Effects of Flourish HEC on Localized Provoked Vulvodynia

Vulvodynia Clinical Trial

Official title:

Effects of Flourish HEC Vaginal Care System on Reduction of Pain in Women With Localized Provoked Vulvodynia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05478746
• Other study ID #: LPV0522
• Status: Completed
• Phase: N/A
• Start date: September 26, 2022
• Est. completion date: January 15, 2024

Study information

• Verified date: February 2024
• Source: Vaginal Biome Science
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: January 15, 2024
• Est. primary completion date: January 15, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 52 Years

Eligibility

Inclusion Criteria:

1. Premenopausal cis women between ages 18 and 52 diagnosed with LPV via cotton swab test who have experienced symptoms for at least three months, and who do not have another diagnosis which may explain the pain.

Exclusion Criteria:

1. Known allergies or sensitivities to aloe or any other ingredients of the Flourish HEC Vaginal Care System

2. Individuals whose pain completely prevents application of intravaginal products (applicators similar in size to a tampon)

3. Individuals who are immunosuppressed or otherwise immunocompromised

4. Known allergy or sensitivity to metronidazole or fluconazole

5. Known active vaginal infection at the beginning of the study

6. Anyone who may have mental health disorders or trauma history triggered by answering questions related to vulvar or vaginal health, by pelvic exams, or self-application of vaginal products

7. Vulnerable populations: adults unable to consent, individuals who are not yet adults, pregnant or lactating women (or those attempting to become pregnant), and prisoners

Related Conditions & MeSH terms

• Vestibulodynia
• Vulvar Diseases
• Vulvar Pain
• Vulvar Vestibulitis
• Vulvodynia

Intervention

Device:
• BioNourish, a component of the Flourish HEC kit
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.

Other:
• Control - no intervention
No intervention; participants only receive routine care.

Locations

Country	Name	City	State
United States	EvoScient Gynecology	Virginia Beach	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Vaginal Biome Science	Evvy

Country where clinical trial is conducted

United States, 

References & Publications (17)

Bedford L, Parker SE, Davis E, Salzman E, Hillier SL, Foxman B, Harlow BL. Characteristics of the vaginal microbiome in women with and without clinically confirmed vulvodynia. Am J Obstet Gynecol. 2020 Sep;223(3):406.e1-406.e16. doi: 10.1016/j.ajog.2020.02.039. Epub 2020 Mar 2. — View Citation

Bornstein J, Goldstein AT, Stockdale CK, Bergeron S, Pukall C, Zolnoun D, Coady D; consensus vulvar pain terminology committee of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women's Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS). 2015 ISSVD, ISSWSH and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. Obstet Gynecol. 2016 Apr;127(4):745-751. doi: 10.1097/AOG.0000000000001359. — View Citation

Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB, Moss LM, Horvath LB, Kuzevska I, Fairley CK. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis. 2006 Jun 1;193(11):1478-86. doi: 10.1086/503780. Epub 2006 Apr 26. — View Citation

Campisciano G, Zanotta N, Licastro D, De Seta F, Comar M. In vivo microbiome and associated immune markers: New insights into the pathogenesis of vaginal dysbiosis. Sci Rep. 2018 Feb 2;8(1):2307. doi: 10.1038/s41598-018-20649-x. — View Citation

Chidawanyika T, Yi CHC, Kelly-Martin R, Cleland J, DuPriest E. Clinical trial to survey results of Flourish vaginal care system for recurrent BV [A80]. Obstet Gynecol. 2022;139:24S. doi:10.1097/01.AOG.0000826648.49549.01

Committee Opinion No 673: Persistent Vulvar Pain. Obstet Gynecol. 2016 Sep;128(3):e78-e84. doi: 10.1097/AOG.0000000000001645. — View Citation

De Seta F, Campisciano G, Zanotta N, Ricci G, Comar M. The Vaginal Community State Types Microbiome-Immune Network as Key Factor for Bacterial Vaginosis and Aerobic Vaginitis. Front Microbiol. 2019 Oct 30;10:2451. doi: 10.3389/fmicb.2019.02451. eCollection 2019. — View Citation

Doerflinger SY, Throop AL, Herbst-Kralovetz MM. Bacteria in the vaginal microbiome alter the innate immune response and barrier properties of the human vaginal epithelia in a species-specific manner. J Infect Dis. 2014 Jun 15;209(12):1989-99. doi: 10.1093/infdis/jiu004. Epub 2014 Jan 7. — View Citation

Falsetta ML, Foster DC, Woeller CF, Pollock SJ, Bonham AD, Piekna-Przybylska D, Maggirwar SB, Haidaris CG, Phipps RP. Toll-Like Receptor Signaling Contributes to Proinflammatory Mediator Production in Localized Provoked Vulvodynia. J Low Genit Tract Dis. 2018 Jan;22(1):52-57. doi: 10.1097/LGT.0000000000000364. — View Citation

Jayaram A, Witkin SS, Zhou X, Brown CJ, Rey GE, Linhares IM, Ledger WJ, Forney LJ. The bacterial microbiome in paired vaginal and vestibular samples from women with vulvar vestibulitis syndrome. Pathog Dis. 2014 Dec;72(3):161-6. doi: 10.1111/2049-632X.12197. Epub 2014 Jul 10. — View Citation

Liao Z, Chakrabarty A, Mu Y, Bhattacherjee A, Goestch M, Leclair CM, Smith PG. A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia. J Pain. 2017 May;18(5):511-525. doi: 10.1016/j.jpain.2016.12.008. Epub 2017 Jan 3. — View Citation

Mitchell CM, Watson L, Mitchell AJ, Hyrien O, Bergerat A, Valint DJ, Pascale A, Hoffman N, Srinivasan S, Fredricks DN. Vaginal Microbiota and Mucosal Immune Markers in Women With Vulvovaginal Discomfort. Sex Transm Dis. 2020 Apr;47(4):269-274. doi: 10.1097/OLQ.0000000000001143. — View Citation

Paavonen J, Eschenbach DA. Localized Provoked Vulvodynia-An Ignored Vulvar Pain Syndrome. Front Cell Infect Microbiol. 2021 Jun 17;11:678961. doi: 10.3389/fcimb.2021.678961. eCollection 2021. — View Citation

Pagan L, Ederveen RAM, Huisman BW, Schoones JW, Zwittink RD, Schuren FHJ, Rissmann R, Piek JMJ, van Poelgeest MIE. The Human Vulvar Microbiome: A Systematic Review. Microorganisms. 2021 Dec 12;9(12):2568. doi: 10.3390/microorganisms9122568. — View Citation

Park SY, Lee ES, Lee SR, Kim SH, Chae HD. Vaginal Microbiome Is Associated With Vulvodynia, Vulvar Pain Syndrome: A Case-Control Study. Sex Med. 2021 Apr;9(2):100314. doi: 10.1016/j.esxm.2020.100314. Epub 2021 Feb 27. — View Citation

Sobel JD, Schmitt C, Meriwether C. Long-term follow-up of patients with bacterial vaginosis treated with oral metronidazole and topical clindamycin. J Infect Dis. 1993 Mar;167(3):783-4. doi: 10.1093/infdis/167.3.783. No abstract available. — View Citation

Tommola P, Unkila-Kallio L, Paetau A, Meri S, Kalso E, Paavonen J. Immune activation enhances epithelial nerve growth in provoked vestibulodynia. Am J Obstet Gynecol. 2016 Dec;215(6):768.e1-768.e8. doi: 10.1016/j.ajog.2016.07.037. Epub 2016 Jul 25. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Vaginal microbiome in women with localized provoked vulvodynia (LPV)	Using whole-genome sequencing, all microbes present in the vaginal microbiome will be identified and reported for relative abundance.	Baseline
Primary	Changes in the vaginal microbiome in women with localized provoked vulvodynia (LPV) with and without Flourish HEC	Using whole-genome sequencing, all microbes present in the vaginal microbiome will be identified and reported for relative abundance. Changes in these values from baseline to 6 weeks will be compared in women using or not using the Flourish HEC system.	Baseline to 6 weeks.
Primary	Changes in the vaginal microbiome in women with localized provoked vulvodynia (LPV) with and without Flourish HEC	Using whole-genome sequencing, all microbes present in the vaginal microbiome will be identified and reported for relative abundance. Changes in these values from baseline to 3 months will be compared in women using or not using the Flourish HEC system.	Baseline to 3 months.
Primary	Changes in the vaginal microbiome in women with localized provoked vulvodynia (LPV) with and without Flourish HEC	Using whole-genome sequencing, all microbes present in the vaginal microbiome will be identified and reported for relative abundance. Changes in these values from 6 weeks to 3 months will be compared in women using or not using the Flourish HEC system.	6 weeks to 3 months.
Primary	Pain intensity by cotton swab test	The PI will gently palpate the study participant at selected vulvar and extra-vulvar sites using a cotton swab; the participant will report pain on a scale of 0 (no pain) to 10 (most intense pain imaginable). Changes in pain intensity per location from baseline to 2 weeks, 6 weeks, and 3 months will be compared between women using and not using the Flourish HEC system.	Baseline to 2 weeks to 6 weeks to 3 months.
Primary	Vulvovaginal symptoms questionnaire (VSQ) and addendum	Study participants responses to questions on the previously-validated VSQ and not-yet-validated additional questions will be collected on a 4-point Likert scale (0=not at all, 3 = all the time), except when questions are binary by nature. Change in question scores between timepoints will be compared between women who use and women who do not use the Flourish HEC system.	Baseline to 2 weeks to 6 weeks to 3 months.
Secondary	Treatment escalation	A typical vulvodynia patient is started on a mild treatment, then escalated over time if symptoms do not improve. Treatment escalation will be compared between women who use and women who do not use the Flourish HEC system.	Baseline to 2 weeks to 6 weeks to 3 months.