Combined Behavioral and Drug Treatment of Overactive Bladder in Men

Study Overview
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Brief Summary
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The primary aim of this project is to evaluate the effectiveness of combined behavioral + drug therapy compared to behavioral treatment alone and drug therapy alone as a way to improve outcomes in the treatment of OAB symptoms in men. We hypothesize that combined therapy will result in better outcomes than either behavioral or drug therapy alone. The second aim is to compare two methods of implementing combined therapy: simultaneously as initial therapy vs. stepped therapy, in which therapies are combined following initial behavioral or drug therapy alone. The third aim is to examine the costs and cost-effectiveness of combined behavioral + drug therapy compared to behavioral or drug therapy alone.

Detailed Description
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Overactive bladder (OAB) is a very common, distressing condition that manifests as bothersome symptoms of urgency, frequent urination, urge incontinence, and nocturia, and impacts the lives of millions of men. OAB symptoms are most often treated with pharmacologic therapies (alpha-blocking agents and/or antimuscarinic agents) or behavioral treatments. Although drug therapies (even combined drug therapies) and behavioral treatments reduce OAB symptoms, few patients are completely cured with either treatment alone. Therefore, there is a need to improve interventions for this common problem. The primary purpose of this study is to test the effectiveness of combining behavioral treatment and drug therapy as a way to improve outcomes in the treatment of OAB symptoms in men. This is a 3-site, 2-stage, 3-arm randomized clinical trial of behavioral treatment, drug therapy, and combined drug + behavioral therapy for men with OAB, to examine the efficacy of combined therapy and whether it yields higher success rates than either therapy alone. 204 men with OAB were enrolled and randomized to 1) drug therapy alone followed by combined therapy, 2) behavioral treatment alone followed by combined therapy, or 3) combined therapy as initial treatment.

Official Title
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Combined Behavioral and Drug Treatment of Overactive Bladder in Men

Conditions
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Overactive Bladder, Lower Urinary Tract Symptoms

Intervention / Treatment
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* Behavioral: Behavioral training
* Drug: Tolterodine + tamsulosin
* Other: Combined Behavioral + Drug Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Community-dwelling men Age 40 years or older Patient-reported urgency and 9.0 or more voids per 24-hour day (on average) on the 7-day baseline bladder diary. Exclusion Criteria: Urinary flow rate < 8.0 mL/sec on a void greater than 125 ml. Post-void residual volume greater than 150 mL (based on bladder ultrasound after voiding in the presence of a normal urge to urinate). Urinary tract infection (defined as growth of greater than 10,000 colonies per ml of a urinary pathogen on urine culture). Patients will be referred for treatment with antibiotics and may be enrolled if OAB symptoms persist after the infection is resolved. Transurethral resection of the prostate (TURP), simple prostatectomy, or other benign prostatic hypertrophy (BPH) related surgery within the past 5 years. Current active treatment for prostate cancer. History of radical prostatectomy. Previous artificial urinary sphincter, sling procedure, bladder-injection of botulinum toxin, or implanted sacral neuromodulation device. Poorly controlled diabetes (glycosylated hemoglobin >9.0 within last 3 months). Subjects with poorly controlled diabetes will be offered enrollment if the OAB symptoms persist after the diabetes is controlled appropriately. Hematuria on microscopic examination in the absence of infection. A urologic consultation will be recommended and enrollment will depend on clearance by a urologist and agreement by the Site PI that entry into the treatment protocol is not contraindicated. Any unstable medical condition (particularly: cancers under active treatment, decompensated congestive heart failure, history of malignant arrhythmias, unstable angina, diagnosed by history or physical exam). Neurologic conditions such as Parkinson's, spinal cord injury, multiple sclerosis, or myasthenia gravis. Impaired mental status. Patients who screen as probable dementia on the Mini-Cog. Contraindications to the study drugs (tolterodine and tamsulosin) including history of postural hypotension with syncope, history of acute urinary retention requiring catheterization, narrow angle glaucoma, or history of gastric retention. Hypersensitivity to tolterodine or tamsulosin. Current use of an alpha blocker agent. Evaluation will be delayed until the drug has been discontinued for 2 weeks. Current use of an anti-muscarinic agent for OAB. Evaluation will be delayed until the drug has been discontinued for 2 weeks. If on a diuretic, dose has not been stable for at least 4 weeks. If taking dutasteride or finasteride, dose has not been stable for at least 6 months. If on an antibiotic for prostatitis. Patients will be offered re-evaluation if OAB symptoms persist when antibiotics are completed. Full course of behavioral training.

Ages Eligible for Study
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Minimum Age: 40 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
Interventional Model Description: The design of this study is a 3 group randomized trial. Group 1 was randomized to drug only for the first 6 weeks, followed by a step up to drug plus behavior from 6 weeks to 12 weeks. Group 2 was randomized to behavior only for the first 6 weeks, followed by a step up to behavior plus drug from 6 weeks to 12 weeks. Group 3 was randomized to behavior plus drug from baseline to 12 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Behavioral Treatment alone<br>Behavioral treatment is implemented in 4 clinic visits over a period of 6 weeks, followed by 6 weeks of combined behavioral + drug therapy. Behavioral treatment consists of behavioral training and includes skills and strategies for postponing urination, controlling urgency and preventing urge incontinence. This includes pelvic floor muscle training, incremental delayed voiding, and daily bladder diaries, supplemented with instructions for daily home practice between clinic visits. In addition to daytime training, nocturia is managed with fluid restriction (3 hours before bedtime and during the night) and with urge strategies. | Behavioral: Behavioral training<br>* Behavioral treatment consists of skills and strategies for postponing urination, controlling urgency and preventing urge incontinence. This includes pelvic floor muscle training, urge suppression techniques, delayed voiding, and daily bladder diaries to track increasing voiding intervals and enhance awareness of bladder habits. Training is supplemented with instructions for daily home practice between clinic visits. In addition to daytime training, nocturia is managed with fluid restriction (3 hours before bedtime and during the night) and with urge strategies.<br>* Other names: Pelvic floor muscle training;|
| Active Comparator: Drug Therapy (Tolterodine + tamsulosin)<br>Drug therapy for 6 weeks implemented in a clinic visit with telephone follow-up at 3 weeks, followed by 6 weeks of combined drug + behavioral therapy. Participants in the drug group will receive an anti-muscarinic (sustained release tolterodine 4 mg) + an alpha blocker (tamsulosin 0.4mg daily). | Drug: Tolterodine + tamsulosin<br>* Patients in drug therapy receive an anti-muscarinic (long acting tolterodine 4 mg daily) and an alpha blocker (tamsulosin 0.4 mg daily).<br>* Other names: Tolterodine tartrate;|
| Experimental: Combined Behavioral + Drug Therapy<br>Combined behavioral and drug therapy implemented in 4 clinic visits over a period of 6 weeks, followed by an additional 6 weeks of combined therapy. Behavioral treatment consists of behavioral training and includes skills and strategies for postponing urination, controlling urgency and preventing urge incontinence. This includes pelvic floor muscle training, incremental delayed voiding, and bladder diaries, supplemented with instructions for daily home practice. Nocturia is managed with fluid restriction (3 hours before bedtime and during the night) and with urge strategies. Drug therapy consists of an anti-muscarinic (sustained release tolterodine 4 mg) + an alpha blocker (tamsulosin 0.4mg daily). | Other: Combined Behavioral + Drug Therapy<br>* Combined behavioral and drug therapy implemented in 4 clinic visits over a period of 6 weeks, followed by an additional 6 weeks of combined therapy. Behavioral treatment consists of behavioral training and includes skills and strategies for postponing urination, controlling urgency and preventing urge incontinence. This includes pelvic floor muscle training, incremental delayed voiding, and bladder diaries, supplemented with instructions for daily home practice. Nocturia is managed with fluid restriction (3 hours before bedtime and during the night) and with urge strategies. Drug therapy consists of an anti-muscarinic (sustained release tolterodine 4 mg) + an alpha blocker (tamsulosin 0.4mg daily).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Frequency of Urination After 6-week Intervention (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following the first phase of treatment was used to calculate changes in frequency of urination. | From Baseline to 6 Weeks | 
| Change in Frequency of Urination From 6 Weeks to 12 Weeks (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following each phase of treatment were used to calculate changes in frequency of urination. | Change from 6 weeks to 12 weeks | 
| Change in Frequency of Urination From Baseline to 12 Weeks (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following the second phase of treatment were used to calculate changes in frequency of urination | Baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Urgency From Baseline to 6 Weeks (Last Observation Carried Forward) | Bladder diaries completed prior to randomization and following each phase of treatment will be used to calculate changes in urgency associated with each void and incontinent episode using the Indevus Urgency Severity Scale (IUSS). IUSS asks patients about the degree of urgency, as meant to describe the urge to urinate. Patients are asked to rate the degree of urgency and its impact on the completion of activity or tasks during the time that the urgency sensation is present and before reaching the toilet for a toilet void. Four distinct, subjective degrees of urgency severity were identified, including 1) no sensation of urgency, 2) awareness of urgency but easily tolerated, 3) urgency that is somewhat uncomfortable and 4) extreme urgency discomfort. | From Baseline to 6 Weeks | 
| Change in Urinary Incontinence From Baseline to 6 Weeks (Last Observation Carried Forward) | Bladder diaries completed prior to randomization and following each phase of treatment will be used to calculate changes in frequency of incontinence episodes. | From Baseline to 6 Weeks | 
| Change in Nocturia From Baseline to 6 Weeks (Last Observation Carried Forward) | Bladder diaries completed prior to randomization and following each phase of treatment will be used to calculate changes in frequency of nocturia. | From Baseline to 6 Weeks | 
| Change in Overactive Bladder Questionnaire (OAB-q) From Baseline to 6 Weeks (Last Observation Carried Forward) | Change from baseline on the OAB-q to measure symptom bother and condition-specific health-related quality of life. This questionnaire asks about how much you have been bothered by selected bladder symptoms during the past 4 weeks. Scale ranges from 8 to 48 with higher scores indicating a greater degree of bother. | From Baseline to 6 Weeks | 
| Change in International Prostate Symptom Score (I-PSS) From Baseline to 6 Weeks. (Last Observation Carried Forward) | Change from baseline to 6 weeks on the International Prostate Symptom Score (IPSS) to measure urinary symptoms related to benign prostatic hypertrophy (BPH). The I-PSS is based on the answers to seven questions concerning urinary symptoms and one question concerning quality of life. Each question concerning urinary symptoms allows the patient to choose one out of six answers indicating increasing severity of the particular symptom. The answers are assigned points from 0 to 5. The total score can therefore range from 0 to 35 (asymptomatic to very symptomatic). | From Baseline to 6 Weeks | 
| Patient Satisfaction | Patient global ratings of satisfaction using the validated Patient Satisfaction Question | From Baseline to 6 Weeks | 
| Patient Perceptions of Improvement | Patient global ratings of improvement using the validated Estimated Percent Improvement and Global Perception of Improvement | From Baseline to 6 Weeks | 
| How Bothersome Were Side Effects? 6 Week Report | Ordinal Rating regarding how bothersome side effects were | From Baseline to 6 weeks | 
| Change in Urgency Score From 6 Weeks to 12 Weeks (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following each phase of treatment will be used to calculate changes in urgency associated with each void and incontinent episode using the Indevus Urgency Severity Scale (IUSS). IUSS asks patients about the degree of urgency, as meant to describe the urge to urinate. Patients are asked to rate the degree of urgency and its impact on the completion of activity or tasks during the time that the urgency sensation is present and before reaching the toilet for a toilet void. Four distinct, subjective degrees of urgency severity were identified, including 1) no sensation of urgency, 2) awareness of urgency but easily tolerated, 3) urgency that is somewhat uncomfortable and 4) extreme urgency discomfort. | Change from 6 weeks to 12 weeks | 
| Change in Urinary Incontinence From 6 Weeks to 12 Weeks (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following each phase of treatment will be used to calculate changes in frequency of incontinence episodes. | Change from 6 weeks to 12 weeks | 
| Change in Nocturia From 6 Weeks to 12 Weeks (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following each phase of treatment will be used to calculate changes in frequency of nocturia | Change from 6 weeks to 12 weeks | 
| Change in Overactive Bladder Questionnaire (OAB-q) From 6 to 12 Weeks (Last Observation Carried Forward) | Change from 6 weeks to 12 weeks on the OAB-q to measure symptom bother and condition-specific health-related quality of life. This questionnaire asks about how much you have been bothered by selected bladder symptoms during the past 4 weeks. Scale ranges from 8 to 48 with higher scores indicating a greater degree of bother. | Change from 6 week to 12 weeks | 
| Change in International Prostate Symptom Score (IPSS) From 6 to 12 Weeks (Last Observation Carried Forward) | Change from 6 weeks to 12 weeks on the International Prostate Symptom Score (IPSS) to measure urinary symptoms related to BPH.The I-PSS is based on the answers to seven questions concerning urinary symptoms and one question concerning quality of life. Each question concerning urinary symptoms allows the patient to choose one out of six answers indicating increasing severity of the particular symptom. The answers are assigned points from 0 to 5. The total score can therefore range from 0 to 35 (asymptomatic to very symptomatic). | Change from 6 weeks to 12 weeks | 
| Patient Perception of Improvement at 12 Weeks | Patient global ratings of improvement using the validated Estimated Percent Improvement and Global Perception of Improvement. | 12 weeks post randomization | 
| Satisfaction With Progress at 12 Weeks | Patient global ratings of satisfaction using the validated Patient Satisfaction Question. | 12 weeks post randomization | 
| How Bothersome Were Side Effects? 12 Week Report | Ordinal Rating regarding how bothersome side effects were | 12 weeks post randomization | 
| Change in Nocturia Measured From Baseline to 12 Weeks (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following each phase of treatment will be used to calculate changes in the frequency nocturia | From Baseline to 12 weeks | 
| Change in Urgency Score From Baseline to 12 Weeks (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following each phase of treatment will be used to calculate changes in frequency of urgency associated with each void and incontinent episode using the Indevus Urgency Severity Scale (IUSS). IUSS asks patients about the degree of urgency, as meant to describe the urge to urinate. Patients are asked to rate the degree of urgency and its impact on the completion of activity or tasks during the time that the urgency sensation is present and before reaching the toilet for a toilet void. Four distinct, subjective degrees of urgency severity were identified, including 1) no sensation of urgency, 2) awareness of urgency but easily tolerated, 3) urgency that is somewhat uncomfortable and 4) extreme urgency discomfort. | From Baseline to 12 weeks | 
| Change in Urinary Incontinence Episodes From Baseline to 12 Weeks (Last Observation Carried Forward) | Bladder diaries completed by subjects prior to randomization and following each phase of treatment will be used to calculate changes in frequency of urination | From Baseline to 12 weeks | 
| Change in Overactive Bladder Questionnaire (OAB-q) From Baseline to 12 Weeks (Last Observation Carried Forward) | Change from baseline to 12 weeks on the OAB-q to measure symptom bother and condition-specific health-related quality of life. This questionnaire asks about how much you have been bothered by selected bladder symptoms during the past 4 weeks. Scale ranges from 8 to 48 with higher scores indicating a greater degree of bother. | From Baseline to 12 weeks | 
| Change in International Prostate Symptom Score (I-PSS) From Baseline to 12 Weeks (Last Observation Carried Forward) | Change from Baseline to 12 weeks on the International Prostate Symptom Score (I-PSS) to measure urinary symptoms related to BPH. The I-PSS is based on the answers to seven questions concerning urinary symptoms and one question concerning quality of life. Each question concerning urinary symptoms allows the patient to choose one out of six answers indicating increasing severity of the particular symptom. The answers are assigned points from 0 to 5. The total score can therefore range from 0 to 35 (asymptomatic to very symptomatic). | From Baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Male Urogenital Diseases, Urinary Bladder, overactive, Behavioral Medicine, Drug Therapy