Study of 2 Doses of Solifenacin Succinate in Female Subjects With Overactive Bladder.

Phase 4

Completed

Conditions: Detrusor Overactivity
Overactive Bladder

Interventions: Drug: Placebo
Drug: solifenacin

Registration Number: NCT01093534

Lead Sponsor: Astellas Pharma Inc

Brief Summary: The purpose is to see if solifenacin has any effect on bladder wall thickness and urine inflammatory marker measurements after 12 weeks of treatment.

Detailed Description: Participants satisfying all selection criteria at the end of the 2-week, single blind, placebo run-in period were randomized to receive 12-week double-blind treatment with solifenacin 5 mg or 10 mg once daily, or placebo.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 547

Inclusion Criteria

Symptoms of overactive bladder (OAB), including urinary frequency, urgency or urge incontinence, for greater than or equal to 3 months
Urodynamic diagnosis of detrusor overactivity (DO)
Either naïve to anti-muscarinic treatment (i.e. no prior history of use of anti-muscarinic agents) or 6-months anti-muscarinic treatment free (i.e. have had no anti-muscarinic treatment within 6 months) prior to the screening visit
Bladder post-void residual volume of less than 30 ml
Available to complete the study

Exclusion Criteria

History of stress urinary incontinence, urethral sphincter incompetence or neurogenic detrusor overactivity
History, signs or symptoms suggestive of urinary tract infection (confirmed by positive urine analysis), obstruction or urogenital pro-lapse (greater than grade II)
History of urinary tract operation within 6 months prior to screening
Indwelling catheter or permanent catheter fitted
History of pelvic area radiotherapy treatment
Uncontrolled diabetes mellitus
History of fibromyalgia
Post-partum or breast-feeding within 3 months prior to screening visit
Either pregnant or intends to become pregnant during the study or sexually active, of childbearing potential and is unwilling to utilize a reliable method of birth control (note: reliable methods are contraceptive pills of combination type, hormonal implants or injectable contraceptives)
Positive pre-study hepatitis B surface antigen, hepatitis C antibody or human immunodeficiency virus (HIV) result at time of screening
History of drug and / or alcohol abuse at time of screening
History of urinary retention, severe gastrointestinal obstruction (including paralytic ileus or intestinal atony or toxic megacolon or severe ulcerative colitis), myasthenia gravis, uncontrolled narrow angle glaucoma or shallow anterior chamber or deemed to be at risk for these conditions
Undergoing hemodialysis or has severe renal impairment or moderate hepatic impairment or who are on treatment with a potent cytochrome p450 (CYP) 3A4 inhibitor, e.g. Ketoconazole
Currently dosing with medication(s) intended to treat overactive bladder symptoms or has a history of non-drug treatment, such as electrical therapy, magnetic field stimulation, pelvic floor treatment or bladder training intended to treat overactive bladder symptoms within 6 months prior to screening, as described in the list of prohibited medications
Currently receiving or has a history of treatment with alpha blockers, botulinum toxin (cosmetic use is acceptable), resiniferatoxin or pelvic floor muscle relaxants within 9 months prior to screening
Participated in any clinical study less than or equal to 3 months prior to screening

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Solifenacin 5 mg	Placebo	Participants received one 5 mg solifenacin tablet and one placebo tablet, once daily for 12 weeks.
Placebo	Placebo	Participants received 2 placebo tablets once daily for 12 weeks.
Solifenacin 5 mg	solifenacin	Participants received one 5 mg solifenacin tablet and one placebo tablet, once daily for 12 weeks.
Solifenacin 10 mg	solifenacin	Participants received two 5 mg solifenacin tablets once daily for 12 weeks.

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Week 12 in Bladder Wall Thickness	Baseline and Week 12	Bladder wall thickness (BWT) measurements were obtained using transvaginal ultrasound. The BWT was derived as one mean value per image pooled over measurements of 3 locations (anterior wall, dome and trigone), and performed by 2 central readers and 1 adjudicator.
Neutralized Urinary Nerve Growth Factor Normalized by Urine Creatinine at Week 12	Week 12	Free (neutralized) urinary nerve growth factor (uNGF) and creatinine (Cr) were measured from urine samples by the central laboratories. Free (neutralized) uNGF/Cr was derived by dividing free (neutralized) uNGF concentrations \[pg/mL\] by the urine creatinine concentrations (µmol/mL) from the same participant.

Secondary Outcome Measures

Name	Time	Method
Total Urinary Nerve Growth Factor Normalized by Urine Creatinine at Week 12	Week 12	Total (acidified) urinary nerve growth factor (uNGF) and creatinine (Cr) were measured from urine samples by the central laboratories. Total uNGF/Cr was derived by dividing total uNGF concentrations \[pg/mL\] by the urine creatinine concentrations (µmol/mL) from the same participant.
Brain Derived Neurotrophic Factor Normalized by Urine Creatinine (uBDNF/Cr) at Week 12	Week 12	Brain derived neurotrophic factor (uBDNF) and creatinine (Cr) were measured from urine samples by the central laboratories. uBDNF/Cr was derived by dividing uBDNF concentrations \[pg/mL\] by the urine creatinine concentrations (µmol/mL) from the same participant.
Change From Baseline to Week 6 and Week 12 in Bladder Wall Thickness	Baseline, Week 6 and Week 12	Bladder wall thickness (BWT) measurements were obtained using transvaginal ultrasound. The BWT was derived as one mean value per image pooled over measurements of 3 locations (anterior wall, dome and trigone), and performed by 2 central readers and 1 adjudicator.
Change From Baseline to Week 6 and Week 12 in Neutralized Urinary Nerve Growth Factor Normalized by Urine Creatinine	Baseline, Week 6 and Week 12	Free (neutralized) urinary nerve growth factor (uNGF) and creatinine (Cr) were measured from urine samples by the central laboratories. Free (neutralized) uNGF/Cr was derived by dividing free (neutralized) uNGF concentrations \[pg/mL\] by the urine creatinine concentrations (µmol/mL) from the same participant.
Change From Baseline to Week 12 in Mean Number of Events (Micturitions Plus Incontinence Episodes) Per 24 Hours	Baseline and Week 12	The average number of micturitions (urinations) and incontinence episodes (any involuntary leakage of urine) per day was derived from the number of events recorded by the participant in an electronic diary for 3 days before the Baseline and Week 12 clinic visits.
Change From Baseline to Week 12 in Mean Number of Urgency Events Per 24 Hours	12 weeks	The intensity of urgency of each micturition (urination) and incontinence episode (any involuntary leakage of urine) was recorded by the participant in an electronic diary according to the Patient Perception of Intensity of Urgency Scale (PPIUS) as follows: 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet. An urgency event is defined as any micturition or incontinence episode classified by the participant as a grade 3 or 4 on the PPIUS scale. The average number of urgency events per day is derived from the diary data completed by participants on the 3 days prior to the Baseline and Week 12 visits.
Change From Baseline to Week 12 in Mean Number of Micturitions Per 24 Hours	Baseline and Week 12	The average number of micturitions (urinations) per 24 hours was derived from the number of micturitions recorded by the participant in an electronic diary for 3 days before the Baseline and Week 12 clinic visits.
Change From Baseline to Week 12 in Mean Number of Urgency Micturitions Per 24 Hours	Baseline and Week 12	An urgency micturition is defined as any micturition classified by the participant as a grade 3 or 4 on the Patient Perception of Intensity of Urgency Scale (PPIUS) as follows: 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet. The average number of urgency micturitions per 24 hours was derived from the number of urgency micturitions recorded by the participant in an electronic diary for 3 days before the Baseline and Week 12 clinic visits.
Change From Baseline to Week 12 in Mean Number of Incontinence Episodes Per 24 Hours	Baseline and Week 12	The average number of incontinence episodes (any involuntary leakage of urine) per 24 hours was calculated from the number of incontinence episodes recorded by the participant in an electronic diary for 3 days before the Baseline and Week 12 clinic visits.
Change From Baseline in Mean Number of Urgency Incontinence Episodes With PPIUS Grade 3 or 4 Per 24 Hours	Baseline and Week 12	An urgency incontinence episode is defined as any incontinence episode classified by the participant as a grade 3 or 4 on the Patient Perception of Intensity of Urgency Scale (PPIUS) as follows: 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet. The average number of grade 3 or 4 urgency incontinence episodes per 24 hours was calculated from the number of urgency incontinence episodes recorded by the participant in an electronic diary for 3 days before the Baseline and Week 12 clinic visits.
Change From Baseline in Mean Number of Urgency Incontinence Episodes With PPIUS Grade 4 Per 24 Hours	Baseline and Week 12	An urgency incontinence episode is defined as any incontinence episode classified by the participant as a grade 4 on the Patient Perception of Intensity of Urgency Scale (PPIUS) as follows: 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet. The average number of grade 4 urgency incontinence episodes per 24 hours was calculated from the number of urgency incontinence episodes recorded by the participant in an electronic diary for 3 days before the Baseline and Week 12 clinic visits.
Change From Baseline to Week 12 in Brain Derived Neurotrophic Factor Normalized by Urine Creatinine (uBDNF/Cr)	Baseline and Week 12	Brain derived neurotrophic factor (uBDNF) and creatinine (Cr) were measured from urine samples by the central laboratories. uBDNF/Cr was derived by dividing uBDNF concentrations \[pg/mL\] by the urine creatinine concentrations (µmol/mL) from the same participant.
Change From Baseline to Week 12 in Mean Level of Urgency	Baseline and Week 12	The intensity of urgency of each micturition (urination) and incontinence episode (any involuntary leakage of urine) was recorded by the participant in an electronic diary according to the Patient Perception of Intensity of Urgency Scale (PPIUS) as follows: 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet. The mean level of urgency was calculated by adding the PPIUS grade for all events (micturition or incontinence) and dividing by the number of episodes recorded in the diary over 3 days prior to the Baseline and Week 12 visits.
Change From Baseline to Week 12 in Total Urgency Score	Baseline and Week 12	The intensity of urgency of each micturition (urination) and incontinence episode (any involuntary leakage of urine) was recorded by the participant in an electronic diary according to the Patient Perception of Intensity of Urgency Scale (PPIUS) as follows: 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet. The total urgency score was calculated by adding all PPIUS scores over a 3-day period prior to the Baseline and Week 12 visits for each participant.
Change From Baseline in Patient Perception of Bladder Condition (PPBC)	Baseline and Week 12	The PPBC scale is a global assessment tool that asks patients to rate their impression of their current bladder condition on a 6-point scale from 1: 'Does not cause me any problems at all'; 2: 'Causes me some very minor problems'; 3: 'Causes me some minor problems'; 4: 'Causes me (some) moderate problems'; 5: 'Causes me severe problems' and 6: 'Causes me many severe problems'. A negative change from Baseline score indicates improvement.
Change From Baseline in Patient Assessment of Urgency Bother	Baseline and Week 12	The participants' perception and impression of bother associated with their condition were assessed using the Urgency Bother-Visual Analog Scale (UB-VAS). The participant was asked to place a vertical mark on a 100 mm line to indicate how much bother has urgency been for them in the past week, whereby 'no bother at all' is represented on the left end (score = 0) and 'worst possible bother' (score = 100) at the right end of the line. A negative change from Baseline indicates improvement.
Change From Baseline in Patient Assessment of Treatment Satisfaction	Baseline and Week 12	The treatment satisfaction visual analog scale (TS_VAS) asks patients to rate their satisfaction with treatment by placing a vertical mark on a 100 mm line where the endpoints are labeled 'No, not at all' on the left (score = 0) to 'Yes, completely satisfied' on the right (score = 100). A positive change from Baseline indicates improvement.
Percentage of Participants With Improvement and Worsening on the 5 Dimensions of the EQ-5D	Baseline and Week 12	The participants' quality of life was assessed using the EuroQoL 5 Dimension Questionnaire (EQ-5D). The EQ-5D is a standardized instrument for use as a measure of health outcome and is based on the following 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. For each dimension participants were asked to select the statement which best described their health that day, from level 1 (indicating no problems) to 3 (indicating extreme problems/unable to perform). Improvement was defined as a change from a state of being unable to perform or extreme problems at Baseline to no problems or to some or moderate problems at Week 12, and from some or moderate problems to no problems. Worsening was defined as a change from no problems at Baseline to some or moderate problems or to a state of being unable to perform or extreme problems at Week 12, and from some or moderate problems to a state of being unable to perform or extreme problems.
Change From Baseline in EuroQoL 5-Dimension Questionnaire Visual Analog Scale	Baseline and Week 12	The participants' quality of life was assessed using the EuroQoL 5 Dimension Questionnaire (EQ-5D) visual analog scale (VAS). Health status is completed by the participant indicating their own health state today by drawing a line on a vertical scale from 0 to 100 where the endpoints are labeled 'Worst imaginable health state' (=0) and 'Best imaginable health state' (=100). On the EQ-5D VAS, a positive change from Baseline indicates improvement.
Change From Baseline in Symptom Bother Score	Baseline and Week 12	Overactive bladder symptoms were assessed using the symptom bother scale of the Overactive Bladder Symptom and Health-Related Quality of Life Questionnaire (OAB-q). The OAB-q is a patient-administered instrument comprising an 8-item symptom bother scale and 25 health-related quality of life items (see next outcome measure). In the symptom bother scale participants were asked how much they had been bothered by selected bladder symptoms during the past 4 weeks. Each question has a 6-point Likert scale response ranging from 'not at all' (1) to 'a very great deal' (6). The total symptom bother score was calculated from the 8 answers and then transformed to range from 0 to 100, with 100 indicating worst severity. A negative change from Baseline in symptom bother score indicates improvement.
Change From Baseline in Health-Related Quality of Life (HRQL)	Baseline and Week 12	Health-related quality of life was assessed by the Overactive Bladder Symptom and Health-Related Quality of Life Questionnaire (OAB-q). The OAB-q is a patient-administered instrument comprising of an 8-item symptom bother scale (see previous outcome measure) and 25 HRQL items comprising 4 subscales (concern, coping, social interaction and sleep) and a total HRQL score. Participants were asked how their overall bladder symptoms had affected their life in the past 4 weeks. Each of the 25 HRQL questions has a 6-point Likert scale response ranging from 'none of the time' (1) to 'all of the time' (6). The HRQL subscale scores were calculated by summing the responses of the items within each subscale.The HRQL total score was calculated by adding the 4 HRQL subscale scores,. All scores were transformed to a scale from 0 to 100 where higher scores indicate better quality of life. A positive change from Baseline in HRQL score indicates improvement.
Change From Baseline to Week 12 in Total Urinary Nerve Growth Factor Normalized by Urine Creatinine	Baseline and Week 12	Total (acidified) urinary nerve growth factor (uNGF) and creatinine (Cr) were measured from urine samples by the central laboratories. Total uNGF/Cr was derived by dividing total uNGF concentrations \[pg/mL\] by the urine creatinine concentrations (µmol/mL) from the same participant.
Percentage of Participants With Improvement or Deterioration in Patient Perception of Bladder Condition (PPBC)	Baseline and Week 12	The PPBC scale is a global assessment tool that asks patients to rate their impression of their current bladder condition on a 6-point scale from 1: 'Does not cause me any problems at all'; 2: 'Causes me some very minor problems'; 3: 'Causes me some minor problems'; 4: 'Causes me (some) moderate problems'; 5: 'Causes me severe problems' and 6: 'Causes me many severe problems'. Improvement: ≥ 1 point improvement compared to Baseline; Major Improvement: ≥ 2 point improvement compared to Baseline; Deterioration: ≥ 1 point deterioration compared to Baseline.