily.

Etonogestrel/ethinyl estradiol vaginal ring is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as NuvaRing for:

• Contraception

Approved in United States as NuvaRing for:

• Contraception

Approved in Canada as NuvaRing for:

• Contraception

Who Is Running the Clinical Trial?

Andrea Roe, MD, MPH

Lead Sponsor

Trials

1

Recruited

30+

Published Research Related to This Trial

In a study of 120 patients undergoing cisplatin chemotherapy, the combination of megestrol acetate with a 5-HT3 receptor antagonist and dexamethasone significantly improved the prevention of chemotherapy-induced nausea and vomiting (CINV), especially during the delayed phase, compared to the control group.

The megestrol combination treatment resulted in higher rates of complete remission of vomiting (76.7% vs. 51.7%) and overall remission (68.3% vs. 46.6%), demonstrating its efficacy with minimal adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Megestrol acetate dispersible tablets with a 5-HT3 receptor antagonist and dexamethasone vs. 5-HT3 receptor antagonist plus dexamethasone, can better control chemotherapy-induced nausea and vomiting: a randomized controlled study. Ma, Y., Zhao, W., Deng, W., et al.[2023]

A systematic review of antiemetic agents for preventing chemotherapy-induced nausea and vomiting (CINV) in children found that these medications, including aprepitant and ondansetron, are generally safe with manageable adverse effects.

While the recommended antiemetics are effective, it is important to consider individual patient risk factors, particularly for rare side effects like cardiac arrhythmia, and further research is needed to assess their long-term safety in pediatric cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of clinical practice guideline-recommended antiemetic agents for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric patients: a systematic review and meta-analysis. Patel, P., Paw Cho Sing, E., Dupuis, LL.[2019]

In a study of 26 Japanese patients receiving highly or moderately emetogenic chemotherapy, repeated doses of palonosetron (0.75 mg) on days 1 and 3 were found to be safe and well tolerated, with a high complete response rate of 96.2% for preventing nausea and vomiting in the acute phase.

The pharmacokinetics showed expected accumulation of the drug, and while the complete response rate in the delayed phase was lower at 76.9%, the results indicate that palonosetron is effective for managing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy. Ikari, Y., Ogata, K., Nakashima, Y., et al.[2021]

The vaginal ring contraceptive, delivering etonogestrel and ethinylestradiol, has a contraceptive efficacy similar to standard combined hormonal contraceptives, with a Pearl index of about 1 per 100 woman-years based on trials involving 2322 women.

While the vaginal ring has comparable efficacy and adherence rates to oral contraceptives, it does not offer significant advantages in terms of adverse effects, with 20% of users experiencing gynecological disorders, and its thromboembolic risk remains unassessed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ethinylestradiol + etonogestrel contraceptive vaginal ring: new drug. Possibly useful in some situations. [2013]

In a study involving 8 premenopausal women, the use of the NuvaRing contraceptive resulted in lower concentrations of ethinyl estradiol (EE) and etonogestrel (ENG) in the endometrial tissue compared to a combined oral contraceptive (COC).

Both the NuvaRing and COC showed similar hormone concentrations in the upper myometrium and cervical region, indicating that the route of administration affects hormone levels in the endometrium, which may have implications for safety and efficacy in contraceptive use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of uterine concentrations of ethinyl estradiol and etonogestrel after use of a contraceptive vaginal ring and an oral contraceptive. Roumen, FJ., Dieben, TO.[2014]

The contraceptive vaginal ring, which releases ethinyl estradiol and etonogestrel, has been shown to be as effective and safe as oral contraceptives, with users reporting higher satisfaction and fewer systemic side effects.

In addition to contraception, the vaginal ring can help manage menstrual symptoms and is being explored for delivering antiretroviral drugs for HIV protection, highlighting its versatility in women's health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaginal ring contraception. Kerns, J., Darney, P.[2014]

In a study of 755 adults undergoing gynecological laparoscopy, ramosetron was found to be more effective than palonosetron in preventing postoperative nausea and vomiting (PONV), with a lower incidence of PONV at postoperative day 0 (26.9% vs. 36.8%).

Patients receiving ramosetron also experienced less severe nausea and had a higher rate of complete response compared to those receiving palonosetron on postoperative day 0, indicating ramosetron's superior efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Ramosetron with Palonosetron for Prevention of Postoperative Nausea and Vomiting in Patients Receiving Opioid-Based Intravenous Patient-Controlled Analgesia after Gynecological Laparoscopy. Ahn, EJ., Choi, GJ., Kang, H., et al.[2018]

In a study of 96 female cancer patients receiving cisplatin-based chemotherapy, a triple therapy regimen of aprepitant, palonosetron, and dexamethasone achieved a complete response rate of 54.2% in preventing chemotherapy-induced nausea and vomiting (CINV).

The triple therapy was effective in both the acute phase (87.5% complete response) and the delayed phase (56.3% complete response) after chemotherapy, with manageable side effects like constipation and fatigue, indicating it is a tolerable option for women at higher risk of CINV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of triple therapy with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy for gynecological cancer: KCOG-G1003 phase II trial. Takeshima, N., Matoda, M., Abe, M., et al.[2022]

The study assessed the pharmacokinetics of etonogestrel and ethinylestradiol from the NuvaRing in 16 healthy women, finding that maximum serum levels were reached in about one week after insertion.

While the NuvaRing provided similar systemic exposure to etonogestrel compared to the oral contraceptive, it resulted in approximately 50% lower exposure to ethinylestradiol, suggesting a potentially different safety and efficacy profile for the vaginal ring compared to the oral contraceptive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring. Timmer, CJ., Mulders, TM.[2018]

In a study of 65 women comparing the NuvaRing (RING) to a low-dose oral contraceptive (PILL) over five cycles, the RING showed a lesser impact on carbohydrate metabolism, indicating it may be a safer option for insulin sensitivity.

The RING also resulted in a greater reduction of free androgen and dehydroepiandrosterone sulfate levels compared to the PILL, suggesting potential benefits in managing hormonal profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contraceptive vaginal ring use for women has less adverse metabolic effects than an oral contraceptive. Elkind-Hirsch, KE., Darensbourg, C., Ogden, B., et al.[2007]

Citations

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Both oral and vaginal CHCs decreased androgenicity and tended to promote insulin resistance in PCOS women. Larger and longer studies are needed ...

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sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0010782407003502

Contraceptive vaginal ring use for women has less adverse ...

Our results showed that use of a low-dose combination OC reduced insulin sensitivity to a larger extent than the contraceptive vaginal ring. Acknowledgments. We ...

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withpower.com

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Vaginal Hormonal Contraception for PCOS

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The maximum serum concentrations of etonogestrel and ethinylestradiol were approximately 40 and 30%, respectively, of those for the DSG/EE COC.

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stuffthatworks.health

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Ethinylestradiol & Etonogestrel in PCOS

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Trials with a duration of 6 to 13 28-day cycles provided safety data. In total, 2,501 women, aged 18 to 41 contributed 24,520 cycles of exposure. Common ...

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Possible Risks and Side Effects of NuvaRing

NuvaRing may cause serious side effects, including: Blood clots. Like pregnancy, combination hormonal birth control methods increase the risk of serious blood ...

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Etonogestrel; Ethinyl Estradiol

As compared to patients never taking OCs, the presence of plaque is increased after 10 years of OC use in a single carotid artery (OR 1.17, 95% ...