Effects of Flourish HEC on Localized Provoked Vulvodynia
Condition: Vulvodynia; Vestibulodynia; Vulvar Diseases; Vulvar Vestibulitis; Vulvar Pain
MeSH terms: Vulvodynia; Vulvar Vestibulitis; Vulvar Diseases
Study type: Interventional

Summary: 
      This study is designed to determine whether improving the vaginal microbiome in women with
      localized provoked vulvodynia (LPV) may help improve pain better than routine care alone. The
      study randomizes women with LPV to either routine care or routine care plus a vaginal hygiene
      system designed to improve the vaginal microbiome. Women will be assessed for vaginal
      microbiome, vaginal pH, and pain before enrollment and after 6 weeks, and after 3 months.
      Women will also have pain assessed 2 weeks after enrollment without assessing vaginal
      microbiome and pH.
    

Detailed description: 
      Vulvodynia is a chronic pain condition affecting the tissues of the external genitalia in
      women. Localized provoked vulvodynia (LPV) is a specific subset of vulvodynia in which pain
      occurs upon touching specific sites on the vestibule (or, less commonly, another defined
      area), and which has been present for more than three months without a known cause. LPV is
      characterized both by allodynia (pain in response to a normally non-painful stimulus) and
      hyperalgesia (excessive pain response), leading to pain with sex, tampon use, and even with
      activities of daily life, such as sitting or wearing tight clothing.

      It is becoming accepted that LPV occurs as a type of hypersensitivity to Candida and other
      antigens which occurs in susceptible women. LPV is an inflammatory condition with increased
      levels of B-cells, T-cells, and macrophages in tender areas vs. non-tender areas. The
      inflammatory process sparks neuroproliferation - growth of new nerve endings - which
      increases the density of nerve fibers in tender spots, especially in areas of lymphoid
      aggregates.

      The vulvar and vaginal microbiomes are connected to each other; species found in one are
      often found in the other. In fact, Jayaram et al. showed that all vaginal species were also
      found on the vestibule, and the dominant vaginal species is also the dominant vestibular
      species, suggesting that vaginal secretions are a major contributor to the vestibular/vulvar
      microbiome. Three recent studies have examined the link between vulvodynia and the vaginal
      microbiome. Results vary by study, with one showing differences in the present vaginal
      microbiomes between women with vulvodynia and healthy women, and others not showing
      differences. These may be explainable by inclusion/exclusion criteria (two studies excluded
      women with active yeast infection; one study specified studying generalized, not localized,
      vulvodynia; while the others did not specify). But it is agreed that past alterations in the
      microbiome primed women for excessive pain in response to gentle stimuli.

      Vaginal microbiome composition is known to affect immune activation in the vagina and vulva.
      Campisciano and colleagues showed that vaginal dysbiosis is associated with elevated levels
      of interleukin (IL)-1ra and IL-2, and lower levels of fibroblast growth factor (FGF)-beta and
      granulocyte-macrophage colony stimulating factor (GM-CSF) than observed in healthy vaginas.
      Another study by the same group reported associations between vaginal microbiome composition
      and IL-1alpha and IL-18. Doerflinger showed activation of the innate immune response by
      Lactobacillus iners (intermediate flora) and Fannyhessea vaginae (associated with bacterial
      vaginosis), but not L. crispatus (healthy flora). Of greatest relevance, Falsetta and
      colleagues investigated expression and activation of the toll-like receptor family and found
      seven of them to be expressed at higher levels in tissue biospies from tender spots in LPV
      than in control tissue, and that exposure to HIV increased expression of TLR7 expression and
      the downstream inflammatory molecule IL-6. Notably, no studies have examined whether
      improving the vaginal microbiome might lead to reductions in immune signaling in vulvodynia.

      Taken together, it is reasonable to hypothesize that the constitution of the vaginal
      microbiome may influence the hypersensitivity to allergens that comprises the cause of LPV.
      It is also possible that improving the vaginal microbiome may reduce immune cell recruitment
      and activation, reducing pain. It is predicted that using sequencing-based technology,
      differences between the vaginal microbiomes of women with LPV and those without will be
      detectable. Furthermore, its is predicted that using an over-the-counter feminine hygiene
      system designed to support a healthy vulvovaginal microbiome will reduce pain in women with
      LPV over and above any reductions observed with standard-of-care treatment.

      The investigators recently conducted an 11-week pilot study of similar design. Women with
      recurrent bacterial vaginosis (BV) were recruited to use the Flourish Vaginal Care System®
      for 11 weeks. Primary outcomes were vaginal fluid pH and whether or not women had BV
      recurrence. By the end of the study, the average vaginal fluid pH had fallen from mean (SD)
      of 4.54 (0.53) at week 0 to 4.08 (0.40) at week 11. At baseline, 30% of women had active BV.
      (These women were treated with standard of care oral metronidazole). The number of
      BV-positive women steadily declined until 5 weeks, at which point no woman had BV. There was
      no recurrence of BV in any woman through the end of the study. Women reported fewer
      vulvovaginal symptoms throughout the study. An ad hoc follow-up phone survey a year later
      showed that only one participant had a recurrence of BV since the end of the study. This
      study shows that the system we propose to use in the present study is able to effect positive
      changes in the vaginal microbiome.

      A follow-up trial at the same center examining the vaginal microbiome using the same system
      for 6 months has shown very low recurrence rates, based on preliminary analysis, less than
      20% in 6 months, compared with other studies showing 3-month recurrence rates of 43% or 62%.
      This study, which has completed data collection but has not yet been published, also showed
      that the vaginal microbiome was in a healthy or intermediate community state type (CST; not
      BV) during use of the system, though it took over 5 weeks of usage for one woman to move from
      a BV-like CST to a healthy CST. A similar study is underway using the "Flourish HEC" system -
      a nearly identical kit with a different vaginal moisturizing gel, gentler for those with
      sensitivities. To date, five participants are enrolled, and only the initial microbiome tests
      are available. However, study subjects are reporting that they are feeling good while using
      the system. It is this Flourish HEC system that will be tested in the present study. We
      emphasize that the vaginal care system is not intended to modify the body; it has no active
      drug components. Instead, it is a hygiene system that mimics the proper vaginal environment
      for a healthy microbiome to develop and thrive.

      The investigators hypothesize that regular use of the Flourish HEC Vaginal Care System by
      women with LPV for three months will colonize the vagina and vulva with healthy bacteria, and
      that this will reduce inflammation, immune system activation, and neuroproliferation,
      ultimately reducing pain.
    

Intervention name(s): BioNourish, a component of the Flourish HEC kit; Control - no intervention
Intervention type(s): Device; Other
Intervention description(s): BioNourish is a vaginal moisturizing gel which obtained FDA 510k clearance in 2020. It is one component of the full system being tested. The main intervention is to use this kit to improve the vaginal microbiome.; No intervention; participants only receive routine care.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Longitudinal open-label randomized controlled trial. Patients enrolled for 3 months in one of two concurrently enrolling groups.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Localized provoked vulvodynia; Vaginal microbiome; Probiotic; Lactobacillus