Dutasteride With Tolterodine ER or Placebo to Treat Lower Urinary Tract Symptoms (LUTS)

Study Overview
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Brief Summary
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This is an investigator-initiated study of safety, efficacy and tolerability of dutasteride given for 18 months, including a 1-year double-blind randomized co-administration with either tolterodine ER or placebo in men suffering from lower urinary tract symptoms (LUTS) including urgency and frequency, with or without urgency urinary incontinence (i.e., overactive bladder (OAB) symptoms).

Detailed Description
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Men who are treated with an alpha blocker (AB) or 5-alpha reductase inhibitor (5-ARI) for benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS) often have symptoms including urinary frequency and urgency. ABs and 5-ARIs may improve the obstructive voiding symptoms but not necessarily the storage symptoms. This study will evaluate the safety and efficacy of dutasteride 0.5 mg once daily for 6 months in an open label fashion. Those patients who continue to report storage urinary symptoms, will be randomized to receive dutasteride 0.5 mg once daily for an additional one year together with double-blind tolterodine ER 4 mg or matched tolterodine ER placebo once daily.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Study of Safety and Efficacy of Dutasteride in Combination With Tolterodine ER or Placebo in Men With Lower Urinary Tract Symptoms (LUTS) Including Urgency and Frequency

Conditions
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Benign Prostatic Hyperplasia (BPH)

Intervention / Treatment
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* Drug: Tolterodine ER 4mg
* Drug: Placebo
* Drug: Pre-randomization Dutasteride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: This subject population will consist of males ≥ 50 years of age who have lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE) for a minimum of 3 months Inclusion criteria at screening: Subjects who understand and speak English and are able to comply with the protocol, complete the diaries, and other study tools Subject has provided written informed consent and HIPAA authorization Ambulatory male subjects ≥ 50 years of age Able to use the toilet without difficulty History of LUTS due to BPE, as diagnosed by history as well as digital rectal exam (DRE), for ≥ 3 months suitable for medical therapy with 5-ARI in combination with antimuscarinic drugs Prostate volume (PV) ≥ 30 cc as measured by transrectal ultrasound (TRUS) International prostate symptoms score (IPSS) ≥12 Post Void Residual Volume < 150 mL at baseline Uroflowmetry-Qmax > 5 mL/sec and ≤ 15 mL/sec Prostate specific antigen (PSA) ≥ 1.5 ng/ml and in normal age-adjusted range. For those subjects with an elevated age-adjusted PSA, it is the responsibility of the investigator to take standard of care measures to assure reasonable absence of prostate cancer Have an average of ≥ 8 micturitions per 24 hrs Have an average of 2 episodes of urgency per 24 hrs (defined as those with the Urinary Sensation Scale rating of 3 or more) Exclusion Criteria: Concurrent use of 5-ARI therapy within the past 3 months Concurrent use of alpha blockers within the past 2 weeks Concurrent use of antimuscarinics within the past 4 weeks Concurrent use of Phosphodiesterase type 5 (PDE-5) inhibitors on a daily basis Evidence of chronic inflammation such as interstitial cystitis and bladder stones. Evidence of untreated urethral stricture disease Uncontrolled narrow angle glaucoma Increased post-void residual volume (PVR) defined as PVR > 150 mL Uroflowmetry-Qmax ≤ 5 mL/sec Acute urinary tract infection (UTI). These subjects may be treated and re-screened Acute urinary retention (AUR) requiring catheter within the last 3 months Previous or planned transurethral resection of the prostate (TURP) Minimally invasive surgery (MIS) such as transurethral microwave treatment (TUMT), transurethral needle ablation (TUNA), laser, or other minimally invasive procedures within 12 months. Those patients who in the opinion of the investigator did not respond adequately to MIS and fulfill the inclusion criteria are eligible to participate A known diagnosis of prostate cancer. A known diagnosis of bladder cancer within 5 years of screening. Those patients with history of non-muscle invasive bladder cancer who have not had a recurrence in the past 5 years are eligible to screen for this study and must maintain continued adequate bladder cancer screening at the discretion of the Investigator Renal or hepatic impairment defined as 2.5 x upper limit of normal. Some isolated abnormalities would be left at the discretion of the investigator with always keeping in mind to not pose a hazard to the patient. PSA > 10 ng/mL (if the PSA is greater than 4 ng/mL and less than or equal to 10 ng/mL, subjects may be included at the discretion of the Investigator if the PSA has been stable and the patient has had a prostate biopsy showing no evidence of prostate cancer) Known or suspected hypersensitivity to dutasteride or tolterodine ER . Participation in a clinical trial involving an investigational drug, within 30 days prior to enrollment. History of diagnosed gastrointestinal obstruction disease. Myocardial infarction within the past 8 weeks. Known or suspected drug and/or alcohol abuse. Any clinical condition, which, in the opinion of the Investigator, would not allow safe completion of the study.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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Male

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolterodine ER 4mg<br>1:1 randomization to either Dutasteride 0.5mg orally once daily plus Tolterodine ER 4mg orally once daily or Dutasteride 0.5mg orally once daily plus placebo once daily | Drug: Tolterodine ER 4mg<br>* 1:1 randomization to either Dutasteride 0.5mg orally once daily plus Tolterodine ER 4 mg orally once daily or Dutasteride 0.5mg orally once daily plus placebo once daily<br>* Other names: Detrol LA;Drug: Pre-randomization Dutasteride<br>* All participants were on Dutasteride 0.5mg orally once daily prior to randomization.<br>|
| Placebo Comparator: placebo<br>1:1 randomization to either Dutasteride 0.5mg orally once daily plus Tolterodine ER 4mg orally once daily or Dutasteride 0.5mg orally once daily plus placebo once daily | Drug: Placebo<br>* 1:1 randomization to either Dutasteride 0.5mg orally once daily plus Tolterodine ER 4mg orally once daily or Dutasteride 0.5mg orally once daily plus placebo once daily<br>Drug: Pre-randomization Dutasteride<br>* All participants were on Dutasteride 0.5mg orally once daily prior to randomization.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-void Residual (PVR) Volume | To evaluate the safety of dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with symptoms of LUTS: post-voiding residual volume measured via ultrasound. | 12 months | 
| Maximum Urine Flow Rate (Qmax). | To evaluate the safety of dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with symptoms of LUTS: maximum urine flow rate (Qmax) measured via uroflowmetry. | 12 months | 
| Urine Voided Volume (Voiding) | To evaluate the safety of dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with symptoms of LUTS: urine voided volume (voiding) measured by uroflowmetry. | 12 months | 
| Acute Urinary Retention (AUR) | To evaluate the safety of dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with symptoms of LUTS: acute urinary attention (AUR) - inability to urinate requiring catheterization. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overactive Bladder Questionnaire (OABq) | To evaluate the efficacy in men taking dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with LUTS including OAB symptoms: overactive bladder questionnaire (OABq) - 33 questions scored via 1-6 (higher scores indicate more severe symptoms), thus values ranged from 33-198. | 12 months | 
| Patient Perception of Bladder Condition (PPBC) | To evaluate the efficacy in men taking dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with LUTS including OAB symptoms: participant reported patient perception of bladder condition (PPBC), one question scored from 1-6, higher scores indicating more severe symptoms. | 12 months | 
| International Prostate Symptoms Score (IPSS), Total | To evaluate the efficacy in men taking dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with LUTS including OAB symptoms: total international prostate symptoms score (IPSS) - 7 questions scored from 0-5 (higher score indicating more severe symptoms), thus total scores ranged from 0-35. | 12 months | 
| International Prostate Symptoms Score, Voiding Subscore | To evaluate the efficacy in men taking dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with LUTS including OAB symptoms: voiding subscore of international prostate symptoms score (IPSS) - 4 questions scored from 0-5 (higher score indicating more severe symptoms), thus total scores ranged from 0-20. | 12 months | 
| International Prostate Symptoms Score (IPSS), Storage Subscore | To evaluate the efficacy in men taking dutasteride 0.5 mg in combination with either tolterodine ER 4mg or placebo for the treatment of men with LUTS including OAB symptoms: storage subscore international prostate symptoms score (IPSS) - 3 questions scored from 0-5 (higher score indicating more severe symptoms), thus total scores ranged from 0-15. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Benign prostatic hyperplasia (BPH), dutasteride, tolterodine ER