Intravaginal LACTIN-V for Prevention of Recurrent Urinary Tract Infection
Condition: Urinary Tract Infection
MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections
Study type: Interventional
Phase: Phase 2

Summary: 
      Recurrent urinary tract infections (RUTIS) continue to be a major health problem in women and
      are now complicated by increasing antibiotic resistance. New preventive approaches are
      needed. Because most women with RUTI lack the normal protective Lactobacillus (LB) in their
      vaginal flora, we hypothesized that restoration of LB would reduce RUTIS. In this trail,
      women with recent UTI are randomized to receive either LB or placebo vaginal capsules and are
      followed for side effects, for colonization with LB and for occurrence of RUTI over hte next
      four months.
    

Detailed description: 
      Purpose: The purpose of this study is to evaluate the safety of the vaginal suppository
      LACTIN-V (Lactobacillus crispatus CTV-05) as well as the efficacy of LACTIN-V use in
      preventing recurrent urinary tract infections (RUTI) in women. Study subjects will include
      pre-menopausal women with a history of frequent RUTI. As part of this study, we will also
      evaluate growth of lactobacilli and urinary tract infection(UTI)-causing bacteria in the
      vaginas of women following use of LACTIN-V.

      Rationale: LACTIN-V is composed of L. crispatus. L. crispatus is a bacteria found to grow
      naturally in the vaginas of healthy women. It is felt to be important in preventing vaginal
      infection and UTI. With regard to prevention of UTI, L. crispatus is thought to prevent the
      growth of UTI-causing bacteria (such as E. coli) in the vagina, and so prevent these
      UTI-causing bacteria from being able to enter the female urethra and cause infection in the
      bladder (cystitis). There is epidemiologic evidence to support this prevention mechanism, as
      absence of L. crispatus and related lactobacilli from the vagina has been associated with
      vaginal E. coli growth and with UTI. Scientific evidence supports the ability of lactobacilli
      to prevent vaginal E. coli growth by out-competing E. coli in vaginal colonization, and
      through the production of toxins such as lactic acid, hydrogen peroxide, and bacteriocins.

      LACTIN-V contains a specific strain of L. crispatus, CTV-05, which was isolated from the
      vagina of a healthy woman. It was prepared as a vaginal suppository with the purpose of
      restoring growth of healthy L. crispatus in the vaginas of women who experience frequent
      RUTI. As indicated above, these women often have a deficiency of healthy vaginal lactobacilli
      growth, and therefore may not experience the protective function of these natural organisms.
      It is hoped that use of LACTIN-V will lead to vaginal growth of protective lactobacilli in
      these women wich will, in turn, prevent the vaginal growth of E. coli and other UTI-causing
      bacteria. Phase 1 and 2 studies of LACTIN-V to date have shown this "probiotic" to be safe
      and well tolerated.

      The impetus for this study is the urgent need for non-antibiotic strategies to prevent UTI.
      UTI is one of the most common bacterial infections. It leads to substantial morbidity and
      health care costs. Frequent use of antibiotics for treatment of and prophylaxis against UTI
      is contributing to the prevalence of antibiotic resistant bacteria, which are also making it
      more difficult to treat UTI. Therefore, the potential advantage of LACTIN-V is that it is a
      natural product that may prevent UTI without the use of antibiotics. If it proves to be
      efficacious, it could decrease the morbidity and health care costs associated with UTI as
      well as decrease overall antibiotic use and the corresponding prevalence of antibiotic
      resistance among UTI-causing bacteria.

      Primary Objective: The primary objective is to evaluate the safety of LACTIN-V, compared to
      placebo, in pre-menopausal women with recurrent uncomplicated UTI.

      Secondary objectives:

        1. To evaluate the efficacy of LACTIN-V, compared to placebo, in reducing the incidence of
           Symptomatic and Probable UTI (defined below).

        2. To evaluate the efficacy of LACTIN-V, compared to placebo, in decreasing the time to
           recurrence of Symptomatic and Probable UTI.

        3. To evaluate the efficacy of LACTIN-V, compared to placebo, in reducing the prevalence of
           Asymptomatic UTI (defined below).

        4. To evaluate vaginal growth of CTV-05 in subjects using LACTIN-V compared to placebo.

        5. To evaluate vaginal growth of lactobacilli in subjects using LACTIN-V compared to
           subjects using placebo.

        6. To evaluate vaginal growth of E. coli in subjects using LACTIN-V compared to subjects
           using placebo.

      Case Definitions:

      Symptomatic UTI: One or more UTI symptoms (dysuria, urgency, frequency, suprapubic pain,
      flank pain), with a positive urine culture. In symptomatic subjects, a positive urine culture
      is defined as >= 10^2/ml of an UTI-causing bacteria. UTI episodes will be recorded as
      Symptomatic UTI if a negative urine culture at Visit 2, or at another interim study visit,
      confirms resolution of the prior UTI (in order to distinguish a new Symptomatic UTI from a
      Persistent UTI).

      Asymptomatic UTI: A positive urine culture in a subject who reports no urinary symptoms. In
      asymptomatic subjects, a positive urine culture is defined as >= 10^5/ml of an UTI-causing
      bacteria. UTI episodes will be recorded as Asymptomatic UTI if a negative urine culture at
      Visit 2, or at another interim study visit, confirms resolution of the prior UTI (in order to
      distinguish a new Asymptomatic UTI from a Persistent UTI).

      Probable UTI: One or more UTI symptoms (dysuria, urgency, frequency, suprapubic pain, flank
      pain) in a subject who contacted a healthcare provider and was treated with antibiotics for a
      UTI without confirmatory urine culture. UTI episodes will be recorded as Probable UTI if a
      negative urine culture at Visit 2, or at another interim study visit, confirms resolution of
      the prior UTI (in order to distinguish a new Probable UTI from a Persistent UTI).

      Persistent UTI: A positive urine culture following antibiotic treatment for a UTI.

      General Procedures: This will be a randomized, double-blind, placebo-controlled trial of
      LACTIN-V. Subjects will include 100 pre-menopausal women with a history of frequent RUTI who
      are currently or recently being treated for a symptomatic UTI with
      trimethoprim-sulfamethoxazole. Trimethoprim-sulfamethoxazole is one of several antibiotics
      considered standard-of-care for treatment of symptomatic UTI. Subjects will be randomized
      such that 50 women will receive LACTIN-V at a dose of 5x10^8 CFU/suppository and 50 women
      will receive placebo. LACTIN-V and placebo are to be taken once per day for five days during
      the first week of use followed by once per week for 10 weeks on Days 8, 15, 22, 29, 36, 43,
      50, 57, 64, and 71 for a total of 15 doses over 11 weeks. Subjects will undergo five
      scheduled visits and receive two telephone calls:

      Visit 1 is the Screening Visit. This visit will take place during or soon after evaluation
      for a symptomatic UTI. The following will occur during Visit 1: informed consent, review of
      eligibility, history, physical exam, pelvic exam, Pap smear, urine pregnancy test, and
      screening tests for gonorrhea, chlamydia, bacterial vaginosis, yeast, and trichomonas.
      Subjects will provide urine samples for microscopic analysis, dipstick analysis, culture, and
      antibiotic susceptibility testing and vaginal fluid specimens for laboratory assessment of
      vaginal growth of lactobacilli (including CTV-05).

      Visit 2 is the Randomization Visit and represents Week 1 of the study. Visit 2 will take
      place 3-10 days after completion of antibiotic therapy for UTI. Subjects will have their
      eligibility confirmed and undergo a focused pelvic exam without speculum or bimanual exam
      unless clinically indicated, have a screening test for bacterial vaginosis, yeast, and
      trichomonas, and have a repeat pregnancy test. Subjects will also provide urine and vaginal
      fluid specimens as in Visit 1. Subjects will then be randomized to LACTIN-V or placebo.
      Subjects will place the first suppository under supervision and will be instructed to use a
      7-day study calendar to record study product use and related symptoms during the first week,
      and to use a 10-week study calendar to record study product use and related symptoms
      thereafter.

      Day 4-7 phone call: The purpose of this phone call is to assess use of the study product as
      well as any associated symptoms.

      Visit 3 will occur during Week 2, days 8-14 following randomization. Subjects will be asked
      about study product use, adverse events, and symptoms. Subjects will undergo focused physical
      and pelvic exams without speculum or bimanual exam unless clinically indicated. Subjects will
      have a screening test for bacterial vaginosis and provide urine and vaginal fluid specimens
      as before.

      Visit 4 will occur during Week 11 and will be similar to Visit 3.

      Visit 5 will occur during Week 16. The procedures for Visit 5 will be similar to those of
      Visits 3 and 4. However, during this visit, subjects will undergo a complete pelvic exam
      including speculum and bimanual exams and undergo a repeat pregnancy test.

      9 Month telephone call: The purpose of this phone call is to assess the occurrence of adverse
      events, symptoms of UTI, new UTI or other medical diagnoses,and pregnancy.

      In addition to the above schedules visits, subjects will be asked to come to the research
      clinic for Unscheduled Visits if they experience any adverse events or new symptoms of UTI.
      During these unscheduled visits, subjects will undergo history, physical and complete pelvic
      exams, screening tests for bacterial vaginosis, yeast, and trichomonas, as well as for other
      sexually transmitted diseases as clinically indicated. Subjects will provide urine samples
      for microscopic analysis, dipstick analysis, culture, and antibiotic susceptibility testing.
      Subjects will provide vaginal fluid samples for assessment of CTV-05, lactobacillus, and E.
      coli growth.

      Subjects diagnosed with a Symptomatic UTI during the study will be treated with an
      antibiotic. They will then be asked to return to the study clinic for a follow-up urine
      culture two weeks later to confirm UTI resolution.

      Laboratory procedures will include:

        -  wet mount slides of vaginal fluid (all Visits)

        -  urine dipstick testing (all Visits)

        -  urine pregnancy testing (Visits 1, 2, and 5)

        -  Pap smear (Visit 1)

        -  Testing for gonorrhea and chlamydia by culture (Visit 1, other visits as indicated)

        -  urinalysis (all Visits)

        -  urine culture (all Visits)

        -  gram stain and culture of vaginal fluid specimens (All Visits)

        -  Rep-PCR for CTV-05 (Visits 2-5)

        -  DNA amplification of vaginal flora (all Visits)

      Statistical Analysis: The primary cohort for analysis will be the intent-to-treat (ITT)
      cohort. The ITT cohort is defined as subjects who are randomized in the study. Other cohorts
      to be evaluated will include the modified ITT, Evaluable, and according-to-protocol cohorts.
    

Intervention name(s): Lactin-V; Placebo
Intervention type(s): Drug; Drug
Other intervention name(s): no other names; no other names
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: urinary tract infection; cystitis; Lactobacillus; probiotic; prevention