Clinical trial NCT01958073: Vaginal Estrogen for the Prevention of Recurrent Urinary Tract Infection in Postmenopausal Women
Official title: Vaginal Estrogen for the Prevention of Recurrent Urinary Tract Infection in Postmenopausal Women: A Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Recurrent Urinary Tract Infection
Keywords: Recurrent Urinary Tract Infection
Postmenopausal
Vaginal Estrogen
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: American Urogynecologic Society
name: NYU Langone Health
First posted: 2013-10-08
Enrollment: 35
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The investigators would like to know if the use of vaginally applied estrogen can prevent the problem of repeated urinary tract infections (UTI) in women who have gone through menopause. The investigators will use two forms of vaginal estrogen that are available by prescription (a ring and a cream) and compare their efficacy to that of a placebo (without any active ingredient). The investigators are going to look at if the vaginal estrogen can prevent UTIs altogether and also the number of UTIs each group experiences over a 6 month period. After 6 months, all subjects will receive vaginal estrogen and the women on the non-active treatment will be able to choose whether they would like to use either the estrogen ring or cream. The investigators will then be able to compare the number of UTIs on and off active vaginal estrogen treatment within those subjects who started on the placebo. The investigators are also going to look at quality of life before and during treatment using questionnaires and whether subjects stop using the treatments or do not use them as directed (compliance).

Detailed description: This was an investigator-initiated, multicenter, single-blind, randomized placebo-controlled trial of vaginal estrogen (delivered by estradiol ring or conjugated estrogen cream) compared to placebo cream. This study was conducted by the Divisions of Female Pelvic Medicine and Reconstructive Surgery at three academic institutions.

Potential participants were recruited from women receiving care for rUTIs in the clinics of each institution. Women were postmenopausal as defined by amenorrhea for \>12 months, history of bilateral salpingoophrectomy, or in patients with prior hysterectomy defined as menopausal symptoms for \>1 year or age \>55. Participants had documented rUTI (three or more in one year or two in six months) by positive urine culture. Participants were excluded if they had undergone urologic surgery within three months of screening or planned surgery within one year of screening, had the diagnosis of painful bladder syndrome, history of UTI requiring the use of intravenous antibiotics or one oral antibiotic available for treatment based on allergies and resistance profiles, known etiology of infections (e.g. urologic stones, fistulas, fecal incontinence, catheterization or poorly controlled diabetes), urothelial cancer, or actively treated estrogen sensitive tumor. Participant enrollment was deferred in the setting of undiagnosed hematuria or vaginal bleeding, but enrollment could occur after negative workup for malignancy. Participants deferred enrollment if they used vaginal androgens, estrogens or progestins within six months or if they used medications or supplements known to prevent UTI (e.g. cranberry products, D mannose, prophylactic antibiotics, methenamine hippurate) within three months of enrollment, but could enroll after washout. Those with a remote history of estrogen-sensitive tumor required approval by her oncologist or primary care physician.

Participants were initially randomized to receive either vaginal estrogen (via estradiol ring or conjugated estrogen cream) or placebo cream in a 1:1:1 fashion and were told that there were placebo and vaginal estrogen arms, but were unaware that there was not a placebo ring. Participants were randomized to either conjugated estrogen cream at a strength of 0.625 mg/g dosed at 0.5g (0.312 mg) twice a week, estradiol ring containing 2mg of estradiol placed vaginally every three months by study personnel, or placebo cream which was an over-the-counter lubricant containing mineral oil, petrolatum, ceresin and paraffin dosed at 0.5g twice a week. If participants in any arm developed three UTI in the six-month treatment period, they were unblinded. If on placebo, they were provided active study drug or if they were in the vaginal estrogen arm, they were treated according to the provider's clinical practice and their outcomes recorded for the remainder of the study. The primary outcome of occurrence of UTI was assessed at six months or the end of study blinding, whichever occurred first. In order to improve recruitment and assess long-term compliance, satisfaction and efficacy, we offered open label use of estradiol ring or conjugated estrogen cream after unblinding until month 12 of the study.

Clean-catch urine cultures were collected when participants were symptomatic: fever (\>38 degrees C), urgency, frequency, dysuria or suprapubic tenderness. Women were asked to have all urine labs done at the parent site as per standard clinical practice. The primary outcome of the study was the presence of a UTI in the randomized six months. We also assessed rates of UTI over the course of the 12-month study in all participants as-treated. Quality of life (QOL) questionnaires were administered at baseline, six months or unblinding, and 12 months. Questionnaires included the Pelvic Floor Distress Inventory (PFDI-20), Pelvic Floor Impact Questionnaire (PFIQ-7), Medical, Epidemiologic, and Social Aspects of Aging Questionnaire (MESA), Female Sexual Function Index (FSFI) and Patient Satisfaction Questionnaire (PSQ), Global Perception of Improvement (GPI) and Estimated Percent Improvement (EPI) rating scales. Baseline medical history and concomitant pelvic medicine diagnoses were also collected. Participants using a cream treatment were asked to keep medication diaries and return tubes for weighing at months three, six, nine and 12. Adherence was defined as presence of the estrogen ring or tube weights within 20% of expected at follow up visits. In addition, before unblinding, the participants were asked whether they believed they were on active treatment, placebo, or were unsure.

Eligibility criteria: Inclusion Criteria:

1. Postmenopausal status as defined by amenorrhea for \>12 months, OR history of bilateral salpingoophrectomy, OR if the patient has had a hysterectomy defined by menopausal symptoms for \>1 year OR age \>55
2. Documented recurrent UTIs (3 or more in the last year or 2 or more in the last 6 months)- one UTI must be documented by culture, others may be documented by urinalysis
3. Ability to provide informed consent

Exclusion Criteria:

1. Use of any investigational drug or device within thirty days of screening
2. Urologic surgery within the past 3 months of screening or plan for surgery within one year of screening
3. Diagnosis of Interstitial Cystitis/painful bladder syndrome
4. History of urinary tract infections which require the use of IV antibiotics or where only one oral antibiotic is available for treatment, or where the risk of treatment with vaginal estrogen only is deemed unacceptable by the principle investigator secondary to the severity of prior urinary tract infections
5. Known etiology of infection such as, but not limited to: kidney or bladder stones, enterovaginal/vesical fistula, fecal incontinence, intermittent catheterization, indwelling catheter, poorly controlled diabetes
6. Urothelial cancer
7. Actively treated estrogen sensitive tumor (breast or endometrial cancer)
8. Undiagnosed vaginal bleeding
9. Inability to use a vaginal ring (secondary to advanced prolapse or shortened vaginal length)
10. Any medical reason the investigator deems incompatible with treatment with vaginal estrogen
11. Prolapse requiring pessary use

Deferral Criteria

1. Undiagnosed hematuria - may enroll after malignancy is ruled out
2. Use of a progestin containing intrauterine device or use of any vaginal androgens, estrogens or progestins within 3 months of enrollment - may enroll after wash out
3. Use of drugs/supplements known to prevent UTIs (ie cranberry products, prophylactic antibiotics, methenamine hippurate) 1 month prior to enrollment - may enroll after wash out if still meets inclusion criteria.
4. History of estrogen sensitive tumor (breast or endometrial cancer) - requires approval by the subject's primary oncologist or primary care physician

Primary outcomes:
measure: Occurrence of UTI During Randomization
timeFrame: 6 months of the randomized period
Secondary outcomes:
measure: Rates of UTI in Both Randomization Period and Within Placebo When Changed to Open Label Estrogen
timeFrame: Assessed at 6 months for 'a'; assessed over 12 months for 'b'
measure: Quality of Life Questionnaire: Female Sexual Function Index
timeFrame: 6 months of the randomized period
measure: Compliance During Randomization
timeFrame: 6 months of the randomized period
measure: Occurrence of UTI in Those Compliant With Treatment During Randomization
timeFrame: 6 months of the randomized period
measure: Quality of Life Questionnaire: MESA I
timeFrame: 6 months of the randomized period
measure: Quality of Life Questionnaire: MESA II
timeFrame: 6 months of the randomized period
measure: Quality of Life Questionnaire: Pelvic Floor Disability Index
timeFrame: 6 months of the randomized period
measure: Quality of Life Questionnaire: Pelvic Floor Impact Questionnaire
timeFrame: 6 months of the randomized period
measure: Quality of Life Questionnaire: Estimated Percentage of Improvement
timeFrame: 6 months of the randomized period
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
Study officials:
References:
citation: Ferrante KL, Wasenda EJ, Jung CE, Adams-Piper ER, Lukacz ES. Vaginal Estrogen for the Prevention of Recurrent Urinary Tract Infection in Postmenopausal Women: A Randomized Clinical Trial. Female Pelvic Med Reconstr Surg. 2021 Feb 1;27(2):112-117. doi: 10.1097/SPV.0000000000000749.