Detrusor Overactivity, Overactive Bladder
Conditions
Brief summary
The purpose of this study is to assess if the study drug, Vardenafil (approved by Health Authorities is available on the market for treatment of erectile dysfunction) has an effect on bladder function and micturition frequency. The study drug is to be taken in the form of tablets twice a day, one tablet in the morning and one tablet in the evening. A non-active treatment (placebo), a sugar pill, will be used as a comparator to see if the new study drug works better than no drug. The timing of visits for the study is as follows: the 1st visit (screening visit) at beginning of run-in-assessment with qualifying tests for patients: electrocardiogram (ECG), safety laboratory and residual urine (by ultrasonography: a non-invasive examination using ultrasound for the assessment of the bladder). 2nd visit (randomization visit). During visit this should be performed: urodynamic measurements (filling cystometry and pressure flow investigations), ECG and safety laboratory. 3rd visit (safety visit) takes place at two up to three weeks of randomized treatment. 4th visit (final visit)-following test should be done: urodynamic measurements (filling cystometry and pressure flow investigations), ECG, safety laboratory and residual urine (by ultrasonography); A phone call 24 hours after visit 4 to assess any SAEs.
Interventions
DRUGVardenafil HCl (Levitra, BAY38-9456)
vardenafil hydrochloride 10 mg film-coated tablets twice daily (BID) for oral (by mouth) intake for 6 weeks
DRUGPlacebo
vardenafil hydrochloride-matching film-coated tablets BID for oral intake for 6 weeks
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients aged \> 18 years (females either postmenopausal or using adequate birth control) * Urodynamic criteria: * Entire bladder capacity (= maximum cystometric bladder capacity) \< 300 mL OR * In accordance with International Continence Society (ICS)-guidelines: Detrusor overactivity as defined as spontaneous involuntary detrusor contraction during filling phase OR * Detrusor contraction during filling phase leading to involuntarily initiated micturition before a normal bladder capacity is reached * Patient micturition diary criteria: at least 8 micturitions per day AND at least 1 urgency episode per day * Signed and dated written Patient Informed Consent Form
Exclusion criteria
* Treatment with drugs known to affect urinary bladder function * Known other reasons for micturition problems than detrusor overactivity * Recent intervention in urogenital tract * Abnormal liver or renal lab values * Treatment with nitrates or nitric oxide donors, alpha-blockers, potent inhibitors of CYP-450 3A4, acenocoumarol, heparin, drugs known to prolong QT-interval * NAION, hereditary regenerative retinal disorders, severe cardiovascular conditions, recent history of myocardial infarction/stroke/life-threatening arrhythmia * congenital QT-prolongation, left ventricular outflow obstruction, severe hypo- or hypertension, symptomatic postural hypotension * History of positive test for Hepatitis B surface antigen (HBsAg) or Hepatitis C * Significant active peptic ulceration * Severe chronic or acute liver disease, history of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment * In men: Clinically significant chronic haematological disease which may lead to priapism * History of malignancy of any organ system within the past 5 years * Bleeding disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Bladder Volume at First Detrusor Contraction at 6 Weeks | baseline and up to 6 weeks of treatment Last Observation Carried Forward (LOCF) | Bladder volume was measure by means of urodynamic assessments (cystometry) for up to 6 weeks. Missing data were imputed with last observation carried forward (LOCF). |
| Change From Baseline in Average Number of Daily Micturitions at 6 Weeks | baseline and up to 6 weeks of treatment LOCF | Change from baseline in the number of daily micturitions (bladder voidings), as reported in the participant diaries for up to 6 weeks. Missing data were imputed with last observation carried forward (LOCF). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Maximum Cystometric Bladder Capacity at 6 Weeks | baseline and up to 6 weeks of treatment LOCF | Maximum cystometric bladder capacity was defined as the volume at which either significant leakage or discomfort/pain occurred. Missing data were imputed by last observation carried forward (LOCF). |
| Change From Baseline in Volume at First Desire to Void at 6 Weeks | baseline and up to 6 weeks of treatment LOCF | Volume at first desire to void was recorded during urodynamic assessments. Missing data were imputed by last observation carried forward (LOCF). |
| Change From Baseline in Average Number of Urgencies Per Day at 6 Weeks | baseline and up to 6 weeks of treatment LOCF | The average number of urgencies was derived from the number of urgencies reported by the participants in a 7 day micturition diary. Missing data were imputed by last observation carried forward. |
| Change From Baseline in H2O Detrusor Pressure at First Contraction at 6 Weeks | baseline and up to 6 weeks of treatment LOCF | Detrusor pressure was measured by means of urodynamic assessment (cystometry) for up to 6 weeks. Missing data were imputed by last observation carried forward (LOCF). |
| Change From Baseline in Peak Urinary Flow at 6 Weeks in Men Aged 50 Years and Older | baseline and up to 6 weeks of treatment LOCF | Peak urinary flow (Qmax) was measured using urodynamic assessments (voiding / flow cystometry) for up to 6 weeks. Missing data were imputed by last observation carried forward (LOCF). |
| Change From Baseline in the Total Score of the Overactive Bladder Questionnaire (OAB-q) at 6 Weeks | baseline and up to 6 weeks of treatment LOCF | The OAB-q is a validated, self-administered questionnaire that quantifies bladder symptoms and quality of life. It comprises 33 items (6-point scale for each item). The total score ranges from 33 (minimum symptoms) to 198 (maximum symptoms). On each item, participants provide their rating over the past 4 weeks. Missing data were imputed by LOCF. |
| Change From Baseline in Average Number of Daily Involuntary Discharges of Urine at 6 Weeks | baseline and up to 6 weeks of treatment LOCF | The average number of daily involuntary discharges of urine was derived from the number of discharges reported by the participants in a 7 day micturition diary. Missing data were imputed by last observation carried forward. |
| Change From Baseline in Volume at First Detectable Leakage at 6 Weeks | baseline and up to 6 weeks of treatment LOCF | First detectable leakage was determined by means of cystometry as an obligatory urodynamic measure. Missing data was imputed by last observation carried forward (LOCF). |
Countries
Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Netherlands, Poland, Portugal, Russia, Spain, Switzerland
Participant flow
Recruitment details
Enrollment started on 31 August 2007 and the last study visit occurred on 13 November 2008. The study was conducted at 56 centers in 13 countries: 45 centers in Europe, 4 centers in Canada, 4 centers in Russia, and 3 centers in Israel.
Pre-assignment details
Number of participants screened: 635. Number of participants enrolled and randomized (started Overall study): 397. Number of participants who had taken at least one dose (Safety population): 396.
Participants by arm
| Arm | Count |
|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) vardenafil hydrochloride 10 mg film-coated tablets twice daily (BID) for oral (by mouth) intake for 6 weeks | 198 |
| Placebo vardenafil hydrochloride-matching film-coated tablets BID for oral intake for 6 weeks | 198 |
| Total | 396 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 31 | 12 |
| Overall Study | Lack of Efficacy | 0 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-Compliance with Study Medication | 0 | 2 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 2 |
Baseline characteristics
| Characteristic | Vardenafil HCl (Levitra, BAY38-9456) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 14.2 | 58.3 years STANDARD_DEVIATION 12.8 | 56.9 years STANDARD_DEVIATION 13.5 |
| Sex: Female, Male Female | 116 Participants | 113 Participants | 229 Participants |
| Sex: Female, Male Male | 82 Participants | 85 Participants | 167 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 78 / 198 | 39 / 198 |
| serious Total, serious adverse events | 4 / 198 | 4 / 198 |
Outcome results
Primary
Change From Baseline in Average Number of Daily Micturitions at 6 Weeks
Change from baseline in the number of daily micturitions (bladder voidings), as reported in the participant diaries for up to 6 weeks. Missing data were imputed with last observation carried forward (LOCF).
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: Intent-to-treat (ITT) population: all randomized participants with at least one study drug medication were to be included provided they had a baseline measurement (if scheduled) and a follow-up measurement in any clinical variable. The number is not identical to participants who completed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in Average Number of Daily Micturitions at 6 Weeks | -2.247 micturitions per day | Standard Error 0.253 |
| Placebo | Change From Baseline in Average Number of Daily Micturitions at 6 Weeks | -1.579 micturitions per day | Standard Error 0.2431 |
Comparison: Countries were pooled into 2 clusters, which allowed for testing of Treatment by Center interaction. An ANCOVA including Baseline (Visit 2) as a covariate with main effects for treatment and country (see pooling above) was used to test treatment difference for the primary variable and co-primary variable.p-value: 0.057595% CI: [-0.021, 1.358]ANCOVA
Primary
Change From Baseline in Bladder Volume at First Detrusor Contraction at 6 Weeks
Bladder volume was measure by means of urodynamic assessments (cystometry) for up to 6 weeks. Missing data were imputed with last observation carried forward (LOCF).
Time frame: baseline and up to 6 weeks of treatment Last Observation Carried Forward (LOCF)
Population: Modified intention-to-treat (mITT): participants included in the safety sample (received at least one dose), randomized correctly according to the Urodynamic Adjudication Board (UDAB), having one valid baseline and one valid (UDAB) on treatment urodynamic measurement. The number is not identical to participants who completed the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in Bladder Volume at First Detrusor Contraction at 6 Weeks | 44.993 mL | Standard Error 9.2774 |
| Placebo | Change From Baseline in Bladder Volume at First Detrusor Contraction at 6 Weeks | 36.948 mL | Standard Error 8.7786 |
Comparison: Countries were pooled into 2 clusters, which allowed for testing of Treatment by Center interaction. An ANCOVA including Baseline (Visit 2) as a covariate with main effects for treatment and country (see pooling above) was used to test treatment difference for the primary variable and co-primary variable.p-value: 0.529395% CI: [-33.194, 17.104]ANCOVA
Secondary
Change From Baseline in Average Number of Daily Involuntary Discharges of Urine at 6 Weeks
The average number of daily involuntary discharges of urine was derived from the number of discharges reported by the participants in a 7 day micturition diary. Missing data were imputed by last observation carried forward.
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: Intent-to-treat (ITT) population: all randomized participants with at least one study drug medication were to be included provided they had a baseline measurement (if scheduled) and a follow-up measurement in any clinical variable. The number is not identical to participants who completed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in Average Number of Daily Involuntary Discharges of Urine at 6 Weeks | -0.566 involuntary discharges per day | Standard Error 0.1241 |
| Placebo | Change From Baseline in Average Number of Daily Involuntary Discharges of Urine at 6 Weeks | 0.447 involuntary discharges per day | Standard Error 0.1188 |
Comparison: ANCOVA models used for the secondary efficacy variables were the models determined for the primary efficacy variable or co-primary efficacy variable depending on the type of variable.p-value: 0.492895% CI: [-0.22, 0.456]ANCOVA
Secondary
Change From Baseline in Average Number of Urgencies Per Day at 6 Weeks
The average number of urgencies was derived from the number of urgencies reported by the participants in a 7 day micturition diary. Missing data were imputed by last observation carried forward.
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: Intent-to-treat (ITT) population: all randomized participants with at least one study drug medication were to be included provided they had a baseline measurement (if scheduled) and a follow-up measurement in any clinical variable. The number is not identical to participants who completed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in Average Number of Urgencies Per Day at 6 Weeks | -1.861 urgencies per day | Standard Error 0.2768 |
| Placebo | Change From Baseline in Average Number of Urgencies Per Day at 6 Weeks | -1.139 urgencies per day | Standard Error 0.2658 |
Comparison: ANCOVA models used for the secondary efficacy variables were the models determined for the primary efficacy variable or co-primary efficacy variable depending on the type of variable.p-value: 0.060995% CI: [-0.033, 1.476]ANCOVA
Secondary
Change From Baseline in H2O Detrusor Pressure at First Contraction at 6 Weeks
Detrusor pressure was measured by means of urodynamic assessment (cystometry) for up to 6 weeks. Missing data were imputed by last observation carried forward (LOCF).
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: Modified intent-to-treat (mITT) population: participants included in the safety sample (received at least one dose), randomized correctly according to the Urodynamic Adjudication Board (UDAB), having one valid baseline and one valid (UDAB) on treatment urodynamic measurement. The number is not identical to participants who completed the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in H2O Detrusor Pressure at First Contraction at 6 Weeks | 0.085 millimeters of mercury (mmHg) | Standard Error 2.5821 |
| Placebo | Change From Baseline in H2O Detrusor Pressure at First Contraction at 6 Weeks | 0.743 millimeters of mercury (mmHg) | Standard Error 2.4199 |
Comparison: ANCOVA models used for the secondary efficacy variables were the models determined for the primary efficacy variable or co-primary efficacy variable depending on the type of variable.p-value: 0.853395% CI: [-6.335, 7.65]ANCOVA
Secondary
Change From Baseline in Maximum Cystometric Bladder Capacity at 6 Weeks
Maximum cystometric bladder capacity was defined as the volume at which either significant leakage or discomfort/pain occurred. Missing data were imputed by last observation carried forward (LOCF).
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: Modified intent-to-treat (mITT): participants included in the safety sample (received at least one dose), randomized correctly according to the Urodynamic Adjudication Board (UDAB), having one valid baseline and one valid (UDAB) on treatment urodynamic measurement. The number is not identical to participants who completed the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in Maximum Cystometric Bladder Capacity at 6 Weeks | 40.274 mL | Standard Error 7.4986 |
| Placebo | Change From Baseline in Maximum Cystometric Bladder Capacity at 6 Weeks | 27.900 mL | Standard Error 7.1839 |
Comparison: ANCOVA models used for the secondary efficacy variables were the models determined for the primary efficacy variable or co-primary efficacy variable depending on the type of variable.p-value: 0.234895% CI: [-32.834, 8.087]ANCOVA
Secondary
Change From Baseline in Peak Urinary Flow at 6 Weeks in Men Aged 50 Years and Older
Peak urinary flow (Qmax) was measured using urodynamic assessments (voiding / flow cystometry) for up to 6 weeks. Missing data were imputed by last observation carried forward (LOCF).
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: mITT: Participants who received at least one dose, randomized correctly according to Urodynamic Adjudication Board (UDAB), having one valid baseline and one valid (UDAB) on treatment urodynamic measurement. Qmax is based on men predominantly aged 50 years and older but includes a few males who had Qmax collected even if younger than 50 years.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in Peak Urinary Flow at 6 Weeks in Men Aged 50 Years and Older | 1.129 milliliter per second (mL/s) | Standard Error 0.6301 |
| Placebo | Change From Baseline in Peak Urinary Flow at 6 Weeks in Men Aged 50 Years and Older | 0.306 milliliter per second (mL/s) | Standard Error 0.5351 |
Comparison: ANCOVA models used for the secondary efficacy variables were the models determined for the primary efficacy variable or co-primary efficacy variable depending on the type of variable.p-value: 0.324895% CI: [-2.476, 0.829]ANCOVA
Secondary
Change From Baseline in the Total Score of the Overactive Bladder Questionnaire (OAB-q) at 6 Weeks
The OAB-q is a validated, self-administered questionnaire that quantifies bladder symptoms and quality of life. It comprises 33 items (6-point scale for each item). The total score ranges from 33 (minimum symptoms) to 198 (maximum symptoms). On each item, participants provide their rating over the past 4 weeks. Missing data were imputed by LOCF.
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: Intent-to-treat (ITT) population: all randomized participants with at least one study drug medication were to be included provided they had a baseline measurement (if scheduled) and a follow-up measurement in any clinical variable. The number is not identical to participants who completed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in the Total Score of the Overactive Bladder Questionnaire (OAB-q) at 6 Weeks | 8.929 scores on a scale | Standard Error 1.2627 |
| Placebo | Change From Baseline in the Total Score of the Overactive Bladder Questionnaire (OAB-q) at 6 Weeks | 7.834 scores on a scale | Standard Error 1.2181 |
Comparison: ANCOVA models used for the secondary efficacy variables were the models determined for the primary efficacy variable or co-primary efficacy variable depending on the type of variable.p-value: 0.531295% CI: [-4.533, 2.342]ANCOVA
Secondary
Change From Baseline in Volume at First Desire to Void at 6 Weeks
Volume at first desire to void was recorded during urodynamic assessments. Missing data were imputed by last observation carried forward (LOCF).
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: Modified intent-to-treat (mITT): participants included in the safety sample (received at least one dose), randomized correctly according to the Urodynamic Adjudication Board (UDAB), having one valid baseline and one valid (UDAB) on treatment urodynamic measurement. The number is not identical to participants who completed the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in Volume at First Desire to Void at 6 Weeks | 30.655 mL | Standard Error 6.0503 |
| Placebo | Change From Baseline in Volume at First Desire to Void at 6 Weeks | 22.460 mL | Standard Error 5.7959 |
Comparison: ANCOVA models used for the secondary efficacy variables were the models determined for the primary efficacy variable or co-primary efficacy variable depending on the type of variable.p-value: 0.328995% CI: [-24.692, 8.303]ANCOVA
Secondary
Change From Baseline in Volume at First Detectable Leakage at 6 Weeks
First detectable leakage was determined by means of cystometry as an obligatory urodynamic measure. Missing data was imputed by last observation carried forward (LOCF).
Time frame: baseline and up to 6 weeks of treatment LOCF
Population: Modified intent-to-treat (mITT): participants included in the safety sample (received at least one dose), randomized correctly according to the Urodynamic Adjudication Board (UDAB), having one valid baseline and one valid (UDAB) on treatment urodynamic measurement. The number is not identical to participants who completed the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vardenafil HCl (Levitra, BAY38-9456) | Change From Baseline in Volume at First Detectable Leakage at 6 Weeks | 42.307 mL | Standard Error 7.9013 |
| Placebo | Change From Baseline in Volume at First Detectable Leakage at 6 Weeks | 26.717 mL | Standard Error 7.5039 |
Comparison: ANCOVA models used for the secondary efficacy variables were the models determined for the primary efficacy variable or co-primary efficacy variable depending on the type of variable.p-value: 0.153995% CI: [-37.057, 5.876]ANCOVA