A Study to Investigate How Effective and Safe Solifenacin Succinate Suspension is in Treating Children/Adolescents Aged 5 to Less Than 18 Years With Symptoms of Overactive Bladder (OAB) Compared to a Non-active Drug

Study Overview
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Brief Summary
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Solifenacin succinate as a tablet formulation is already on the market for the treatment of symptoms of overactive bladder in adults. For the use in children and adolescent patients a new formulation of solifenacin has been developed. This study investigated the effect and safety of solifenacin succinate liquid suspension compared to a non-active drug (placebo) over a 12-week period. The 2 weeks prior to the double blind period was a single-blind placebo run-in period in combination with behavioral urotherapy (Non-interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB), followed by a 12 week daily treatment period. The study also investigated how well solifenacin succinate suspension is taken-up by the body and how long it stays in the body during this time.

Official Title
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A Phase 3, Double-Blind, Randomized, Multi-center, Placebo-Controlled Sequential Dose Titration Study to Assess Efficacy, Safety and Population Pharmacokinetics of Solifenacin Succinate Suspension in Pediatric Subjects From 5 to Less Than 18 Years of Age With Overactive Bladder (OAB)

Conditions
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Urinary Bladder, Overactive

Intervention / Treatment
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* Drug: Solifenacin Succinate Suspension
* Drug: Placebo
* Behavioral: Urotherapy


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Written Informed Consent has been obtained OAB (symptoms of urgency) according to International Children's Continence Society (ICCS) criteria Daytime incontinence with at least 4 or more episodes of incontinence confirmed by 7 day participant diary Main Exclusion Criteria: Daily voiding frequency less than 5 Extraordinary daytime urinary frequency according to the International Children's Continence Society (ICCS) definition Uroflow indicative of pathology other than OAB Maximum voided volume (morning volume excluded) > expected bladder capacity for age [(age +1) x 30] in ml or a maximum voided volume (morning volume excluded) above 390 ml Post Void Residual (PVR) > 20 ml Monosymptomatic enuresis Polyuria defined as > 75 ml/kg/b.w./24 hours Dysfunctional voiding Congenital anomalies affecting lower urinary tract function Current constipation Current Urinary Tract Infection (UTI) Catheterization within 2 weeks prior to screening

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Children<br>Children aged 5 to 11 years received matching placebo suspension once a day for 12 weeks. | Drug: Placebo<br>* Children aged 5 to 11 years and adolescents aged 12 to 17 years received matching placebo liquid suspension once a day orally via syringe for 12 weeks along with non interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB. The initial dose started with the equivalent of 5 mg in adults, referred to as pediatric equivalent dose (PED) of 5 mg (PED5), based on body weight for three weeks and was titrated up or down in up to three titration steps of three weeks each to reach the optimal dose. Titration up or down could lead to weight-based doses equivalent to doses in adults of 2.5 mg, 5 mg, 7.5 mg or 10 mg once daily and were referred to as PED2.5, PED5, PED7.5 and PED10. The minimum dose was PED2.5, and the maximum dose was PED10. The decision to titrate up or down was made by the investigator using information from the 7 day patient diary.<br>Behavioral: Urotherapy<br>* Non interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB.<br>* Other names: Bladder training;|
| Experimental: Solifenacin Succinate Suspension Children<br>Children aged 5 to 11 years received solifenacin succinate suspension once a day for 12 weeks. The initial dose started with pediatric equivalent dose (PED) of 5 mg (PED5) based on weight and was titrated up or down to reach the optimal dose. The minimum dose was PED2.5, and the maximum dose was PED10. | Drug: Solifenacin Succinate Suspension<br>* Children aged 5 to 11 years and adolescents aged 12 to 17 years received solifenacin succinate liquid suspension once a day orally via syringe for 12 weeks along with non interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB. The initial dose started with the equivalent of 5 mg in adults, referred to as pediatric equivalent dose (PED) of 5 mg (PED5), based on body weight for three weeks and was titrated up or down in up to three titration steps of three weeks each to reach the optimal dose. Titration up or down could lead to weight-based doses equivalent to doses in adults of 2.5 mg, 5 mg, 7.5 mg or 10 mg once daily and were referred to as PED2.5, PED5, PED7.5 and PED10. The minimum dose was PED2.5, and the maximum dose was PED10. The decision to titrate up or down was made by the investigator using information from the 7 day patient diary.<br>* Other names: YM905;Behavioral: Urotherapy<br>* Non interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB.<br>* Other names: Bladder training;|
| Placebo Comparator: Placebo Adolescents<br>Adolescents aged 12 to 17 years received matching placebo suspension once a day for 12 weeks. | Drug: Placebo<br>* Children aged 5 to 11 years and adolescents aged 12 to 17 years received matching placebo liquid suspension once a day orally via syringe for 12 weeks along with non interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB. The initial dose started with the equivalent of 5 mg in adults, referred to as pediatric equivalent dose (PED) of 5 mg (PED5), based on body weight for three weeks and was titrated up or down in up to three titration steps of three weeks each to reach the optimal dose. Titration up or down could lead to weight-based doses equivalent to doses in adults of 2.5 mg, 5 mg, 7.5 mg or 10 mg once daily and were referred to as PED2.5, PED5, PED7.5 and PED10. The minimum dose was PED2.5, and the maximum dose was PED10. The decision to titrate up or down was made by the investigator using information from the 7 day patient diary.<br>Behavioral: Urotherapy<br>* Non interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB.<br>* Other names: Bladder training;|
| Placebo Comparator: Solifenacin Succinate Suspension Adolescents<br>Adolescents aged 12 to 17 years received solifenacin succinate suspension once a day for 12 weeks. The initial dose started with pediatric equivalent dose (PED) of 5 mg (PED5) based on weight and was titrated up or down to reach the optimal dose. The minimum dose was PED2.5, and the maximum dose was PED10. | Drug: Solifenacin Succinate Suspension<br>* Children aged 5 to 11 years and adolescents aged 12 to 17 years received solifenacin succinate liquid suspension once a day orally via syringe for 12 weeks along with non interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB. The initial dose started with the equivalent of 5 mg in adults, referred to as pediatric equivalent dose (PED) of 5 mg (PED5), based on body weight for three weeks and was titrated up or down in up to three titration steps of three weeks each to reach the optimal dose. Titration up or down could lead to weight-based doses equivalent to doses in adults of 2.5 mg, 5 mg, 7.5 mg or 10 mg once daily and were referred to as PED2.5, PED5, PED7.5 and PED10. The minimum dose was PED2.5, and the maximum dose was PED10. The decision to titrate up or down was made by the investigator using information from the 7 day patient diary.<br>* Other names: YM905;Behavioral: Urotherapy<br>* Non interventional diary assisted urotherapy consisting of overactive bladder (OAB) information, awareness, instruction, life-style advice and documentation of voiding habits and symptoms for OAB.<br>* Other names: Bladder training;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of Treatment (EoT) in Mean Volume Voided (MVV) Per Micturition | The mean voided volume was calculated from the participant diary data recorded during two measuring days (i.e., those days when the participant recorded the volume of each micturition) in the 7 days prior to the baseline and end of treatment visits. The MVV is equal to the mean of the non-zero volumes recorded over the 2 measuring days. A micturition is any voluntary urination, excluding episodes of incontinence. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of Treatment in Daytime Maximum Volume Voided (DMaxVV) Per Micturition | The mean daytime maximum volume voided (DMaxVV) was determined using the participant diary data recorded during two measuring days (i.e., those days when the participant recorded the volume of each micturition) in the 7 days prior to the Baseline and end of treatment visits. The daytime maximum volume voided (DMaxVV) is the largest (non-zero) volume recorded over both of the 2 measuring days in the diary. The first morning void is excluded from the calculation. Daytime is defined as the time between waking up in the morning and going to bed later the same day. A micturition is any voluntary urination, excluding episodes of incontinence. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Incontinence Episodes Per 24 Hours | An incontinence episode is defined as an episode with any involuntary loss of urine. The mean number of incontinence episodes was determined using the patient diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Daytime Incontinence Episodes Per 24 Hours | The mean number of incontinence episodes was determined using the patient diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. An incontinence episode is defined as an episode with any involuntary loss of urine. Daytime is defined as the time between waking up in the morning and going to bed later the same day. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Nighttime Incontinence Episodes Per 24 Hours | The mean number of incontinence episodes was determined using the patient diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. An incontinence episode is defined as an episode with any involuntary loss of urine. Nighttime is defined as the time between going to bed and waking up the following morning. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Dry (Incontinence-Free) Days Per 7 Days | The mean number of dry days was determined using the patient diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. An incontinence episode is defined as an episode with any involuntary loss of urine. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Dry (Incontinence-Free) Nighttimes Per 7 Days | The mean number of dry nights was determined using the patient diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. An incontinence episode is defined as an episode with any involuntary loss of urine. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Micturitions Per 24 Hours | The mean number of micturitions was determined using the patient diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. A micturition is any voluntary urination, excluding episodes of incontinence. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Daytime Micturitions Per 24 Hours | The mean number of micturitions was determined using the patient diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. A micturition is any voluntary urination, excluding episodes of incontinence. Daytime is defined as the time between waking up in the morning and going to bed later the same day. | Baseline and week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Nighttime Micturitions Per 24 Hours | The mean number of micturitions was determined using the patient diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. A micturition is any voluntary urination, excluding episodes of incontinence. Nighttime is defined as the time between going to bed and waking up the following morning. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Grade 3 or 4 Urgency Episodes Per 24 Hours in Adolescents | Adolescent participants were asked to record the degree of urgency associated with each micturition and incontinence episode according to the Patient Perception of Intensity of Urgency Scale (PPIUS) scale (0 - no urgency, 1 - mild urgency, 2 - moderate urgency, 3 - severe urgency, 4 - urge incontinence). The mean number of grade 3 or 4 urgency episodes was determined using using diary data recorded by the participant in the 7 days prior to baseline visit and end of treatment visit. | Baseline and Week 12 | 
| Maximum Concentration (Cmax) of Solifenacin | Pharmacokinetic sampling was performed at steady state at the end of treatment. Cmax could not be calculated for 2 children and 1 adolescent in the Pharmacokinetic Analysis Set (PKAS). | Week 12/Day 84 (within 3 hours before dosing, 1-3 hours, 4-5 hours, 7-10 hours after dosing) and one sample at Visit 8/Day 87 (2-3 days after last dose intake). | 
| Time to Attain Maximum Concentration (Tmax) of Solifenacin | Pharmacokinetic sampling was performed at steady state at the end of treatment. Tmax could not be calculated for 2 children and 1 adolescent in the PKAS. | Week 12/Day 84 (within 3 hours before dosing, 1-3 hours, 4-5 hours, 7-10 hours after dosing) and one sample at Visit 8/Day 87 (2-3 days after last dose intake). | 
| Plasma Concentration Before Drug Administration (Ctrough) of Solifenacin | Pharmacokinetic sampling was performed at steady state at the end of treatment. Ctrough could not be calculated for 2 children and 1 adolescent in the PKAS. | Week 12/Day 84 (within 3 hours before dosing, 1-3 hours, 4-5 hours, 7-10 hours after dosing) and one sample at Visit 8/Day 87 (2-3 days after last dose intake). | 
| Area Under the Plasma Concentration - Time to Curve (AUC) for a Dose Interval (AUCtau) of Solifenacin | Pharmacokinetic sampling was performed at steady state at the end of treatment. | Week 12/Day 84 (within 3 hours before dosing, 1-3 hours, 4-5 hours, 7-10 hours after dosing) and one sample at Visit 8/Day 87 (2-3 days after last dose intake). | 
| Apparent Terminal Elimination Half-Life (T1/2) of Solifenacin | Pharmacokinetic sampling was performed at steady state at the end of treatment. | Week 12/Day 84 (within 3 hours before dosing, 1-3 hours, 4-5 hours, 7-10 hours after dosing) and one sample at Visit 8/Day 87 (2-3 days after last dose intake). | 
| Apparent Total Body Clearance (CL/F) of Solifenacin | Pharmacokinetic sampling was performed at steady state at the end of treatment. | Week 12/Day 84 (within 3 hours before dosing, 1-3 hours, 4-5 hours, 7-10 hours after dosing) and one sample at Visit 8/Day 87 (2-3 days after last dose intake). | 
| Apparent Volume of Distribution (Vz/F) of Solifenacin | Pharmacokinetic sampling was performed at steady state at the end of treatment. | Week 12/Day 84 (within 3 hours before dosing, 1-3 hours, 4-5 hours, 7-10 hours after dosing) and one sample at Visit 8/Day 87 (2-3 days after last dose intake). | 
| Number of Participants With Adverse Events (AEs) | A treatment emergent adverse event (TEAE) was defined as an AE that occurred after the first dose of study drug and within 7 days after last dose of study medication. | From the first dose of study drug until 7 days after last dose of study medication (13 weeks). | 
| Change From Baseline in Post Void Residual (PVR) Volume | Post Void Residual (PVR) Volume was assessed by ultrasonography or bladder scan. | Baseline and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, Solifenacin succinate suspension, Phase 3, Pharmacokinetics, Overactive bladder (OAB)