Combined Behavioral and Drug Treatment of Overactive Bladder in Men (COBALT)

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.

Study Overview

• Status: Completed
• Conditions: Overactive Bladder; Lower Urinary Tract Symptoms
• Intervention / Treatment: Behavioral: Behavioral training; Drug: Tolterodine + tamsulosin; Other: Combined Behavioral + Drug Therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 204
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Georgia
    • Atlanta, Georgia, United States, 30033
      • Emory University
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Community-dwelling men
2. Age 40 years or older
3. Patient-reported urgency and 9.0 or more voids per 24-hour day (on average) on the 7-day baseline bladder diary.

Exclusion Criteria:

1. Urinary flow rate < 8.0 mL/sec on a void greater than 125 ml.
2. Post-void residual volume greater than 150 mL (based on bladder ultrasound after voiding in the presence of a normal urge to urinate).
3. 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.
4. Transurethral resection of the prostate (TURP), simple prostatectomy, or other benign prostatic hypertrophy (BPH) related surgery within the past 5 years.
5. Current active treatment for prostate cancer.
6. History of radical prostatectomy.
7. Previous artificial urinary sphincter, sling procedure, bladder-injection of botulinum toxin, or implanted sacral neuromodulation device.
8. 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.
9. 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.
10. 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).
11. Neurologic conditions such as Parkinson's, spinal cord injury, multiple sclerosis, or myasthenia gravis.
12. Impaired mental status. Patients who screen as probable dementia on the Mini-Cog.
13. 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.
14. Hypersensitivity to tolterodine or tamsulosin.
15. Current use of an alpha blocker agent. Evaluation will be delayed until the drug has been discontinued for 2 weeks.
16. Current use of an anti-muscarinic agent for OAB. Evaluation will be delayed until the drug has been discontinued for 2 weeks.
17. If on a diuretic, dose has not been stable for at least 4 weeks.
18. If taking dutasteride or finasteride, dose has not been stable for at least 6 months.
19. If on an antibiotic for prostatitis. Patients will be offered re-evaluation if OAB symptoms persist when antibiotics are completed.
20. Full course of behavioral training.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Behavioral Treatment alone; 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; 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.; Other Names: Pelvic floor muscle training; Urge suppression; Delayed voiding
Active Comparator: Drug Therapy (Tolterodine + tamsulosin); 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; Patients in drug therapy receive an anti-muscarinic (long acting tolterodine 4 mg daily) and an alpha blocker (tamsulosin 0.4 mg daily).; Other Names: Flomax; Tolterodine tartrate; Detrol Long-Acting (LA)
Experimental: Combined Behavioral + Drug Therapy; 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; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Investigators: Principal Investigator: Kathryn L Burgio, PhD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Burgio KL, Kraus SR, Johnson TM 2nd, Markland AD, Vaughan CP, Li P, Redden DT, Goode PS. Effectiveness of Combined Behavioral and Drug Therapy for Overactive Bladder Symptoms in Men: A Randomized Clinical Trial. JAMA Intern Med. 2020 Mar 1;180(3):411-419. doi: 10.1001/jamainternmed.2019.6398.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: August 3, 2010
• First Submitted That Met QC Criteria: August 3, 2010
• First Posted (Estimate): August 4, 2010

Study Record Updates

• Last Update Posted (Actual): May 25, 2017
• Last Update Submitted That Met QC Criteria: April 17, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Drug Therapy; Male Urogenital Diseases; Behavioral Medicine; Urinary Bladder, overactive
• Additional Relevant MeSH Terms: Urologic Diseases; Urinary Bladder Diseases; Urological Manifestations; Urinary Bladder, Overactive; 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; Tolterodine Tartrate
• Other Study ID Numbers: 1R01DK082548-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No