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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Interstitial Cystitis, Bladder Pain Syndrome

Intervention / Treatment
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* Diagnostic Test: Polymerase Chain Reaction and Next-Generation DNA Sequencing


Participation Criteria
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Eligibility Criteria
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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. Subjects are capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in this protocol. 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) 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. Subjects who have experienced a minimum of 3 months of continuous symptoms Subjects who have a minimum average daily bladder pain score of ≥ 3 on a 0-10 NRS scale in the past 3 months Subjects with no antibiotic therapy for the previous 2 weeks 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: 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. Subjects who are pregnant or planning a pregnancy during the study period Subjects with a history of previous urinary diversion procedure with or without bladder removal or bladder augmentation. 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. Subjects undergoing active treatment for cancer - urologic (eg bladder) or other - with surgery, radiation or chemotherapy within previous 8 weeks of screening. Subjects with a neurogenic bladder (due to spinal cord injury, stroke, Parkinson's disease, multiple sclerosis, spina bifida, or diabetic cystopathy). Subjects with genital herpes active within 3 months prior to screening. Subjects with a history of gross (visible) hematuria within 1 year prior to screening that has not been evaluated. Subjects who have had major surgery within the past 3 months or has surgery planned during the study period 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. Subjects catheterized in the past month Subjects that have received antibiotic treatment based on MicroGenDX's NGS results in the prior 12 months Subjects with indwelling ureteral stents Subjects that have received a bladder instillation within the last 4 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: Single group assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single arm<br>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<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IC, NGS, BPS, PCR