Vaginal Creams to Reduce Vaginal Erosion in Pessary Users

Pelvic organ prolapse (POP) is a health concern for millions of women worldwide. Patients
have a variety of symptoms from POP including: vaginal bulging, vaginal pressure,
constipation and urinary incontinence (1). It is estimated that the lifetime risk of
undergoing surgery for prolapse or incontinence is 11%. The lifetime risk for recurrence of
POP after surgery is 10-20% (2). Treatment options for POP include kegel exercises,
pessaries or surgical management. Due to lifestyle, timing or inability to undergo surgery
secondary to medical comorbidities the pessary can be a very reasonable alternative to
surgical management of POP.

There are two categories of pessaries: support and space occupying. Support pessaries are
usually recommended for early stage of prolapse with adequate perineal support and include
the ring pessary, Gehrung, Hodge and Shaatz. While space-occupying pessaries such as the
Donut, Gellhorn, Cube and Inflataball are used for advanced stage prolapse with less
perineal support and a wide genital hiatus (3). As the ring and the Gellhorn pessary are the
most commonly used pessaries and can be inserted for all stages of prolapse, our study will
focus on the use of the ring with support and the Gellhorn for treatment of POP (4).

After menopause, estrogen levels decline. This may allow postmenopausal vaginal pH to
increase to the range of 5.0-7.5. At these higher pH levels, lactobacillus survival is
hindered, and vaginal colonization by other bacterial species predisposes women to
symptomatic vaginitis (5). Discontinuation of pessary use is often due to discomfort,
expulsion, urinary retention bothersome vaginal discharge and vaginal erosion (6). Common
complications with pessary use are erosions (8.9%), or vaginal infections (2.5%) (7). Some
studies have shown an erosion rate as high as 21% (6). Patients often complain of vaginal
discharge with pessary use that is malodorous and bothersome. Local estrogen can help to
restore the vaginal pH and help reduce vaginal discharge. The moisturizing properties of
vaginal lubricants and creams may help reduce vaginal erosion in pessary users. We would
like to compare Estrace ® to a placebo. The placebo will be the hormone replacement therapy
(HRT) base cream in Estrace ® without the estradiol.

No randomized control trials (RCT) have been performed showing if application of local
hormone (Estrace) is superior to application of local nonhormonal vaginal cream for
reduction of the bothersome symptom of vaginal discharge and subsequently erosion. We would
like to compare vaginal estrogen against placebo as a mechanism to prevent bothersome
discharge and prevention of vaginal erosion in women fitted with pessaries for pelvic organ
prolapse.

Study Population In general, the study population will be patients of the Urogynecology
practice of North Shore-Long Island Jewish Health System who present to the clinic for their
initial pessary fitting. Patients will be fitted with either a ring with support or Gellhorn
pessary and will return at intervals of 2, 6 and 12 weeks for follow up.

All subjects over 18 yrs of age will be screened for eligibility relative to the patient
inclusion and exclusion criteria. If a patient is eligible to enroll in the study, the
nature and purpose of the study will be explained to the subject with a witness present. The
subject will review and sign the written Informed Consent Form indicating informed and
voluntary participation in the study. A copy of the consent form including all risks and
benefits to the research subjects is attached as a separate document.

Recruitment for the study will be done via direct contact from our patient population. If a
subject is found to be eligible to participate, an approved study investigator will approach
her during her scheduled initial pessary visit. No form of advertisement will be used. The
recruitment methods used will provide equitable selection of subjects.

After determination of eligibility based on inclusion/exclusion criteria the patient will be
consented for the study related procedures. The subject must consent to participate and sign
the specific Institutional Review Board approved Informed Consent Form prior to the conduct
of the study specific procedure. Patient may be consented in the clinic for the department
of urogynecology.

New patients who present for their initial pessary fitting will have the appropriate sized
ring with support or Gellhorn pessary placed as per standard of care. The patient will
return for her 2 week follow up visit as per standard of care.

If no change in pessary is indicated the patient will be approached for participation in the
study. If she agrees to participate, she will be randomized to use estrogen cream (Estrace)
or placebo stratified on type of pessary.

Estrace contains 0.1 mg estradiol per gram of cream. The recommended dosing is 2-4 grams
daily for 1-2 weeks with a gradual reduction to half the initial dose over 1-2 weeks, and
then 1 gram 1-3 times weekly for maintenance.

Participants will be provided with the medication in prepackaged 0.5cc syringe. Either
digitally or by using the syringe, she will then place 1cm distal to the introitus. This
technique will be reviewed with the participant and she will also have to demonstrate
correct application. She will use the cream nightly for 1 week then reduce the dose to 2
times weekly for maintenance. Participants will use the cream nightly for 1 week then twice
weekly at night.

The patient will be given a 3 month supply of the vaginal cream that she is randomized to.
We will preload syringes with 0.5cc of either estrace or placebo cream. These will be
randomized by a non-blinded study personnel.

Study participants will return for follow-up appointments at 2 weeks, 6 weeks, 12 weeks and
6 months. Participants will also be expected to return all syringes that she has used prior
to the scheduled visit. This will aid in our assessment of patient compliance with suggested
use of medication and also ensure that correct disposal of the vaginal cream.

As per standard of care, a vaginal culture will be obtained at any visit if the patient
complains of a bothersome, malodorous discharge. In addition to the vaginal culture,
patients who report a malodorous discharge will undergo saline irrigation at time of visit
and examination of vaginal tissue for erosion. If no vaginal erosion present the pessary
will be replaced and the patient will be instructed to continue the previously prescribed
regimen of 3 times weekly application of vaginal cream. If vaginal erosion is noted, the
pessary will be left out for 3 weeks and the patient will be instructed to use the vaginal
cream daily for 3 weeks. The patient will then return to the office after 3 weeks for a
vaginal exam and replacement of pessary upon resolution of vaginal erosion.

We will assess for atrophy, erosion, vaginal discharge and obtain a vaginal culture if
clinically applicable. Questionnaires will be completed at baseline, 12 week and 6 month
follow-up visits and include: Pelvic Floor Distress Inventory (PFDI), Pelvic Floor Impact
Questionnaire (PFIQ). We will assess patient satisfaction for use of pessary at each
follow-up using a Liekhart scale. Patients with bothersome vaginal discharge will use a VAS
scale with a rating of with a 10cm linear continuum in which 0 represents very bothersome
and 10 represents not at all bothersome. Vaginal erosion will be clinically described as
minimal, moderate or severe.

This research may not benefit study participants directly. However, knowledge gained from
this study may help physicians and patients in the future with regard to the best treatment
to reduce vaginal discharge and vaginal erosion in pessary users.

Potential risks for this study outside of the risks associated with pessary use are minimal.
Complications with pessary use include: vaginal erosion, urinary retention, urinary
incontinence and discomfort. These complications will be reviewed with the patient prior to
insertion of pessary. Potential risks encountered when using vaginal estrogen are low.
Estrace contains 0.1 mg estradiol per gram of cream. The recommended dosing is 2-4 g daily
for 1-2 weeks, a gradual reduction to half the initial dose over 1-2 weeks, and then 1 g 1-3
times weekly for maintenance. Our patients will be using half the recommended daily dose for
maintenance and at the most, 1/4th the recommended dose for priming the atrophic tissue.

We are also reducing an additional minimal risk associated with local vaginal estrogen in
our exclusion criteria.

If a participant reports that she has not used the cream or has returned the syringes
unused, she will be removed from the study for lack of compliance. Study participants will
also be removed from the study if they develop or have a new diagnosis of any conditions
that are listed in the exclusion criteria. Finally, they will be removed if any allergic
reactions/adverse events occur from the use of Estrace or placebo. There will be no
replacement procedure for study participants if they are withdrawn. No actions will follow
or are warranted after study participant removal.

This is a double-blinded randomized control trial of subjects with pelvic organ prolapse
who, after counseling at their initial visit, opt for treatment with a vaginal pessary.
Patients who have a Gellhorn or Ring with support pessary placed with then be randomized to
one of two arms for application of a local vaginal cream: estrogen or placebo. The object of
the study is to compare the incidence of vaginal discharge and vaginal erosion in each study
arm. We will also compare subjective measures including quality of life and satisfaction
with their treatment plan.

Our Primary Objective is to compare the use of Estrace® or placebo in reducing symptomatic
vaginal discharge and vaginal erosion in patients using Gellhorn or Ring pessaries.

Prior to randomization subjects will be stratified according to type of pessary (Gellhorn or
Ring). Within a stratum, subjects will be randomly assigned in a 1:1 ratio to Estrace® or
placebo.

The Biostatistics Unit will develop a computer-generated randomization list that utilizes a
permuted block design, and will develop and implement a well documented double-blind
randomization procedure.

Intention-to-treat (ITT):

Data collected will be analyzed according to the ITT principle. The ITT population will be
all patients randomized, regardless of whether or not the study cream was applied. All
patients will be analyzed in the group to which they were randomized (even if they are
switched over to another cream.)

Patients will be assessed for study data at baseline (once the pessary is placed
successfully, week 0), 6, 12, and 24 weeks.

Descriptive statistics (means ± standard deviations or medians and interquartile range [25th
percentile, 75th percentile] for continuous data; frequencies and percentages for
categorical data) will be calculated for subjects on demographic and clinical
characteristics as well as outcomes observed at the end of the trial.

The two groups will be compared for categorical variables using the chi-square test or
Fisher's exact test, as deemed appropriate. The two-sample t-test or Mann-Whitney test will
be used to compare the two groups for continuous data.

Separate repeated measures analysis of variance (RMANOVA) models using a mixed models
approach will be used to compare the two treatment arms with respect to their vaginal
discharge, POP-Q staging , PFDI, and PFIQ trajectories from baseline to 24 weeks. Each model
will include the main effects of treatment arm (Estrace® or placebo) and time (0, 12, and 24
weeks), as well as the treatment x time interaction. If an interaction between group and
time is not found to be statistically significant, only the main effects of treatment group
and time will be analyzed. For all analyses, the standard assumptions of Gaussian residuals
and quality of variance will be tested. If the standard assumptions are not met, a
transformation will be performed.

A result will be considered statistically significant at the p<0.05 level of significance.
All analyses will be performed using SAS version 9.3 (SAS Institute, Cary, NC).

The proposed sample size for this double-blind randomized control trial is n=246 subjects
(n=123 per arm).

Based on data published by Manchana , 21% of symptomatic pelvic organ prolapse patients
fitted successfully with a pessary had vaginal erosion. Let us assume a 60% reduction from
this estimate (21% to 8.4%) after using Estrace®. A two group χ2 test with a 0.05 two-sided
significance level will have 80% power to detect the difference between a vaginal erosion
rate for the placebo group = 0.21 and a vaginal erosion rate of the Estrace® group = 0.084
when the sample size in each group is 123.

Our study limitations are that our primary outcome is a subjective assessment of vaginal
discharge and vaginal erosion. Our population is an older, postmenopausal population and
therefore may be more susceptible to vaginal erosion. Patient compliance to use of the
vaginal cream 2 times weekly is also another limitation as this is a patient directed cannot
be controlled, however we will try to reduce this limitation by requiring that patients
bring their used syringes back to the office.

The PI will monitor data, with emphasis on data integrity and patient welfare concerns
including: recommendations concerning continuation or conclusion of the study, protection of
the confidentiality of the trial data and the results of monitoring, review of data and
study quality.

Any adverse events, unanticipated problems, and protocol deviations will be reported to the
Institutional Review Board as per North Shore-Long Island Jewish Health System policy.

Confidentiality will be maintained by using patient identification numbers instead of names.
Original documents including consent forms that contain subjects' PHI, as well as
questionnaires, will be stored in a locked cabinet within the office of Urogynecology, 865
Northern Blvd., Suite 202, Great Neck, New York 11021. These documents will be kept
separately from any de-identified research data that will be stored electronically as
mentioned below. Institutional Review Board approved investigators will be the only
individuals with access to research data that contains PHI. Any documents that contain
subjects' PHI will be accessible on the North Shore-Long Island Jewish Health System network
server through a password protected computer document/database. These documents are
separated from any de-identified research data files. Institutional Review Board approved
investigators will be the only individuals with access to research data that contains PHI.
De-identified data research files will be stored on the network server.

Inclusion Criteria:

- Age >/= 18 years

- Female gender

- >/= Stage II pelvic organ prolapse

- Clinical diagnosis of pelvic organ prolapse and desiring non-surgical management with
pessary

- Ability to provide informed consent and complete all study requirements

Exclusion Criteria:

- Life expectancy < 12 months

- Current pregnancy

- Patients will undergo a urine pregnancy test

- Already using vaginal estrogen

- Limited manual dexterity

- History of vaginal erosion with prior pessary use

- All patients with a past or present diagnosis of Breast cancer

- Patients with any pathology of the female reproductive organs

- Patients with undiagnosed abnormal genital bleeding

- Patients with known or suspected estrogen-dependent neoplasia

- Active deep vein thrombosis, pulmonary embolism or history of these conditions

- Active or recent (within last year) arterial thromboembolic disease

- Patients with liver dysfunction or disease

- Patients with known hypersensitivity to Estrace's ingredients