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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Lower Urinary Tract Symptoms	Drug: Tamsulosin; Drug: Solifenacin	Phase 4

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	10 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Urinary Nerve Growth Factor as a Biomarker for Medical Treatment of Male Lower Urinary Tract Symptoms: A Pilot Trial
Actual Study Start Date :	October 2011
Actual Primary Completion Date :	July 2014
Actual Study Completion Date :	July 2014

Arms and Interventions

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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 Name: 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 Name: solifenacin succinate, VESIcare®, Vesicare®

Outcome Measures

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Primary Outcome Measures :

1. Change in Urinary Nerve Growth Factor (pg/mL) at Baseline Compared to Post Dose Exposure at Mo.3/Wk12 [ Time Frame: Change from baseline to week 12 (3 months) ]
   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.
2. Change From Baseline in Urinary Growth Factor to Creatinine Ratio (GF/Cr) [ Time Frame: change from baseline score to Month 3 ]
   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.

Secondary Outcome Measures :

1. Change in Post Void Residual (mL) at Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12 [ Time Frame: Change from baseline to months 1, 2 and 3 ]
   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.
2. Change in Maximum Urinary Flow Rate (ml/s) at Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12 [ Time Frame: Change from baseline to months 1, 2 and 3 ]
   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.
3. Change in IPSS-International Prostate Score Scale at Baseline Compared to Post Dose Survey at Month 1, 2, and Month 3/Week12. [ Time Frame: Change from baseline to months 1, 2 and 3 ]
   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.
4. 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 [ Time Frame: Change from baseline to months 1, 2 and 3 ]
   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.
5. Change in PBC-Patient Perception of Bladder Condition at Baseline Compared to Post Dose Exposure at Mo.1, Mo, 2, and Mo. 3/Wk12 [ Time Frame: Change from baseline to months 1, 2 and 3 ]
   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.
6. 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 [ Time Frame: Change from baseline to months 1, 2 and 3 ]
   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.
7. 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 [ Time Frame: Change from baseline to months 1, 2 and 3 ]
   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.
8. Change in Urinary Nerve Growth Factor (pg/mL) at Baseline Compared to Post Dose Exposure at Mo.1/Wk4 and Mo.2/Wk8 [ Time Frame: Change from baseline to 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.
9. Change in Urinary Growth Factor to Creatinine Ratio (GF/Cr) From Baseline Compared to Month 1/Week4 and Month 2/Week 8. [ Time Frame: change from baseline score to Mo.1/Wk4 and Mo.2/Wk8 scores ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	45 Years and older (Adult, Senior)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Timothy Boone, MD, PhD

Astellas Pharma US, Inc.

Investigators

Principal Investigator:	Timothy Boone, MD,PhD	The Methodist Hospital System

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Dmochowski RR, Gomelsky A. Overactive bladder in males. Ther Adv Urol. 2009 Oct;1(4):209-21. doi: 10.1177/1756287209350383.

Other Publications:

McVary KT. 2010 AUA Benign Prostatic Hyperplasia Clinical Guidelines. Panel Chair, AUA News 2010; 15 (3) 10 - 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. Epub 2006 Feb 17. Review.

Kaplan SA. New data on Tolterodine: Do recent findings dispel questions about treating overactive bladder in men? Eur Urology 2007; Suppl 6: 10-16.

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.

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. Erratum in: JAMA. 2007 Mar 21:297(11):1195. JAMA. 2007 Oct 24;298(16):1864.

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.

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.

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.

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.

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, Hessdörfer E, Milani R, Arañó 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.

Responsible Party:	Timothy Boone, MD, PhD, Sponsor-Investigator/Principal Investigator, The Methodist Hospital System
ClinicalTrials.gov Identifier:	NCT01457573 History of Changes
Other Study ID Numbers:	Pro00006253; IRB# 0711-0124 ( Other Identifier: HMRI IRB )
First Posted:	October 24, 2011
Results First Posted:	April 2, 2018
Last Update Posted:	April 2, 2018
Last Verified:	March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided
Plan Description:	Plan to share data to be determined.

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

Additional relevant MeSH terms:

Lower Urinary Tract Symptoms; Urological Manifestations; Signs and Symptoms; Mitogens; Tamsulosin; Solifenacin Succinate; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Adrenergic alpha-1 Receptor Antagonists	Adrenergic alpha-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Urological Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents