Vaginal Estrogen for Improvement of Outcomes Following Pelvic Organ Prolapse Surgery

Multi-center, randomized, open-label, parallel-group, feasibility-controlled trial

The intervention is the use of vaginal estrogen for 6 weeks after pelvic organ prolapse surgery. Participants will be randomized into 3 groups:

• No vaginal estrogen
• Vaginal estrogen 2 times per week
• Vaginal estrogen daily

Participants may be enrolled after diagnosis of pelvic organ prolapse and decision to proceed with surgery. Participants will be seen for a randomization visit within 6 weeks of their scheduled surgery. The intervention lasts from the day of surgery until 6 weeks after surgery. Participants will be seen for a post-operative follow-up visit at 6 weeks, and study follow-up visits at 6 months, 1 year and 2 years.

Sample Size: N=60 in each group, for a total of N=180 participants. For this pilot trial, we will recruit approximately 15% of the sample size required for the full-scale trial. Data from this pilot trial will be used to adjust the event rate in the sample size calculation for the full trial, if needed. Our sample size accounts for a non-compliance rate of 5% and a loss to follow-up rate of 5%.

After enrollment, participants will complete a baseline questionnaire that collects information on demographics and health history. This may be completed online via an email link sent through REDCap, in person on a hard copy questionnaire, or the questions can be administered verbally by study staff.

After enrollment, a study investigator or delegate will complete a case report for that collects additional information on the participant's pregnancy and pelvic health history.

At each study visit, a study investigator or delegate will complete a case report form that captures any changes in the participant's health history since the previous visit.

At all post-surgical visits, a study investigator or delegate will collect information in these same case report forms on complications and treatment failure. The questions in these case report forms will be administered verbally, with verification through chart review as appropriate or as needed.

At each study visit a Pelvic Organ Prolapse Quantification (POP-Q) and Visual Analog Scale (VAS) on GSM symptoms assessment will be completed by a study investigator or medical learner under direct supervision of a study investigator. As well, height, weight and blood pressure will be measured. If any of these are collected/done for clinical reasons at the same visit, the clinically collected data will be used for study purposes. The measurements and assessments will not be repeated for study purposes.

At each study visit the Prolapse Quality of Life Questionnaire (P-QOL) and incontinence questionnaires including the International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), the Incontinence Impact Questionnaire Short Form (IIQ-7), and the Urogenital Distress Inventory Short Form (UDI-6) will be administered. These may be completed online via an email link sent through REDCap, in person on a hard copy questionnaire, or the questions can be administered verbally by study staff.

At the 6 week and 6 month post-surgical visit the Surgical Satisfaction Questionnaire (SSQ-8) will be administered. These may be completed online via an email link sent through REDCap, in person on a hard copy questionnaire, or the questions can be administered verbally by study staff.

At the 6 week post-surgical visit adherence to the study intervention will be assessed through collection of study product diaries and by querying participants on vaginal estrogen usage in the intervention period.

Inclusion criteria

Participants must meet all the following inclusion criteria to be eligible for enrollment into the study:

• Participant who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
• The participant has given written consent after the study has been explained according to local regulatory requirements and before any study specific procedures.
• Age ≥18 years at the time of consent.
• Undergoing an apical suspension (vaginal or abdominal, mesh or native tissue) for pelvic organ prolapse at one of the participating centers.
• Primary or recurrent prolapse surgery without a history of mesh surgery.
• Willing to complete surveys related to demographics, pelvic health and function, and sexual health and function.
• Plans to reside in the study area for at least 2 years after their surgery.

Exclusion criteria

Any individual meeting any of the following criteria is not eligible for participation in this study:

• Participant undergoing anterior and/or posterior repair only (no apical prolapse repair).
• Participant undergoing obliterative procedures.
• Participant with a history of mesh surgery for prolapse.
• Participant undergoing uterine sparing surgery.
• Participant with a contraindication to vaginal estrogen use, including but not limited to the following list, at the discretion of the study investigator:

• Patients who are hypersensitive to the drug or to any ingredient in the formulation or component of the container.
• Liver dysfunction or disease as long as liver function tests have failed to return to normal.
• Known or suspected estrogen-dependent malignant neoplasia (e.g. endometrial cancer).
• Endometrial hyperplasia.
• Known, suspected, or past history of breast cancer.
• Undiagnosed abnormal genital bleeding.
• Known or suspected pregnancy
• Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease).
• Partial or complete loss of vision due to ophthalmic vascular disease.
• Known thrombophilic disorders (e.g., protein C, protein S OR antithrombin deficiency); prothrombin mutation or anticardiolipin antibodies).
• Any conditions that, in the Investigator's judgement, may interfere with participant's ability to comply with study procedures or receipt of care, such as behavioral or cognitive impairment or neuropsychiatric illness.
• Concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational vaccine/product.