Urethral Sphincter Activity
Conditions
Brief summary
Lower urinary tract symptoms such as urinary leakage and overactive bladder affect millions of American women. Women may develop these problems because the innervation of the muscles of the bladder and urethra are injured. Most research on treating these problems has focused on the abnormalities of the bladder muscle, but newer studies have shown abnormalities in the innervation and muscle function of the urethra. Women with these symptoms may benefit from treatment with medications to improve their urethral function. However, to truly understand what types of medications will help women with these symptoms, the investigators wish to study how these medications affect innervation and muscle function in healthy women who do not have lower urinary tract symptoms.
Detailed description
Women without urinary incontinence or bladder symptoms (healthy controls)will undergo urethral testing prior to randomization to one of 5 medications or placebo. Participants will take an oral medication for 2 weeks and then return for repeat testing.
Interventions
DRUGPseudoephedrine
Pseudoephedrine ER 120 mg by mouth once daily for 2 weeks
DRUGTamsulosin
Tamsulosin 0.4mg by mouth daily for 2 weeks
DRUGImipramine
Imipramine 25mg daily by mouth for 2 weeks
DRUGCyclobenzaprine
Cyclobenzaprine 10mg daily by mouth for 2 weeks
DRUGLactose capsule
Lactose capsule 1 by mouth daily for 2 weeks
DRUGSolifenacin
Solifenacin 5mg by mouth daily for 2 weeks
Sponsors
Astellas Pharma Inc
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
19 Years to 51 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy Females only * Ages 19-51 and up including pre-menopausal older women who have had a normal menstrual cycle for the prior 3 months * Able to take oral medication for 2 weeks * For women of child bearing potential,willing to use an approved method of birth control during the study
Exclusion criteria
* Urinary Incontinence or other bladder symptoms * Known neurologic disease that may impair urethral tone or sensation * Currently taking a class of medication that is being tested (alpha-antagonists, anticholinergics, sympathomimetics, tricyclic antidepressants, or skeletal muscle relaxants) * History of QTc prolongation or cardiac arrhythmia * Pregnant, breastfeeding, or are less than 6 months postpartum * Known hypersensitivity to or other contraindications to taking any of the study medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference (Pre - Post) in Amplitude (Microvolts) of Urethral Sphincter Activity as Measured by Quantitative Concentric Needle EMG | 2 weeks | Concentric needle EMG was used to measure urethral sphincter activity at 2-3 sites around the urethral meatus before and after 2 weeks of therapy with one of 6 randomly assigned medications. Two methods of quantitative electromyography were performed on all subjects. (1) Multi-Motor Unit Action Potential (MUP) analysis, which has been shown to be the most sensitive technique in distinguishing neuropathic from control muscles; and (2) interference pattern analysis (IPA) which reflects changes in MUP recruitment from weak effort to maximal contraction. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Difference (Pre - Post) in Urethral Sensation (Milliamps) as Measured by Current Perception Threshold Testing. | 2 weeks | Current Perception Threshold testing was used to measure urethral sensation before and after 2 weeks of therapy with one of 6 randomly assigned medications. We performed CPT testing in the urethra using a Neurometer®, which is a constant current stimulator capable of delivering sine wave electrical stimuli at 3 frequencies (2000 Hz, 250 Hz and 5 Hz). At all 3 frequencies, the stimulus intensity was gradually increased until first perceived, and then decreased until no longer perceptible. CPT values were obtained using a semi-automated forced choice paradigm. |
| Difference (Pre - Post) in Maximum Urine Flow Rate (Qmax) (Milliliters Per Second) as Measured by Pressure Flowmetry | 2 weeks | Pressure Flowmetry was used to measure maximum urine flow rate (Qmax)before and after 2 weeks of therapy with one of 6 randomly assigned medications. A 300 cc bladder fill was performed through the catheter, the catheter was removed, and transurethral and transrectal pressure transducers were placed for the pressure flow study. Voiding was performed in the seated position. Information obtained for the database included Qmax, average flow rate, time to Qmax, detrusor pressure at maximum flow rate, voided volume, and a calculated post-void residual. |
Countries
United States
Participant flow
Recruitment details
Healthy women,ages 19-51 and up including pre-menopausal older women who have had a normal menstrual cycle for the prior 3 months.Participants were recruited via local newspaper. The first participant was enrolled 5/27/10. Recruitment ended August 31, 2010
Participants by arm
| Arm | Count |
|---|---|
| Pseudoephedrine 120mg ER Daily 120 mg extended release, 1 daily for 14 days | 10 |
| Solifenacin 5mg Daily 5 mg capsule, 1 daily for 14 days | 10 |
| Tamsulosin 0.4mg Daily 0.4 mg capsule, 1 daily for 14 days | 10 |
| Imipramine 25mg Daily 25 mg tablet, 1 daily for 14 days | 10 |
| Cyclobenzaprine 10mg Daily 10 mg tablet, 1 daily for 14 days | 10 |
| Lactose Capsules, One Daily sham lactose capsules, 1 daily for 14 days | 6 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 | 0 | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Solifenacin 5mg Daily | Tamsulosin 0.4mg Daily | Imipramine 25mg Daily | Pseudoephedrine 120mg ER Daily | Cyclobenzaprine 10mg Daily | Lactose Capsules, One Daily | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 6 Participants | 56 Participants |
| Age Continuous | 31.6 years | 35.5 years | 33.1 years | 36.6 years | 38 years | 28.7 years | 34.3 years |
| Region of Enrollment United States | 10 participants | 10 participants | 10 participants | 10 participants | 10 participants | 6 participants | 56 participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 6 Participants | 56 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 10 | 1 / 10 | 1 / 10 | 2 / 10 | 0 / 10 | 1 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 6 |
Outcome results
Primary
Difference (Pre - Post) in Amplitude (Microvolts) of Urethral Sphincter Activity as Measured by Quantitative Concentric Needle EMG
Concentric needle EMG was used to measure urethral sphincter activity at 2-3 sites around the urethral meatus before and after 2 weeks of therapy with one of 6 randomly assigned medications. Two methods of quantitative electromyography were performed on all subjects. (1) Multi-Motor Unit Action Potential (MUP) analysis, which has been shown to be the most sensitive technique in distinguishing neuropathic from control muscles; and (2) interference pattern analysis (IPA) which reflects changes in MUP recruitment from weak effort to maximal contraction.
Time frame: 2 weeks
Population: The planned number of participants was per protocol based on power calculation. Actual number may differ based on withdrawal from the study or loss to follow-up.Participants randomized to Pseudoephedrine 120 mg ER,Solifenacin 5 mg, Tamsulosin 0.4mg, Imipramine 25mg, Cyclobenzaprine 10 mg, or a sham Lactose capsule, 1 a day for 14 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pseudoephedrine 120mg ER Daily | Difference (Pre - Post) in Amplitude (Microvolts) of Urethral Sphincter Activity as Measured by Quantitative Concentric Needle EMG | -18 microvolts |
| Solifenacin 5mg Daily | Difference (Pre - Post) in Amplitude (Microvolts) of Urethral Sphincter Activity as Measured by Quantitative Concentric Needle EMG | 10 microvolts |
| Tamsulosin 0.4mg Daily | Difference (Pre - Post) in Amplitude (Microvolts) of Urethral Sphincter Activity as Measured by Quantitative Concentric Needle EMG | 11 microvolts |
| Imipramine 25mg Daily | Difference (Pre - Post) in Amplitude (Microvolts) of Urethral Sphincter Activity as Measured by Quantitative Concentric Needle EMG | -15 microvolts |
| Cyclobenzaprine 10mg Daily | Difference (Pre - Post) in Amplitude (Microvolts) of Urethral Sphincter Activity as Measured by Quantitative Concentric Needle EMG | 12 microvolts |
| Lactose Capsules, One Daily | Difference (Pre - Post) in Amplitude (Microvolts) of Urethral Sphincter Activity as Measured by Quantitative Concentric Needle EMG | 36 microvolts |
Comparison: Using difference in EMG amplitude as primary outcome, assuming standard deviation of 6, we had greater than 80% power to detect a 10-microvolt change in urethral muscle activity with sample size of 9 participants per group. Due to non-normality and small sample sizes, non-parametric tests were used and data presented as median (IQR). Kruskal-Wallis p-values are reported to compare median scores across groups. Wilcoxon sign-test p-values are reported to evaluate 2-week change within groups.p-value: >0.05Wilcoxon (Mann-Whitney)
Other Pre-specified
Difference (Pre - Post) in Maximum Urine Flow Rate (Qmax) (Milliliters Per Second) as Measured by Pressure Flowmetry
Pressure Flowmetry was used to measure maximum urine flow rate (Qmax)before and after 2 weeks of therapy with one of 6 randomly assigned medications. A 300 cc bladder fill was performed through the catheter, the catheter was removed, and transurethral and transrectal pressure transducers were placed for the pressure flow study. Voiding was performed in the seated position. Information obtained for the database included Qmax, average flow rate, time to Qmax, detrusor pressure at maximum flow rate, voided volume, and a calculated post-void residual.
Time frame: 2 weeks
Population: The planned number of participants was per protocol based on power calculation. Actual number may differ based on withdrawal from the study or loss to follow-up.Participants randomized to Pseudoephedrine 120 mg ER,Solifenacin 5 mg, Tamsulosin 0.4mg, Imipramine 25mg, Cyclobenzaprine 10 mg, or a sham Lactose capsule, 1 a day for 14 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pseudoephedrine 120mg ER Daily | Difference (Pre - Post) in Maximum Urine Flow Rate (Qmax) (Milliliters Per Second) as Measured by Pressure Flowmetry | -7.3 milliliters per second |
| Solifenacin 5mg Daily | Difference (Pre - Post) in Maximum Urine Flow Rate (Qmax) (Milliliters Per Second) as Measured by Pressure Flowmetry | 5.0 milliliters per second |
| Tamsulosin 0.4mg Daily | Difference (Pre - Post) in Maximum Urine Flow Rate (Qmax) (Milliliters Per Second) as Measured by Pressure Flowmetry | -5.6 milliliters per second |
| Imipramine 25mg Daily | Difference (Pre - Post) in Maximum Urine Flow Rate (Qmax) (Milliliters Per Second) as Measured by Pressure Flowmetry | -6.6 milliliters per second |
| Cyclobenzaprine 10mg Daily | Difference (Pre - Post) in Maximum Urine Flow Rate (Qmax) (Milliliters Per Second) as Measured by Pressure Flowmetry | 10.3 milliliters per second |
| Lactose Capsules, One Daily | Difference (Pre - Post) in Maximum Urine Flow Rate (Qmax) (Milliliters Per Second) as Measured by Pressure Flowmetry | 10.4 milliliters per second |
Other Pre-specified
Difference (Pre - Post) in Urethral Sensation (Milliamps) as Measured by Current Perception Threshold Testing.
Current Perception Threshold testing was used to measure urethral sensation before and after 2 weeks of therapy with one of 6 randomly assigned medications. We performed CPT testing in the urethra using a Neurometer®, which is a constant current stimulator capable of delivering sine wave electrical stimuli at 3 frequencies (2000 Hz, 250 Hz and 5 Hz). At all 3 frequencies, the stimulus intensity was gradually increased until first perceived, and then decreased until no longer perceptible. CPT values were obtained using a semi-automated forced choice paradigm.
Time frame: 2 weeks
Population: The planned number of participants was per protocol based on power calculation. Actual number may differ based on withdrawal from the study or loss to follow-up.Participants randomized to Pseudoephedrine 120 mg ER,Solifenacin 5 mg, Tamsulosin 0.4mg, Imipramine 25mg, Cyclobenzaprine 10 mg, or a sham Lactose capsule, 1 a day for 14 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pseudoephedrine 120mg ER Daily | Difference (Pre - Post) in Urethral Sensation (Milliamps) as Measured by Current Perception Threshold Testing. | 0.06 Milliamps |
| Solifenacin 5mg Daily | Difference (Pre - Post) in Urethral Sensation (Milliamps) as Measured by Current Perception Threshold Testing. | 0.06 Milliamps |
| Tamsulosin 0.4mg Daily | Difference (Pre - Post) in Urethral Sensation (Milliamps) as Measured by Current Perception Threshold Testing. | -0.8 Milliamps |
| Imipramine 25mg Daily | Difference (Pre - Post) in Urethral Sensation (Milliamps) as Measured by Current Perception Threshold Testing. | -0.12 Milliamps |
| Cyclobenzaprine 10mg Daily | Difference (Pre - Post) in Urethral Sensation (Milliamps) as Measured by Current Perception Threshold Testing. | 0.0 Milliamps |
| Lactose Capsules, One Daily | Difference (Pre - Post) in Urethral Sensation (Milliamps) as Measured by Current Perception Threshold Testing. | 0.03 Milliamps |
Comparison: Using difference in EMG amplitude as primary outcome, assuming standard deviation of 6, we had greater than 80% power to detect a 10-microvolt change in urethral muscle activity with sample size of 9 participants per group. Due to non-normality and small sample sizes, non-parametric tests were used and data presented as median (IQR). Kruskal-Wallis p-values are reported to compare median scores across groups. Wilcoxon sign-test p-values are reported to evaluate 2-week change within groups.p-value: >0.05Wilcoxon (Mann-Whitney)