Vaginal Estrogen for Urinary Tract Infection

Overseen By CHARLOTTE TER HAAR, MD

Age: 18+

Sex: Female

Trial Phase: Phase 4

Sponsor: University of California, Irvine

Must not be taking: Vaginal estrogen

Disqualifiers: Diabetes, Fecal incontinence, Catheterization, 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

Compensation: Varies

Number of Visits: 4

Duration: 6 months

111 Participants Needed

Trial Summary

What is the purpose of this trial?

* The goal of this clinical trial is to learn about medication adherence to difference types of vaginal estrogen in women with low levels of estrogen (for example, post-menopausal women) who have recurrent urinary tract infections. Medication adherence means whether patients take their medicine as prescribed. * Another goal of the study is to learn about changes to the skin of the vagina before and after estrogen treatment, using a specialized imaging modality called optical coherence tomography, which is similar to receiving an ultrasound. * A third goal of the study is to learn about changes to the microbiome (all the bacteria that naturally live in our bodies) before and after treatment with vaginal estrogen. The researchers will be looking specifically at the microbiome in the urine and the vagina. Participants will be assigned by chance (like the flip of a coin) to receive one of three possible vaginal estrogen treatments - cream, tablets, or drug-eluting ring. * The main study tests and procedures include an initial visit in which the researchers will collect baseline information about participants and have participants complete a series of questionnaires. * There will then be 3 and 6 month follow-ups in which the researchers will have participants complete additional questionnaires and the researchers also assess whether participants are using the vaginal estrogen treatment that you were prescribed. If a participant is part of the microbiome cohort, they will also be asked to do the following: * a baseline visit in which urinary and vaginal specimens are collected to assess their baseline microbiome. The vaginal specimen collection will involve a q-tip swab inside the vagina; it is similar to a pap smear. * Finally, participants will have an imaging modality performed on their vagina called optical coherence tomography, which allows the researchers to assess the thickness of the vaginal walls and the blood vessel density. This imaging modality involves the insertion of a thin probe into the vagina to obtain the images of the vaginal wall. * These tests will then be repeated at 6 months to assess if vaginal estrogen treatment causes changes to the vagina.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It might be best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of this treatment for preventing urinary tract infections?

Research shows that vaginal estrogen, like the estradiol-releasing vaginal ring, can help prevent recurrent urinary tract infections in postmenopausal women by improving the health of the vaginal and urethral tissues. ^{1 2 3 4 5}

Is vaginal estrogen generally safe for humans?

Research shows that vaginal estrogen treatments, like estradiol vaginal rings and tablets, are generally safe for humans. They have a low risk of side effects because they deliver low doses of estrogen directly to the area, minimizing the amount that enters the bloodstream. ^{2 3 5 6 7}

How does vaginal estrogen treatment for urinary tract infections differ from other treatments?

Vaginal estrogen treatment is unique because it directly targets the vaginal area, helping to restore the natural balance and reduce urinary tract infections in postmenopausal women, unlike systemic treatments that affect the whole body. This localized approach minimizes side effects and is particularly effective for women with low estrogen levels. ^{1 2 4 8 9}

Research Team

CHARLOTTE TER HAAR, MD

Principal Investigator

University of California, Irvine

Olivia Chang, MD

Principal Investigator

University of California, Irvine

Eligibility Criteria

This trial is for hypoestrogenic women, typically post-menopausal, who frequently suffer from urinary tract infections. Participants should be willing to use one of three vaginal estrogen treatments and attend follow-up visits. Details about their health will be collected via questionnaires and medical tests.

Inclusion Criteria

I am a woman over 18 with low estrogen and frequent UTIs.

Exclusion Criteria

I have a short vaginal length or difficulty moving that may stop me from using an estrogen ring.

I use vaginal estrogen more than twice a month.

I cannot use vaginal estrogen due to an allergy, a hormone-sensitive tumor, or application issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Initial visit to collect baseline information, complete questionnaires, and collect specimens for microbiome assessment

1 day

1 visit (in-person)

Treatment

Participants receive one of three vaginal estrogen treatments: cream, tablets, or drug-eluting ring

6 months

Ongoing treatment with periodic assessments

Follow-up

3 and 6 month follow-ups to assess adherence, complete questionnaires, and repeat imaging and microbiome assessments

6 months

2 visits (in-person)

Treatment Details

Interventions

• Estrace 0.01% Vaginal Cream
• Estring Vaginal Product
• Vagifem

Trial Overview The study compares adherence to different forms of vaginal estrogen therapy: a cream (Estrace), tablets (Vagifem), or a drug-eluting ring (Estring). It also examines changes in the vagina's skin and microbiome using optical coherence tomography imaging and specimen collection.

Participant Groups

Group I: Estrogen tablet Experimental Treatment 1 Intervention

Participants in this arm will receive the vaginal estrogen tablets (Vagifem) for treatment. Participants will place one tablet (10 mcg) into the vagina twice per week for the duration of the study.

Group II: Estrogen drug-eluting ring Experimental Treatment 1 Intervention

Participants in this arm will receive the vaginal estrogen drug-eluting ring (Estring) for treatment. Participants will have the ring placed by a provider at their clinical visit. The ring will be exchanged every 12 weeks.

Group III: Estrogen cream Experimental Treatment 1 Intervention

Participants in this arm will receive the vaginal estrogen cream (Estrace 0.01%) for treatment. Participants will apply 0.5gm twice per week for the duration of the study.

Estrace 0.01% Vaginal Cream is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Estrace 0.01% Vaginal Cream for:

• Moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause

Approved in Canada as Estradiol 0.01% Vaginal Cream for:

• Atrophic vaginitis, kraurosis vulvae, and moderate to severe dyspareunia

Approved in European Union as Estradiol 0.01% Vaginal Cream for:

• Vulvar and vaginal atrophy due to estrogen deficiency

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Findings from Research

The estradiol-releasing silicone vaginal ring (Estring) significantly prolongs the time until the first recurrence of urinary tract infections in postmenopausal women, with a cumulative likelihood of remaining free of infection at 45% compared to 20% in the control group after 36 weeks.

Estring not only lowers vaginal pH and improves mucosal health but is also safe and well tolerated, showing no unexpected adverse events during the study involving 108 women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Eriksen, B.[2019]

Menopausal women experience significant urogenital changes due to reduced ovarian steroids, with estrogen therapy effectively alleviating symptoms like atrophic vaginitis and dryness, and reducing urinary tract infections.

Low-dose estrogen therapies, even in minimal amounts, can be absorbed systemically and help preserve bone density and improve lipid profiles, but should be combined with progestogen to mitigate the risk of endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaginal hormone therapy for urogenital and menopausal symptoms. Ballagh, SA.[2005]

Both 25-microg 17beta-estradiol vaginal tablets and 1.25-mg conjugated equine estrogen vaginal cream effectively relieve symptoms of atrophic vaginitis in menopausal women, as shown in a study with 159 participants over 24 weeks.

The vaginal tablets were associated with fewer systemic side effects, lower rates of endometrial proliferation, and higher patient satisfaction, leading to a lower withdrawal rate compared to the vaginal cream.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Rioux, JE., Devlin, C., Gelfand, MM., et al.[2022]

In a study of 5,638 women with hypoestrogenism, prescribing vaginal estrogen led to a significant reduction in urinary tract infections (UTIs), with the frequency dropping from an average of 3.9 to 1.8 infections per year, representing a 51.9% decrease.

Factors such as older age, higher baseline UTI frequency, urinary incontinence, urinary retention, and diabetes were linked to an increased risk of UTIs after starting vaginal estrogen, while surprisingly, women with higher medication adherence had a smaller reduction in UTI frequency, suggesting potential confounding factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of vaginal estrogen for recurrent urinary tract infection prevention in hypoestrogenic women. Tan-Kim, J., Shah, NM., Do, D., et al.[2023]

Both 25-μg 17β-estradiol vaginal tablets and 1.25-mg conjugated equine estrogen vaginal cream effectively relieve symptoms of atrophic vaginitis in menopausal women, as shown in a study of 159 participants over 24 weeks.

The vaginal tablets resulted in fewer systemic side effects and lower rates of endometrial proliferation compared to the cream, along with higher patient satisfaction and lower withdrawal rates, indicating they may be a safer and more acceptable option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17β-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Rioux, JE., Devlin, MC., Gelfand, MM., et al.[2022]

A study involving 185 women found that both the continuous low-dose estradiol-releasing vaginal ring (ESTring) and the vaginal estradiol tablet (Vagifem) were equally effective in relieving symptoms of urogenital estrogen deficiency over 12 months.

The ESTring showed a significant safety advantage with no reported bleeding or spotting, while Vagifem users experienced some bleeding, indicating that the vaginal ring may be a preferable option for long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. Weisberg, E., Ayton, R., Darling, G., et al.[2013]

The estradiol vaginal ring provides controlled local delivery of low doses of estradiol, resulting in minimal changes to plasma estradiol levels and a high margin of safety for postmenopausal women.

Clinical studies indicate that this method has very low systemic exposure to estradiol, which reduces the risk of estrogen-related side effects and drug interactions compared to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic data on estradiol in light of the estring concept. Estradiol and estring pharmacokinetics. Gabrielsson, J., Wallenbeck, I., Birgerson, L.[2013]

A review of 8 studies on systemic estrogen therapy for preventing recurrent urinary tract infections (rUTI) in postmenopausal women found that none met all criteria for ideal research, indicating a lack of strong evidence for its efficacy.

Current guidelines recommend vaginal estrogen for rUTI prevention, but the evidence for systemic estrogen is inconclusive and based on studies with significant methodological limitations, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of systemic estrogen for preventing urinary tract infections in postmenopausal women. Fox, KA., Lokken, EM., Reed, SD., et al.[2023]

In a study of 167 postmenopausal women with recurrent urinary tract infections (rUTIs), 67.7% experienced improvement or resolution of symptoms with vaginal estrogen cream alone, indicating its efficacy as a first-line treatment.

Women with urinary incontinence were found to be 2.3 times more likely to require additional therapies for rUTIs, highlighting the importance of this condition as a risk factor in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaginal Estrogen as First-Line Therapy for Recurrent Urinary Tract Infections in Postmenopausal Women and Risk Factors for Needing Additional Therapy. Chang, E., Kent, L., Prieto, I., et al.[2022]

References

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

A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. [2019]

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

Vaginal hormone therapy for urogenital and menopausal symptoms. [2005]

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

17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. [2022]

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

Efficacy of vaginal estrogen for recurrent urinary tract infection prevention in hypoestrogenic women. [2023]

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

17β-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. [2022]

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

Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. [2013]

7. Denmark pubmed.ncbi.nlm.nih.gov

Pharmacokinetic data on estradiol in light of the estring concept. Estradiol and estring pharmacokinetics. [2013]

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

Evaluation of systemic estrogen for preventing urinary tract infections in postmenopausal women. [2023]

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

Vaginal Estrogen as First-Line Therapy for Recurrent Urinary Tract Infections in Postmenopausal Women and Risk Factors for Needing Additional Therapy. [2022]