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 (LION)

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)

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.

Study Overview

• Status: Completed
• Conditions: Urinary Bladder, Overactive
• Intervention / Treatment: Drug: Placebo; Behavioral: Urotherapy; Drug: Solifenacin Succinate Suspension

• Study Type: Interventional
• Enrollment (Actual): 189
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, 2020
    • Site: 3202
  • Antwerp, Belgium, 2650
    • Site: 3209
  • Charleroi, Belgium, 6000
    • Site: 3208
  • Gent, Belgium, 9000
    • Site: 3201
  • Gent, Belgium, 9000
    • Site: 3203
  • Kortrijk, Belgium, 8500
    • Site: 3204
  • Leuven, Belgium, 3000
    • Site: 3205
• Brazil
  • Campinas, Brazil, 13087-567
    • Site: 5507
  • Curitiba, Brazil, 80240-060
    • Site: 5506
• Canada
  • Hamilton, Canada, L8N 3Z5
    • Site: 1005
  • Quebec, Canada, G1V 4G2
    • Site: 1001
• Denmark
  • Aalborg, Denmark, DK-9000
    • Site: 4503
  • Aarhus N, Denmark, 8200
    • Site: 4501
  • Koge, Denmark, 4600
    • Site: 4504
  • Kolding, Denmark, 6000
    • Site: 4502
• Former Serbia and Montenegro
  • Belgrade, Former Serbia and Montenegro, 11 000
    • Site: 3810
  • Novi Sad, Former Serbia and Montenegro, 21000
    • Site: 3812
• Korea, Republic of
  • Daegu, Korea, Republic of, 705717
    • Site:8203
  • Incheon, Korea, Republic of, 400-711
    • Site: 8206
  • Seoul, Korea, Republic of, 110744
    • Site: 8207
  • Seoul, Korea, Republic of, 120752
    • Site: 8201
  • Seoul, Korea, Republic of, 156707
    • Site:8202
• Mexico
  • Mexico City, Mexico, 4530
    • Site: 5202
  • Mexico City, Mexico, C.P.06700
    • Site: 5205
• Norway
  • Bergen, Norway, 5021
    • Site: 4701
  • Trondheim, Norway, 7030
    • Site: 4702
• Philippines
  • Quezon City, Philippines, 1108
    • Site: 6301
• Poland
  • Gdansk, Poland, 80-803
    • Site: 4805
  • Gdansk, Poland, 80-952
    • Site: 4803
  • Lubin, Poland, 20-093
    • Site: 4804
  • Warsaw, Poland, 04-736
    • Site: 4801
• South Africa
  • Cape Town, South Africa, 7700
    • Site: 2703
• Sweden
  • Gothenburg, Sweden, 41685
    • Site: 4606
  • Jonkoping, Sweden, 55185
    • Site: 4601
  • Skovde, Sweden, 54185
    • Site: 4603
  • Stockholm, Sweden, 11883
    • Site: 4602
  • Umea, Sweden, 90185
    • Site: 4605
• Turkey
  • Ankara, Turkey, 6100
    • Site: 9001
  • Izmir, Turkey, 35100
    • Site: 9002
• Ukraine
  • Dnipropetrovsk, Ukraine, 49100
    • Site: 3853
  • Kharkiv, Ukraine
    • Site: 3854
  • Kiev, Ukraine, 1103
    • Site: 3850
• United Kingdom
  • Leeds, United Kingdom, LS1 3EX
    • Site: 4403
  • Sheffield, United Kingdom, S10 2TH
    • Site: 4401
• United States
  • Louisiana
    • Shreveport, Louisiana, United States, 71106
      • Site: 1006
  • New York
    • Albany, New York, United States, 12208
      • Site: 1015

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo Children; Children aged 5 to 11 years received matching placebo suspension once a day for 12 weeks.	Drug: Placebo; 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.; 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.; Other Names: Bladder training
EXPERIMENTAL: Solifenacin Succinate Suspension Children; 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.	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.; Other Names: Bladder training; Drug: Solifenacin Succinate Suspension; 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.; Other Names: YM905
PLACEBO_COMPARATOR: Placebo Adolescents; Adolescents aged 12 to 17 years received matching placebo suspension once a day for 12 weeks.	Drug: Placebo; 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.; 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.; Other Names: Bladder training
PLACEBO_COMPARATOR: Solifenacin Succinate Suspension Adolescents; 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.	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.; Other Names: Bladder training; Drug: Solifenacin Succinate Suspension; 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.; Other Names: YM905

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astellas Pharma Europe B.V.

Publications and helpful links

General Publications

• Tannenbaum S, den Adel M, Krauwinkel W, Meijer J, Hollestein-Havelaar A, Verheggen F, Newgreen D. Pharmacokinetics of solifenacin in pediatric populations with overactive bladder or neurogenic detrusor overactivity. Pharmacol Res Perspect. 2020 Dec;8(6):e00684. doi: 10.1002/prp2.684.
• Snijder R, Bosman B, Stroosma O, Agema M. Relationship between mean volume voided and incontinence in children with overactive bladder treated with solifenacin: post hoc analysis of a phase 3 randomised clinical trial. Eur J Pediatr. 2020 Oct;179(10):1523-1528. doi: 10.1007/s00431-020-03635-2. Epub 2020 Apr 1.
• Newgreen D, Bosman B, Hollestein-Havelaar A, Dahler E, Besuyen R, Sawyer W, Bolduc S, Rittig S. Solifenacin in Children and Adolescents with Overactive Bladder: Results of a Phase 3 Randomised Clinical Trial. Eur Urol. 2017 Mar;71(3):483-490. doi: 10.1016/j.eururo.2016.08.061. Epub 2016 Sep 28.

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 7, 2012
• Primary Completion (ACTUAL): December 31, 2013
• Study Completion (ACTUAL): January 2, 2014

Study Registration Dates

• First Submitted: March 27, 2012
• First Submitted That Met QC Criteria: March 27, 2012
• First Posted (ESTIMATE): March 29, 2012

Study Record Updates

• Last Update Posted (ACTUAL): October 30, 2018
• Last Update Submitted That Met QC Criteria: October 1, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Pediatric; Pharmacokinetics; Phase 3; Overactive bladder (OAB); Solifenacin succinate suspension
• Additional Relevant MeSH Terms: Urologic Diseases; Urinary Bladder Diseases; Lower Urinary Tract Symptoms; Urological Manifestations; Urinary Bladder, Overactive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Urological Agents; Solifenacin Succinate
• Other Study ID Numbers: 905-CL-076; 2011-002066-20 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR