Assessment of Urinary Polymerase Chain Reaction (PCR) and Next Generation Sequencing (NGS) Technology in the Evaluation and Management of Females With Chronic Bladder Pain and Cystitis-like Symptoms

Real-world clinical practice multicenter study to determine the clinical implications of employing PCR/NGS technology to identify and treat potential urinary pathogens in female participants identified with bladder pain and/or cystitis-like symptoms.

Study Overview

• Status: Recruiting
• Conditions: Interstitial Cystitis; Bladder Pain Syndrome
• Intervention / Treatment: Diagnostic test: Polymerase Chain Reaction and Next-Generation DNA Sequencing

Detailed Description

This is a real-world clinical practice multicenter study to determine the clinical implications of employing PCR/NGS technology to identify and treat potential urinary pathogens in female patients identified with BPS and/or CCS symptoms. Eligible subjects will undergo a baseline/screening visit at which time the following will be collected: demographics/history, physical examination, Numerical Rating Scale (NRS) pain (average and maximum), Female Genito-Urinary Pain Index (F-GUPI), Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index (ICSI/ICPI), Acute Cystitis Symptom Score (ACSS), and the Short Form -12.v2 Quality of Life Questionnaire (SF-12). MSU and catheterized urine specimens will be collected for urinalysis (UA), standard culture, and PCR/NGS. Subjects will be stratified based on BPS (NIDDK MAPP criteria) or CCS (based on ACSS criteria) symptoms.

Uropathogens detected on PCR/NGS catheterized specimens will be treated with 10 days of PCR/NGS directed antibiotic therapy which will be recommended by a centralized infectious disease consultant. If there are no uropathogenic bacteria in the catheter specimen, the MSU specimen will be used if positive. Prescribing physicians will adjust those recommendations (choice of antibiotic as well as duration of therapy) based on individual patient's history of antibiotic therapy and known allergies and sensitivities. Subjects with negative PCR/NGS findings for potential uropathogens will be treated with 10 days of empiric antibiotic therapy chosen by the investigator from this list b: 1. Trimethoprim sulfamethoxazole, 2. Macrocrystalline nitrofurantoin, 3. Fosfomycin, and 4. Investigator choice. More than one antibiotic may be prescribed if two or more uropathogens are identified. At the discretion of the treating physician with the consent and shared decision making with the patient, a decision may be made to continue antibiotic therapy beyond 10 days if the patient subjectively believes she is responding. In this study, all subjects will be offered antibiotic therapy, either NGS directed or empiric. Fourteen days after beginning antibiotics, the Subjective Global Assessment (SGA), compliance and safety will be determined via phone call. A clinic visit will be scheduled for 14 days after finishing antibiotics for repeat evaluation of symptoms (NRS pain, F-GUPI, ICSI/ICPI, ACSS, SF-12, SGA) and safety. A MSU urine specimen will be collected from all subjects and submitted for PCR/NGS analysis. Subjects who were PCR/NGS negative and failed empiric therapy will be notified that they likely do not have an infection. Primary analyses will be based on the responder rate (SGA responder rate will be the primary efficacy parameter), symptom change based on the other questionnaires, and safety in BPS/CCS subjects treated with PCR/NGS as well as those treated with empiric therapy. A 40% SGA responder rate, where a responder is defined as markedly or moderately improved on the GRA 7-point scale, will be considered a clinically significant impact. A follow-up visit 4 weeks later will collect similar data as collected at the efficacy visit.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • UCLA Center for Women's Pelvic Health
      • Contact: Crystal Cisneros; Phone Number: 833-825-2974; Email: CCisneros@mednet.ucla.edu
      • Principal Investigator: Anne L Ackerman, MD
    • San Diego, California, United States, 92103
      • Recruiting
      • The University of California San Diego Health
      • Contact: Trisha Kanie; Phone Number: 619-543-6544; Email: tkanie@health.ucsd.edu
      • Principal Investigator: Jennifer Anger, MD
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Recruiting
      • Cooper University Health Care
      • Contact: Bhaven Murji; Phone Number: 856-968-7547; Email: murji-bhaven@cooperhealth.edu
      • Principal Investigator: Lioudmila Lipetskaia, MD
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Completed
      • Wake Forest University Baptist Medical Center Urology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria: Subjects may be included in the study if they have bladder and/or urethral pain and lower urinary tract storage symptoms and only if they meet all of the following criteria at screening/baseline.

1. Subjects are capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in this protocol.
2. Symptomatic subjects with BPS (NIH/NIDDK/MAPP definition) with perceived bladder pain +/- urinary storage symptoms) or symptomatic patients with CCS (chronic UTI definition based on modified ACSS with dysuria)
3. Subjects with previous failure of standard urine culture directed therapy approach, eg. antibiotic treatment based on previous urine culture results (positive, sterile, or nebulous) failed to provide appreciable clinical benefit.
4. Subjects who have experienced a minimum of 3 months of continuous symptoms
5. Subjects who have a minimum average daily bladder pain score of ≥ 3 on a 0-10 NRS scale in the past 3 months
6. Subjects with no antibiotic therapy for the previous 2 weeks
7. Subjects with no UTI supplements including cranberry, d-mannose, high dose vitamin C and Lactobacillus probiotics for the previous 2 weeks.

Exclusion Criteria: Subjects will be excluded from participating in this study if they meet any of the following criteria:

1. Subjects with any of the following confounding conditions: bladder stones, lower ureteric stones, vaginal candidiasis, urethral diverticulum, urinary retention (≥ 300 mL), overactive bladder (ie, urinary urgency secondary to urinary incontinence), or any other condition/disease, which, in the opinion of the investigator, could compromise patient safety or confound the collection or interpretation of study results.
2. Subjects who are pregnant or planning a pregnancy during the study period
3. Subjects with a history of previous urinary diversion procedure with or without bladder removal or bladder augmentation.
4. Subjects with a history of bladder cystoscopy only within 1 month or cystoscopy with bladder biopsy, hydrodistension, fulguration or triamcinolone injection or treatment of Hunner ulcer performed within 3 months prior to Screening.
5. Subjects undergoing active treatment for cancer - urologic (eg bladder) or other - with surgery, radiation or chemotherapy within previous 8 weeks of screening.
6. Subjects with a neurogenic bladder (due to spinal cord injury, stroke, Parkinson's disease, multiple sclerosis, spina bifida, or diabetic cystopathy).
7. Subjects with genital herpes active within 3 months prior to screening.
8. Subjects with a history of gross (visible) hematuria within 1 year prior to screening that has not been evaluated.
9. Subjects who have had major surgery within the past 3 months or has surgery planned during the study period
10. Subjects with a history of alcohol and/or drug abuse that in the investigator's opinion could interfere with the study evaluations or the patient's safety.
11. Subjects catheterized in the past month
12. Subjects that have received antibiotic treatment based on MicroGenDX's NGS results in the prior 12 months
13. Subjects with indwelling ureteral stents
14. Subjects that have received a bladder instillation within the last 4 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Single arm; All subject's samples will undergo the same diagnostic test utilizing Polymerase Chain Reaction and Next-Generation DNA Sequencing	Diagnostic test: Polymerase Chain Reaction and Next-Generation DNA Sequencing; The qPCR Rapid Screening Panel is a quantitative real-time PCR test for bacteria and fungi. Next-Generation DNA Sequencing is the Comprehensive Sequencing test will detect virtually all microbial organisms and fungal pathogens that may be present in patient specimens.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effectiveness of PCR/NGS directed antimicrobial therapy assessed by the Global Response Assessment (GRA)	GRA is a 7-point descriptive scale in which subjects self-report that degree that their symptoms improved or worsened compared to baseline. The answers available for the subject includes markedly improved, moderately improved, mildly improved, no change, mildly worse, moderately worse, markedly worse. A responder is a subject who reports that compared to baseline their symptoms are moderately or markedly improved. The primary analysis will determine the proportion of subjects who are responders at the efficacy visit.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of PCR/NGS directed antimicrobial therapy by measuring the incidence of Treatment-Emergent Adverse Events by the SAE questionnaire	Determine the safety of employing a PCR/NGS directed antimicrobial therapy strategy in female subjects with BPS and CCS.	1 year
concordance	Evaluate concordance of culture results with PCR/NGS findings in this population of women.	1 year
Type of sample comparison	Compare the microbiome of midstream and catheterized urine specimens of symptomatic female subjects with BPS and CCS.	1 year
Stratification comparison	Compare urinary microbiome of symptomatic population of women stratified based on PCR/NGS positive and PCR/NGS negative subgroups, positive/negative cultures, and BPS and CCS.	1 year

Collaborators and Investigators

• Sponsor: MicroGenDX

Publications and helpful links

General Publications

• Nickel JC, Stephens-Shields AJ, Landis JR, Mullins C, van Bokhoven A, Lucia MS, Henderson JP, Sen B, Krol JE, Ehrlich GD; MAPP Research Network. A Culture-Independent Analysis of the Microbiota of Female Interstitial Cystitis/Bladder Pain Syndrome Participants in the MAPP Research Network. J Clin Med. 2019 Mar 26;8(3):415. doi: 10.3390/jcm8030415.
• Nickel JC, Stephens A, Landis JR, Mullins C, van Bokhoven A, Lucia MS, Ehrlich GD; MAPP Research Network. Assessment of the Lower Urinary Tract Microbiota during Symptom Flare in Women with Urologic Chronic Pelvic Pain Syndrome: A MAPP Network Study. J Urol. 2016 Feb;195(2):356-62. doi: 10.1016/j.juro.2015.09.075. Epub 2015 Sep 26.
• Hanno PM, Burks DA, Clemens JQ, Dmochowski RR, Erickson D, Fitzgerald MP, Forrest JB, Gordon B, Gray M, Mayer RD, Newman D, Nyberg L Jr, Payne CK, Wesselmann U, Faraday MM; Interstitial Cystitis Guidelines Panel of the American Urological Association Education and Research, Inc. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol. 2011 Jun;185(6):2162-70. doi: 10.1016/j.juro.2011.03.064. Epub 2011 Apr 16.
• O'Leary MP, Sant GR, Fowler FJ Jr, Whitmore KE, Spolarich-Kroll J. The interstitial cystitis symptom index and problem index. Urology. 1997 May;49(5A Suppl):58-63. doi: 10.1016/s0090-4295(99)80333-1.
• Giannantoni A, Bini V, Dmochowski R, Hanno P, Nickel JC, Proietti S, Wyndaele JJ. Contemporary management of the painful bladder: a systematic review. Eur Urol. 2012 Jan;61(1):29-53. doi: 10.1016/j.eururo.2011.07.069. Epub 2011 Sep 9.
• Alidjanov JF, Naber KG, Pilatz A, Wagenlehner FM. Validation of the American English Acute Cystitis Symptom Score. Antibiotics (Basel). 2020 Dec 19;9(12):929. doi: 10.3390/antibiotics9120929.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Anticipated): November 15, 2023
• Study Completion (Anticipated): December 15, 2023

Study Registration Dates

• First Submitted: November 4, 2021
• First Submitted That Met QC Criteria: March 2, 2022
• First Posted (Actual): March 11, 2022

Study Record Updates

• Last Update Posted (Actual): March 15, 2023
• Last Update Submitted That Met QC Criteria: March 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: PCR; NGS; BPS; IC
• Additional Relevant MeSH Terms: Urologic Diseases; Urinary Bladder Diseases; Cystitis; Cystitis, Interstitial
• Other Study ID Numbers: MDX-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Currently no plan to share individual data to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No