Efficacy of Vaginal 17β-Estradiol on the Urinary Storage Symptoms in Postmenopausal Women

Efficacy of Vaginal 17β-Estradiol on the Urinary Storage Symptoms in Postmenopausal Women: A Randomized Double-Blind, Placebo-Controlled Study

The goal of this clinical trial is to evaluate whether vaginal 17β-estradiol effectively treats storage symptoms of lower urinary tract symptoms (LUTS) and enhances quality of life. The main questions it aims to answer are:

• What is the efficacy of vaginal 17β-estradiol treatment compared to placebo in alleviating storage symptoms of LUTS?
• How does vaginal 17β-estradiol treatment affect the urethral maturation index and vaginal pH compared to placebo?
• What impact does vaginal 17β-estradiol treatment have on overall quality of life and patients' perception of global improvement (PGI)?

Participants in the trial will undergo the following procedures:

• Screening procedures at the first visit to exclude correctable causes of LUTS and to complete a bladder diary.
• Visit the clinic at 1-2 weeks for a review of the bladder diary and a check-up. Participants will receive the assigned dosage of vaginal 17β-estradiol or placebo: one vaginal tablet daily for two weeks, followed by one vaginal tablet twice a week for 10 weeks.
• The third and fourth visits (at 4 and 12 weeks after treatment) will involve: completion of bladder diaries, questionnaires, vaginal pH testing, collection of urethral maturation index (UMI), observation of intervention's side effects and monitoring of LUTS symptoms.

I. First Visit and Recruitment

Participants will be recruited from the urogynecology clinic, menopause clinic, and urology clinic using hospital and public advertisement. An information sheet in Thai language will be provided to health care providers in the designated outpatient department (OPD) which can ensure the providers convey the correct study information to potential participant. Participants will only be able to enroll into this study one time.

Informed Consent

Individuals with at least one storage symptom of LUTS presenting to clinics in selected OPD will undergo the informed consent process by principal investigator prior to initiating screening procedures. Consent form in Thai language describing in detail the study procedures will be given to the participant privately in a separate room, and extensive discussion of risks and possible benefits of participation in this study will be provided. Participation will be informed that they may withdraw consent at any time throughout the course of this study.

Screening

After documentation of informed consent, principal investigator will interview the participant and perform vital signs and physical examination. The urinalysis will be performed by urinalysis test strip before the start of the study. Screening procedures are as follows;

• Pelvic exam
• Pelvic floor muscle strength measured as Brink scale
• Pelvic Organ Prolapse Quantification (POP-Q), Stress test
• Gynecologic ultrasonography with post-void residual volumes (PVR)
• Urinalysis by urinalysis test strip
• Bladder diary: consecutive three-day diary which the time of each micturition and the volume voided, fluid intake, incontinence episodes, episodes of urgency and sensation will be recorded, as might be the activities performed during or immediately preceding the involuntary loss of urine.

After screening procedure, the appointment will be made for the next visit, which is one or two weeks after first visit.

Bladder diary

The study will incorporate the use of essential diagnostic tool, namely the bladder diary, to assess and monitor the outcomes. These assessments will be administered under the careful supervision of the study investigators. These diagnostic tests play a pivotal role in our research, serving as indispensable instruments for evaluating the progression and ultimate success of the treatment interventions.

II. Second Visit and Randomization

At one or two weeks after 1st visit, the following study procedure will be performed;

• Bladder diary interpretation
• ICIQ-FLUTS questionnaire
• ICIQ-LUTSqol questionnaire
• Vaginal pH
• Urethral maturation index (UMI)

After evaluating all the data collected during the screening process at the initial visit and combining it with the procedures conducted during the second visit, if the woman does not meet all study inclusion or if the woman has an exclusion criterion, she will not be enrolled into this study. A screening log will be kept of all who were evaluated for participation to document who is and is not enrolled and reason for not enrolling in this study.

Women who meet inclusion criteria will be randomized with block randomization technique and a ratio of treatments of 1:1. The sequence generation will be performed under supervision of a senior statistician at the section of Clinical Epidemiology and Biostatistics in Ramathibodi Hospital. The random sequences will be generated using Stata version 18. This is an automated process with no interfere from the investigators. Upon a subject's successful enrollment in the clinical trial following eligibility assessment, principal investigator or research personnel shall provide participants with a comprehensive Thai guidebook for behavior modification which is designed to ensure the harmonization of knowledge and behaviors among all trial participants. This guidebook was developed and published by The International Urogynecological Association (IUGA) and will be distributed by research assistants.

Trial Treatment: Dosage Form, Regimen, Route of Administration

• 17beta-Estradiol 10 mcg (Femiest® Pharma Munster GMBH, Muenster, Germany (ESTRADIOL HEMIHYDRATE 0.0103 milligram, pH 6.94)

  17beta-Estradiol will be administered to group A treatment arm intravaginally. The assigned dosage will be one vaginal tablet daily for two weeks then one vaginal tablet twice a week for 10 weeks. Participants will be carefully monitored for any changes in clinical condition in each follow-up visits using logbook. It is important to clarify that the investigators are not using 17beta-Estradiol (Vagifem®) 25 mcg as the study drug. Although 17beta-Estradiol 25 mcg is frequently mentioned in literature reviews and has been historically used for treating vaginal dryness, this drug is currently not available in Thailand. Therefore, the investigators are using 17beta-Estradiol (Femiest®) 10 mcg as an alternative for our study drug. Notably, 17beta-Estradiol 10 mcg has been shown to provide a therapeutic dose equivalent to that of 17beta-Estradiol 25 mcg for treatment, as stated by the FDA. This decision ensures that participants receive an effective and appropriate dosage while adhering to the availability of medications in our region.

• Placebo

Placebo will be administered to group B treatment arms intravaginally. The assigned dosage will be one vaginal tablet daily for two weeks then one vaginal tablet twice a week for 10 weeks. Participants will be carefully monitored for any changes in clinical condition in each follow-up visits. Placebo is produced by Chulalongkorn University Drug and Health Products Innovation & Promotion Center, Faculty of Pharmaceutical Sciences, Chulalongkorn University. Details for presentation and packing are as follows;

• Appearance: White, round, biconvex with "E" imprint one side
• Weight: 106 - 110 mg
• Hardness: 4.1 - 4.8 kilopond (kp)
• Thickness: 3.26 - 3.3 mm
• Diameter: 6.02 - 6.03 mm
• Disintegration time: 4 min 58sec - 7min 42sec
• pH: 7.18

Placebo contains

1. Agglomerated Lactose
2. Microcrystalline cellulose PH 102
3. Magnesium stearate

Both subject groups will be counseled on potential signs/symptoms of adverse events and post-marketing experience, such as breast pain, peripheral edema, and postmenopausal bleedings. Due to the vaginal administration and minimal systemic absorption, it is unlikely that any clinically relevant drug interactions will occur with 17beta-Estradiol. However, interactions with other locally applied vaginal treatments will be considered and advised to the patients. If a dose is forgotten, participants will be advised that it should be taken as soon as he/she remembers. A double dose should be avoided.

Random allocation

Each participant in the study will receive a prescription for the research drug, an adequate supply to cover a 12-week treatment duration. This drug will be uniformly packaged within identical containers, featuring a unique alphanumeric code and detailed usage instructions on the label, thereby avoiding the inclusion of the original medication name. The data analysis will be performed by a statistician who will be the sole individual privy to the allocation of drug A or drug B to their respective groups. It is essential to note that the statistician will remain unaware of which of the two is the active drug and which is the placebo. Additionally, an independent statistician will maintain a sealed randomization list as a contingency. Allocation will be as follows;

Group A: 17beta-Estradiol 10 mcg (Femiest® Haupt Pharma Munster GMBH, Muenster, Germany (ESTRADIOL HEMIHYDRATE 0.0103 milligram)

Group B: Placebo

III. Third Visit

At four weeks after 2nd visit, the following study procedure will be performed;

• Bladder diary, the participant will be reminded to provide a three-day diary prior to schedule visit date.
• ICIQ-FLUTS questionnaire
• ICIQ-LUTSqol questionnaire
• PGI-I score
• Vaginal pH
• Urethral maturation index (UMI)

Participants will also have clinical evaluation and vital signs measurements evaluated. Compensation for participants will be provided.

IV. Fourth and Final Visit

At eight weeks after 3rd visit, the following study procedure will be performed;

• Pelvic exam
• Pelvic floor muscle strength measured as Brink scale
• Bladder diary, the participant will be reminded to provide a three-day diary prior to schedule visit date.
• ICIQ-FLUTS questionnaire
• ICIQ-LUTSqol questionnaire
• PGI-I score
• Vaginal pH
• Urethral maturation index (UMI)

Participants will also have clinical evaluation and vital signs measurements evaluated. Compensation for participants will be provided.

Inclusion Criteria:

1. Presenting with storage phase symptom score more than/equal to 1 evaluated by the ICIQ-FLUTS questionnaire in these items

   • Item 2a) nocturia and/or
   • Item 3a) urgency and/or
   • Item 5a) daytime frequency and/or
   • Item 9a) UUI and/or
   • Item 11a) SUI

2. Being natural or surgical menopause for more than 1 year

3. Absence of urinary tract infection or other identifiable cause

4. Not using hormone replacement therapy or any route of estrogen within 4 weeks

5. Never undergone onabotulinumtoxinA therapy, percutaneous tibial nerve stimulation (PTNS), or neuromodulation for overactive bladder (OAB) treatment

6. Willing to adhere to the research protocol and actively participate in the scheduled follow-up appointments as delineated within the framework of this study

Exclusion Criteria:

1. Contraindication for estrogen therapy: undiagnosed abnormal vaginal bleeding, previous thromboembolic event, breast cancer, gynecologic/genitourinary malignancy, active liver disease
2. Pelvic organ prolapse of anterior compartment stage III and IV
3. Immunocompromised patient or taking immunosuppressant drug
4. History of antibiotics drug use within the past 7 days
5. History of bladder outlet obstruction
6. History of using anti-muscarinics, beta3-adrenoceptor agonists, vaginal energy-based devices (laser and radiofrequency) or electromagnetic energy-based therapies within the past 2 weeks
7. History of documented positive urine culture in the past 6 weeks
8. Have an allergic reaction to study's drug
9. Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in this study