Investigation of the Effect of the Female Urinary Microbiome on Incontinence

Overactive Bladder Clinical Trial

— FUM  

Official title:

Investigation of the Effect of the Female Urinary Microbiome on Incontinence

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02835846
• Other study ID #: 207777
• Status: Completed
• Phase: Phase 4
• Start date: September 2016
• Est. completion date: May 2018

Study information

• Verified date: November 2020
• Source: Loyola University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This purpose of this study is to understand the types of bacteria that are in the bladder and vagina in patients with overactive bladder (OAB) symptoms and understand if the types of bacteria change when with the use of estrogen in the vagina. The investigators are also trying to understand how estrogen influences the body's ability to make substances called peptides that can kill bacteria.

Description:

Overactive bladder (OAB) syndrome is characterized by the symptom complex of urinary urgency, usually with associated frequency and nocturia, with or without urgency urinary incontinence in the absence of infection or other pathology. OAB affects approximately 31% of women over the age of 65. Vaginal estrogen, a well-documented treatment for OAB in hypoestrogenic women, has been shown to improve symptoms of frequency, urgency and urgency urinary incontinence (UUI). Several theories have been proposed to explain the mechanism underlying estrogen's effect on lower urinary tract symptoms (LUTS). The investigators propose that estrogen treatment influences bacterial communities (microbiomes) in the vagina and bladder and alters urothelial and vaginal (AMPs) thereby improving OAB symptoms in hypoestrogenic women.

Long-standing medical dogma has been replaced by clear evidence that a female urinary microbiome (FUM) exists. The investigators recently reported that the FUM in women without OAB is less diverse than the FUM of women with OAB. The investigators soon will report that FUM status stratifies women with OAB into treatment response groups and women with less diverse FUMs are more likely to respond to anti-cholinergic OAB therapy (Thomas-White et al., in preparation). This suggests that the FUM is a factor in lower urinary tract symptoms (LUTS) and that FUM diversity contributes to LUTS and treatment response, like the vaginal microbiome and its contribution to vaginal symptoms.

In hypoestrogenic women, the vaginal microbiome shifts from low diversity communities, commonly dominated by Lactobacillus, to more diverse communities dominated by anaerobes; this change can be reversed with estrogen treatment. Since the FUM of women with OAB includes bacteria similar to those of the vaginal microbiome (e.g. Lactobacillus, Gardnerella, and diverse anaerobes), the investigators reason the FUM would respond similarly to estrogen and become less diverse. Although transvaginal medications likely alter nearby bacterial niches (e.g. the bladder), no study has reported the urinary microbiomic response to vaginal estrogen.

While almost nothing is known about urinary/vaginal microbiome interplay, even less is known about immune response modulation in the bladder and vagina. However, estrogen reduces the subsequent urinary tract infection (UTI) rate in hypoestrogenic women affected by recurrent UTI, and estrogen induces urothelial antimicrobial peptide (AMP) expression. Since AMPs exhibit microbicidal activity, stimulate inflammation, and facilitate epithelial barrier homeostasis, estrogen may work through AMPs as mediators to optimize microbial equilibrium.

The investigators hypothesize that, following estrogen treatment of hypoestrogenic women with OAB, symptom improvement will be associated with 1) reduced FUM diversity, 2) alteration of other FUM characteristics and 3) increased AMP levels. The investigators propose two specific aims:

Aim 1: To compare pelvic floor microbiome (PFM) diversity and AMP levels before and after estrogen treatment in hypoestrogenic women with OAB symptoms.

Aim 2: Determine if FUM characteristics correlate with OAB symptoms.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: May 2018
• Est. primary completion date: March 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Women who present with symptoms of OAB, defined as a condition characterized by urgency, with or without urgency incontinence, usually with frequency and nocturia in the absence of obvious pathology or infection [9], with atrophic vaginitis.

• Postmenopausal by history (i.e., defined as twelve months or greater since last menstrual period), surgical menopause with removal of bilateral ovaries, or age over 55 with a previous hysterectomy (without removal of bilateral ovaries).

• English language skills sufficient to complete questionnaires

• Clinical indication for vaginal estrogen use (i.e., hypoestrogenic findings on physical examination)

• Patients not currently receiving vaginal estrogen therapy

Exclusion Criteria:

• Patients currently on systemic hormone replacement therapy (HRT) or who have been on HRT within the past three months

• Patients with current diagnosis or history of estrogen dependent malignancies (e.g., breast or endometrial malignancies)

• Contraindication or allergy to estrogen therapy

• Insufficient English language skills to complete study questionnaires

• Women with active, standard culture positive urinary tract infection at baseline assessment, or those with a urine dip positive for leukocytes and nitrates on straight catheterized sample.

• Patients who have received antibiotics within the past two weeks

• Patients with stage 3 or 4 pelvic organ prolapse based on the pelvic organ prolapse quantitation system (POP-q)

• Patients unwilling to use vaginal estrogen preparation

• Patients currently on anticholinergic medications or who have received anticholinergic medications within the past three months

• Patients who have previously failed two medications for treatment of OAB or have previously received more advanced treatment for OAB including intra-vesicle botulinum toxin injections, posterior tibial nerve stimulation, or implantation of a sacral neuromodulator

• Patients wishing to start anticholinergic medication at the initial encounter

• Undiagnosed abnormal genital bleeding

• Active deep vein thrombosis (DVT), pulmonary embolism (PE), or a history of these conditions

• Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions

• Known liver dysfunction or disease

• Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders

Related Conditions & MeSH terms

• Incontinence
• Nocturia
• Overactive Bladder
• Urinary Bladder, Overactive

Intervention

Drug:
• Estrogen Cream
Participants are provided a vaginal estrogen cream (i.e., Premarin Cream® 0.625 mg conjugated estrogen/gram) and instructed to use 0.5 grams with an applicator twice weekly for 12 weeks.

Locations

Country	Name	City	State
United States	Loyola University Medical Center	Maywood	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Loyola University	Kimberly-Clark Corporation

Country where clinical trial is conducted

United States, 

References & Publications (19)

Brading AF. A myogenic basis for the overactive bladder. Urology. 1997 Dec;50(6A Suppl):57-67; discussion 68-73. Review. — View Citation

Brotman RM, Shardell MD, Gajer P, Fadrosh D, Chang K, Silver MI, Viscidi RP, Burke AE, Ravel J, Gravitt PE. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2014 May;21(5):450-8. doi: 10.1097/GME.0b013e3182a4690b. — View Citation

Cardozo LD, Wise BG, Benness CJ. Vaginal oestradiol for the treatment of lower urinary tract symptoms in postmenopausal women--a double-blind placebo-controlled study. J Obstet Gynaecol. 2001 Jul;21(4):383-5. — View Citation

Coyne KS, Thompson CL, Lai JS, Sexton CC. An overactive bladder symptom and health-related quality of life short-form: validation of the OAB-q SF. Neurourol Urodyn. 2015 Mar;34(3):255-63. doi: 10.1002/nau.22559. Epub 2014 Jan 13. — View Citation

Eriksen PS, Rasmussen H. Low-dose 17 beta-estradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study. Eur J Obstet Gynecol Reprod Biol. 1992 Apr 21;44(2):137-44. — View Citation

Fok CS, McKinley K, Mueller ER, Kenton K, Schreckenberger P, Wolfe A, Brubaker L. Day of surgery urine cultures identify urogynecologic patients at increased risk for postoperative urinary tract infection. J Urol. 2013 May;189(5):1721-4. doi: 10.1016/j.juro.2012.11.167. Epub 2012 Dec 3. — View Citation

Fouts DE, Pieper R, Szpakowski S, Pohl H, Knoblach S, Suh MJ, Huang ST, Ljungberg I, Sprague BM, Lucas SK, Torralba M, Nelson KE, Groah SL. Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. J Transl Med. 2012 Aug 28;10:174. doi: 10.1186/1479-5876-10-174. — View Citation

Griebling TL, Liao Z, Smith PG. Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women. Menopause. 2012 Jun;19(6):630-5. doi: 10.1097/gme.0b013e31823b8983. — View Citation

Haylen BT, Maher CF, Barber MD, Camargo S, Dandolu V, Digesu A, Goldman HB, Huser M, Milani AL, Moran PA, Schaer GN, Withagen MI. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic organ prolapse (POP). Int Urogynecol J. 2016 Apr;27(4):655-84. doi: 10.1007/s00192-016-3003-y. — View Citation

Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, Brubaker L, Gai X, Wolfe AJ, Schreckenberger PC. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014 Mar;52(3):871-6. doi: 10.1128/JCM.02876-13. Epub 2013 Dec 26. — View Citation

Khasriya R, Sathiananthamoorthy S, Ismail S, Kelsey M, Wilson M, Rohn JL, Malone-Lee J. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol. 2013 Jul;51(7):2054-62. doi: 10.1128/JCM.03314-12. Epub 2013 Apr 17. — View Citation

Nelken RS, Ozel BZ, Leegant AR, Felix JC, Mishell DR Jr. Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder. Menopause. 2011 Sep;18(9):962-6. doi: 10.1097/gme.0b013e3182104977. — View Citation

Pearce MM, Hilt EE, Rosenfeld AB, Zilliox MJ, Thomas-White K, Fok C, Kliethermes S, Schreckenberger PC, Brubaker L, Gai X, Wolfe AJ. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio. 2014 Jul 8;5(4):e01283-14. doi: 10.1128/mBio.01283-14. — View Citation

Rahn DD, Ward RM, Sanses TV, Carberry C, Mamik MM, Meriwether KV, Olivera CK, Abed H, Balk EM, Murphy M; Society of Gynecologic Surgeons Systematic Review Group. Vaginal estrogen use in postmenopausal women with pelvic floor disorders: systematic review and practice guidelines. Int Urogynecol J. 2015 Jan;26(1):3-13. doi: 10.1007/s00192-014-2554-z. Epub 2014 Nov 13. Review. — View Citation

Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, Karlebach S, Gorle R, Russell J, Tacket CO, Brotman RM, Davis CC, Ault K, Peralta L, Forney LJ. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4680-7. doi: 10.1073/pnas.1002611107. Epub 2010 Jun 3. — View Citation

Raz R. Urinary tract infection in postmenopausal women. Korean J Urol. 2011 Dec;52(12):801-8. doi: 10.4111/kju.2011.52.12.801. Epub 2011 Dec 20. — View Citation

Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, Wein AJ. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003 May;20(6):327-36. Epub 2002 Nov 15. — View Citation

Tseng LH, Wang AC, Chang YL, Soong YK, Lloyd LK, Ko YJ. Randomized comparison of tolterodine with vaginal estrogen cream versus tolterodine alone for the treatment of postmenopausal women with overactive bladder syndrome. Neurourol Urodyn. 2009;28(1):47-51. doi: 10.1002/nau.20583. — View Citation

Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, Mueller ER, Schreckenberger P, Dong Q, Nelson DE, Brubaker L. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012 Apr;50(4):1376-83. doi: 10.1128/JCM.05852-11. Epub 2012 Jan 25. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the Relative Abundance of Lactobacillus	The relative abundance of Lactobacillus to total microbes per sample was measured before and after treatment. The within-participant change in relative abundance of Lactobacillus was calculated subtracting pre-treatment from post-treatment.	0, 12 weeks
Secondary	Change in OAB Symptoms	OAB symptoms are measured using the Overactive Bladder Questionnaire (OAB-q). The OAB-q symptom score ranges from 0-100 with higher scores indicating greater symptom severity. A change score is calculated as the post-treatment score minus the pre-treatment score.	0, 12 weeks
Secondary	OAB Symptoms Associated With Relative Abundance of Lactobacillus	The investigators will determine whether change in OAB symptoms using the OAB-q before and after treatment is associated with the change in participants' relative abundance of Lactobacillus before and after treatment. The OAB-q symptom score ranges from 0-100 with higher scores indicating greater symptom severity.	0, 12 weeks
Secondary	Change in Urothelial Antimicrobial Peptide (AMP) Levels	The investigators will compare participants' AMP activity levels before and after treatment. AMP activity level is measured as the diffusion of AMPs in bacterial agar from the center of the well to which the patient's purified biological sample is applied. The diffusion of AMPs in the agar results in the killing of bacteria and a clearing around the well. This clearing of bacterial growth is measured in square millimeters and then normalized to the total peptide concentration. Change is calculated as the post-treatment AMP activity level minus the pre-treatment AMP activity level.	0, 12 weeks
Secondary	Change in OAB Symptoms Associated With Change in AMP Levels	The investigators will determine whether any change in OAB symptoms using the OAB-q before and after treatment is associated with the change in participants' AMP levels before and after treatment.	0, 12 weeks