Vaginal Estrogen for the Prevention of Recurrent Urinary Tract Infection in Postmenopausal Women
Condition: Recurrent Urinary Tract Infection
MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Recurrence
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Conjugated Estrogen Vaginal Cream; Estradiol Ring; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Estradiol; Estrogens; Estrogens, Conjugated (USP)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Prevention
Keywords: Recurrent Urinary Tract Infection; Postmenopausal; Vaginal Estrogen