Pilot Trial Of Urinary Nerve Growth Factor (NGF) As Biomarker for Male Lower Urinary Tract Symptoms (LUTS)

Urinary Nerve Growth Factor as a Biomarker for Medical Treatment of Male Lower Urinary Tract Symptoms: A Pilot Trial

A single center, pilot trial using tamsulosin and solifenacin in 10 men with symptomatic lower urinary tract symptoms (LUTS). Subjects will be evaluated at baseline, 1, 2, and 3 months for urinary NGF, urine creatinine, NGF/CR ratio and patient reported outcomes through questionnaires.

Study Overview

• Status: Completed
• Conditions: Lower Urinary Tract Symptoms
• Intervention / Treatment: Drug: Tamsulosin; Drug: Solifenacin

Detailed Description

Single center, pilot trial, single arm study using once daily dosing of tamsulosin and solifenacin in 10 men with symptomatic lower urinary tract symptoms (LUTS). Assessments occur at Baseline, 1 Month, 2 Month and 3 Month to evaluate: urinary NGF (pg/mL), urine creatinine (mg/dL), NGF/Cr ratio and patient reported questionnaire outcomes (AUA Symptom Score/IPSS, Patient Perception of Bladder Condition, Patient Perception of Urge Intensity 'PPIUS', LUTS Urinary Symptoms and Quality of Life). Each participant is assessed from baseline to Month 3 measurements. Protection of human subjects will be provided through the Houston Methodist Research Institute Institutional Review Board (see appendix 2). All men will receive morning dosing with Tamsulosin 0.4 mg (1 tab) and Solifenacin 5 mg (1 tab) orally at the same time.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Men > 45 years old with symptomatic LUTS (clinical benign prostatic hypertrophy/BPH)
• International Prostate Symptom Score (IPSS) > 8
• PSA < 10 ng/ml (negative biopsies within 6 months for any age-specific PSA elevation suspicious for prostate carcinoma)
• Post void residual urine < 150 mls
• Urinary Flow rate > 15 mL/sec

Exclusion Criteria:

• Neurogenic bladder
• Urinary tract infection, Urinary stone(s), Urinary tract tumor
• Radiation therapy for urologic malignancy or prostate surgery; radiation to pelvic, colon, rectum, prostate, bladder, uterus or ovaries
• Alpha blocker therapy or anticholinergic therapy within 3 months of entry or 5 alpha reductase therapy within 18 months.
• History of cataracts with planned surgery

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: One (single arm); All men will receive morning dosing with Tamsulosin (Flomax) 0.4 mg (1 tab) and Solifenacin (Vesicare) 5 mg (1 tab) orally at the same time.

Drug: Tamsulosin; Alpha blocker used to in the treatment of urinary difficulties related to enlarged prostate or symptomatic benign prostatic hypertrophy. All men will receive Tamsulosin (Flomax®) 0.4 mg, 1 tab, per morning with Solifenacin (Vesicare®).; Other Names: tamsulosin hydrochloride, tamsulosin HCl, Flomax®; Drug: Solifenacin; Antispasmodic/anticholinergic used to treat overactive bladder. All men will receive Solifenacin (Vesicare®) 5 mg, 1 tab, per morning with Tamsulosin.; Other Names: solifenacin succinate, VESIcare®, Vesicare®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Urinary Nerve Growth Factor (pg/mL) at Baseline Compared to Post Dose Exposure at Mo.3/Wk12	Urine sample tested for urinary Nerve Growth Factor (uNGF as measured in pg/mL), a small secreted protein in the bladder that supports bladder function regulation, at baseline (pre-dose) and week 12/Month 3 post-dose, after using daily tamsulosin and solifenacin.	Change from baseline to week 12 (3 months)
Change From Baseline in Urinary Growth Factor to Creatinine Ratio (GF/Cr)	The urinary growth factor (GF) to creatinine ratio may be potential biomarker for overactive bladder, based on published articles. Measuring the ratio at baseline and Month 3, comparing the difference after treatment with tamsulosin and solifenacin which may provide insight into how lower urinary tract symptoms in men progresses.	change from baseline score to Month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Post Void Residual (mL) at Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12	Urine sample tested for urinary post void residual (measured in mL) at baseline (pre-dose), Month 1 and Month 2and week 12/Month 3 post-dose, post dose w/tamsulosin and solifenacin.	Change from baseline to months 1, 2 and 3
Change in Maximum Urinary Flow Rate (ml/s) at Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12	Urination flow rate (measured in milliliters per second) at baseline (pre-dose), and Month 1, Month 2, and Month 3/Week 12 pose-dosing with tamsulosin and solifenacin. An average maximum urinary flow rate in males is 21 ml/sec aged 14-45 years-old and 12 ml/sec in males aged 46-65 years-old.	Change from baseline to months 1, 2 and 3
Change in IPSS-International Prostate Score Scale at Baseline Compared to Post Dose Survey at Month 1, 2, and Month 3/Week12.	The survey, IPSS-International Prostate Score Scale, survey responses measured 0-35, is collected at baseline compared to post dose survey response at Month 1, Month 2, and Month 3/Week12 post-dose. The lower the score is indicative of less or fewer urinary symptoms while 35 is consistent with more bothersome symptoms.	Change from baseline to months 1, 2 and 3
Change in PPUS-Patient Perception of Urinary Urgency Survey Score at Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12	The Patient Perception of Urinary Urgency self administered survey score has a maximum score 4, zero to four, for how severe a patient describes their urinary voiding frequency. Four is the most bothersome score, 0 or 1 is the least bothersome. Pre-dose / baseline score is compared at Month 1, Month 2, and Month 3, after dosing with tamsulosin and solifenacin.	Change from baseline to months 1, 2 and 3
Change in PBC-Patient Perception of Bladder Condition at Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12	Change in the Perception of Bladder through a self administered survey at baseline compared to Month 1, Month 2, and Month 3, following exposure to tamsulosin and solifenacin. The survey score measures from zero to 6, with 6 being the most bothersome bladder symptoms and 0 to 1 being the least bothersome.	Change from baseline to months 1, 2 and 3
Change in ICIQ-MLUTS - International Consultation on Incontinence Modular Questionnaire for Male LUTS Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12	Measuring change in the International Consultation on Incontinence Modular Questionnaire for male lower urinary tract symptoms through a self administered survey at baseline compared to Month 1, Month 2, and Month 3, after exposure to tamsulosin and solifenacin. The survey score is a zero to 182 range with 182 being the most bothersome and zero to one being the least bothersome.	Change from baseline to months 1, 2 and 3
Change in ICIQ LUTS QoL -International Consultation on Incontinence Modular Questionnaire LUTS Quality of Life for Male LUTS Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12	Change in the International Consultation on Incontinence Modular Questionnaire on lower urinary tract symptoms quality of life survey for men, self administered, compared to Month 1, Month 2, and Month 3, after exposure to tamsulosin and solifenacin. The survey scoring is zero to 182, with 182 being the most bothersome and 0 to 1 being the least bothersome.	Change from baseline to months 1, 2 and 3
Change in Urinary Nerve Growth Factor (pg/mL) at Baseline Compared to Post Dose Exposure at Mo.1/Wk4 and Mo.2/Wk8	Urine sample tested for urinary Nerve Growth Factor (uNGF as measured in pg/mL), a small secreted protein in the bladder that supports bladder function regulation, at baseline (pre-dose) compared to Month 1/Week 4 and Month 2/Week 8, post dosing with tamsulosin and solifenacin.	Change from baseline to Mo.1/Wk4 and Mo.2/Wk8
Change in Urinary Growth Factor to Creatinine Ratio (GF/Cr) From Baseline Compared to Month 1/Week4 and Month 2/Week 8.	Assessing the change from baseline to Month 1/Week 4 and Month 2/Week 8, of the urinary growth factor (GF) to creatinine ratio in men, which may be potential biomarker for overactive bladder, based on published articles. Measuring the ratio at baseline compared to Month 1 and Month 2 may provide insight into how lower urinary tract symptoms in men progresses.	change from baseline score to Mo.1/Wk4 and Mo.2/Wk8 scores

Collaborators and Investigators

• Sponsor: Timothy Boone, MD, PhD
• Collaborators: Astellas Pharma US, Inc.
• Investigators: Principal Investigator: Timothy Boone, MD,PhD, The Methodist Hospital Research Institute

Publications and helpful links

General Publications

• Liu HT, Kuo HC. Urinary nerve growth factor level could be a potential biomarker for diagnosis of overactive bladder. J Urol. 2008 Jun;179(6):2270-4. doi: 10.1016/j.juro.2008.01.146. Epub 2008 Apr 18.
• Liu HT, Chancellor MB, Kuo HC. Decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. BJU Int. 2009 Jun;103(12):1668-72. doi: 10.1111/j.1464-410X.2009.08380.x. Epub 2009 Feb 11.
• Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol. 2006 Apr;49(4):651-8. doi: 10.1016/j.eururo.2006.02.018. Epub 2006 Feb 17.
• Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder. BJU Int. 2004 Oct;94(6):817-20. doi: 10.1111/j.1464-410X.2004.05039.x.
• Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA. 2006 Nov 15;296(19):2319-28. doi: 10.1001/jama.296.19.2319. Erratum In: JAMA. 2007 Mar 21:297(11):1195. JAMA. 2007 Oct 24;298(16):1864.
• McVary KT. 2010 AUA Benign Prostatic Hyperplasia Clinical Guidelines. Panel Chair, AUA News 2010; 15 (3) 10 - 11.
• Kaplan SA. New data on Tolterodine: Do recent findings dispel questions about treating overactive bladder in men? Eur Urology 2007; Suppl 6: 10-16.
• Kaplan SA, Roehrborn CG, Chancellor M, Carlsson M, Bavendam T, Guan Z. Extended-release tolterodine with or without tamsulosin in men with lower urinary tract symptoms and overactive bladder: effects on urinary symptoms assessed by the International Prostate Symptom Score. BJU Int. 2008 Nov;102(9):1133-9. doi: 10.1111/j.1464-410X.2008.07761.x. Epub 2008 May 26.
• Kaplan SA, Goldfischer ER, Steers WD, Gittelman M, Andoh M, Forero-Schwanhaeuser S. Solifenacin treatment in men with overactive bladder: effects on symptoms and patient-reported outcomes. Aging Male. 2010 Jun;13(2):100-7. doi: 10.3109/13685530903440408.
• Yokoyama T, Kumon H, Nagai A. Correlation of urinary nerve growth factor level with pathogenesis of overactive bladder. Neurourol Urodyn. 2008;27(5):417-20. doi: 10.1002/nau.20519.
• Jacobs BL, Smaldone MC, Tyagi V, Philips BJ, Jackman SV, Leng WW, Tyagi P. Increased nerve growth factor in neurogenic overactive bladder and interstitial cystitis patients. Can J Urol. 2010 Feb;17(1):4989-94.
• Cardozo L, Hessdorfer E, Milani R, Arano P, Dewilde L, Slack M, Drogendijk T, Wright M, Bolodeoku J; SUNRISE Study Group. Solifenacin in the treatment of urgency and other symptoms of overactive bladder: results from a randomized, double-blind, placebo-controlled, rising-dose trial. BJU Int. 2008 Nov;102(9):1120-7. doi: 10.1111/j.1464-410X.2008.07939.x. Epub 2008 Oct 6.
• Dmochowski RR, Gomelsky A. Overactive bladder in males. Ther Adv Urol. 2009 Oct;1(4):209-21. doi: 10.1177/1756287209350383.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2011
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: October 20, 2011
• First Submitted That Met QC Criteria: October 21, 2011
• First Posted (Estimate): October 24, 2011

Study Record Updates

• Last Update Posted (Actual): April 2, 2018
• Last Update Submitted That Met QC Criteria: March 19, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urological Manifestations; Lower Urinary Tract Symptoms; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Urological Agents; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Tamsulosin; Solifenacin Succinate
• Other Study ID Numbers: Pro00006253; IRB# 0711-0124 (Other Identifier: HMRI IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Plan to share data to be determined.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No