A Study to Assess the Long Term Effect, Safety and Metabolism of a Solifenacin Liquid Suspension in Participants 5 to 18 Years of Age With Neurogenic Detrusor Overactivity

A Phase 3, Open-Label, Baseline-controlled, Multicenter, Sequential Dose Titration Study to Assess the Long-Term Efficacy and Safety, and the Pharmacokinetics of Solifenacin Succinate Suspension in Patients From 5 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity (NDO)

The purpose of this study was to investigate a medicine for the treatment of symptoms and complications of neurogenic detrusor overactivity (NDO) in children and adolescents.

Study Overview

• Status: Completed
• Conditions: Neurogenic Detrusor Overactivity
• Intervention / Treatment: Drug: Solifenacin succinate

Detailed Description

The NDO often occurs in patients with spina bifida or other spinal cord damage where the bladder muscle contracts more than normal during filling. These patients often have an inability to void, so that catheterization is required to empty the bladder.

The medicine being tested in this study is called solifenacin succinate. Solifenacin tablets are given to adults for the treatment of overactive bladder. A new liquid suspension has been developed to treat children and adolescents in this and other studies.

The efficacy and safety of the solifenacin suspension was investigated. The take-up and length of time that the solifenacin suspension stays in the body was also investigated during this study. Effectiveness was measured by urodynamics (the filling and emptying of the bladder) and the urine volumes during catheterization together with the diary responses relating to the number of incontinence episodes or incontinence free days.

Safety assessments included analysis of the blood and urine, review of the electrocardiogram (ECG), ultrasound of the kidney, simple memory and understanding tests (cognitive function) and the ability to see near and far objects (visual accommodation).

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Site BE3201
• Brazil
  • Campinas, Brazil, 13060-803
    • Site BR5507
  • Campinas, Brazil, 13083-887
    • Site BR5504
  • Curitiba, Brazil, 80240-060
    • Site BR5506
  • Porto Alegre, Brazil, 90035-903
    • Site BR5503
  • São Paulo
    • Sao Jose do Rio Preto, São Paulo, Brazil, 15090-000
      • Site BR5505
• Denmark
  • Aarhus, Denmark, 8200
    • Site DK4501
• Hungary
  • Miskolc, Hungary, 3526
    • Site HU3602
• Korea, Republic of
  • Seoul, Korea, Republic of, 110744
    • Site KR8207
  • Seoul, Korea, Republic of, 120752
    • Site KR8201
• Mexico
  • Leon, Mexico, 37000
    • Site MX5203
  • Mexico City, Mexico, C.P. 06700
    • Site MX5205
• Philippines
  • Manila, Philippines, 1015
    • Site PH6301
  • Quezon City, Philippines, 1101
    • Site PH6302
• Poland
  • Gdansk, Poland, 80-952
    • Site PL4803
  • Gdansk, Poland, 80803
    • Site PL4805
  • Warszawa, Poland, 04-730
    • Site PL4801
• Turkey
  • Ankara, Turkey, 6100
    • Site TR9003
  • Izmir, Turkey, 35100
    • Site TR9002
• United States
  • New York
    • Tarrytown, New York, United States, 10591
      • Site US1008
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Site US1010

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Documented diagnosis of NDO, confirmed by urodynamics
• Practicing clean intermittent catheterization (CIC)
• Currently on treatment with an antimuscarinic drug

Exclusion Criteria:

• Known genitourinary condition (other than NDO) that may cause incontinence
• Bladder augmentation surgery
• Current Faecal impaction
• Electro-stimulation therapy within 2 weeks prior to screening and at any time during the study
• Subjects with the following gastro-intestinal problems: partial or complete obstruction, decreased motility like paralytic ileus, subjects at risk of gastric retention
• Reflux grade 3 or 4
• Current urinary tract infection (UTI)
• Subject has severe renal impairment (glomerular filtration rate < 30 ml/min)
• Subject has severe hepatic impairment (Child-Pugh score > 9).
• Subject has received intra-vesical botulinum toxin within 9 months prior to screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Solifenacin succinate; Participants aged 5 years to < 18 years received solifenacin orally once a day, with sequential titrated doses for 12 weeks to identify the optimal dose during the dose-titration period. The initial dose was pediatric equivalent dose (PED) 5 mg. After completing the dose titration period participants entered the fixed-dose period during which solifenacin was taken orally once a day for 40 weeks or until the end of study visit (Week 52).

Drug: Solifenacin succinate; Oral suspension administered once a day via syringe.; Other Names: YM905

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 24 in Maximum Cystometric Capacity (MCC)	During urodynamic assessments, the bladder was filled until voiding/leakage begins, or until it was stopped because either the participant experiences pain or discomfort or 135% of expected bladder capacity for age has been reached. MCC is the maximum bladder capacity reached during filling cystometry before either leakage or pain/discomfort was observed.	Baseline and Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Last Possible Titration Step in Maximum Cystometric Capacity	During urodynamic assessments, the bladder was filled until voiding/leakage begins, or until it was stopped because either the participant experiences pain or discomfort or 135% of expected bladder capacity for age has been reached. MCC is the maximum bladder capacity reached during filling cystometry before either leakage or pain/discomfort was observed. Based on study requirements, the last possible titration step was Week 9 for participants enrolled under versions 1.0 and 1.1 and Week 12 under later versions.	Baseline, Week 9 or Week 12
Change From Baseline in Bladder Compliance	Bladder compliance gives an indication of the elasticity of the bladder wall and was calculated by dividing the change in volume by the change in detrusor pressure during the filling of the bladder.	Baseline and Week 24
Change From Baseline in Bladder Volume (mL) Until First Detrusor Contraction > 15 cmH2O as a Percentage of Expected Bladder Capacity (EBC)	Change from baseline in the bladder volume was calculated using urodyanamic assessments. During urodynamic assessments, the bladder is filled until voiding/leakage begins, or until it is stopped because either the subject experiences pain or discomfort or 135% of expected bladder capacity for age has been reached. If no detrusor contraction of at least 15 cmH2O occurs, the bladder volume was imputed with MCC.	Baseline and Week 24
Change From Baseline in Bladder Volume at 30 cmH2O Detrusor Pressure	Bladder volumes at 30 cm H2O detrusor pressure was calculated using the urodynamic assessments. During urodynamic assessments, the bladder is filled until voiding/leakage begins, or until it is stopped because either the participants experiences pain or discomfort or 135% of expected bladder capacity for age has been reached.	Baseline and Week 24
Change From Baseline in Bladder Volume at 40 cmH2O Detrusor Pressure	Bladder volumes at 40 cm H2O detrusor pressure were calculated using urodynamic assessments. During urodynamic assessments, the bladder is filled until voiding/leakage begins, or until it is stopped because either the subject experiences pain or discomfort or 135% of expected bladder capacity for age has been reached.	Baseline and Week 24
Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cmH2O) Until End of Bladder Filling	Change from baseline in number of overactive detrusor contractions until end of bladder filling was measured by urodynamic testing. If leakage occurred, the "Detrusor pressure at leakage" was recorded otherwise the volume of fluid instilled into the bladder was recorded.	Baseline to Week 24
Change From Baseline in Detrusor Pressure at the End of Bladder Filling	The bladder was filled until voiding/leakage began or until it was stopped because either the participant experiences pain or discomfort or 135% of expected bladder capacity for age has been reached. Pressure was recorded for an extra 5 minutes after leakage began or the end of bladder-filling, whichever is sooner.	Baseline to Week 24
Change From Baseline in Average Catheterized Volume Per Catheterization	The average catheterized volume per catheterization was calculated using all available (non-zero) catheterized volumes recorded over both of the 2 measuring days in the diary, whether or not these 2 days are concurrent.	Baseline to Week 24
Change From Baseline in Maximum Catheterized Volume	The maximum catheterized volume per day was calculated using all available (non-zero) catheterized volumes recorded for the 2 measuring days in the diary, whether or not these 2 days were concurrent. The maximum value was calculated separately for each measuring day and the mean of these two values was used.	Baseline to Week 24
Change From Baseline in Average First Morning Catheterized Volume	The average first morning catheterized volume was calculated as the average of the available first morning catheterized volumes recorded for the 2 measuring days in the diary, whether or not these 2 days are concurrent.	Baseline to Week 24
Change From Baseline in Mean Number of Incontinence Episodes Per 24 Hours	The mean of the number of incontinence episodes per 24h was calculated as the mean over the valid diary days in the 7-day diary.	Baseline to Week 24
Change From Baseline in Number of Dry (Incontinence-Free) Days Per 7 Days	The number of incontinence-free days was calculated from the 7-day micturition diary.	Baseline to Week 24
Change From Baseline in Number of Dry (Incontinence-Free) Nights Per 7 Days	The number of incontinence-free nights was calculated from the 7-day micturition diary.	Baseline to Week 24
Change From Baseline in Quality of Life [QoL] (PinQ Questionnaire Score)	Pediatric Incontinence Questionnaire (PinQ) is a 20-item questionnaire addressing quality of life for participants with bladder disorders. Each question was answered on a scale from 0 (no, never) to 4 (all the time). The total score ranged from 0 to 80, with higher scores indicated more impact on the quality of life.	Baseline to Week 24
Number of Participants With Adverse Events	A treatment-emergent adverse event (TEAE) was defined as an adverse event observed after starting administration of the first dose of study medication on Day 1. All adverse events collected within 7 days after taking the last dose of study drug were counted as a TEAE.	Baseline to End of Study Visit (Week 52)

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.
• Franco I, Hoebeke P, Baka-Ostrowska M, Bolong D, Davies LN, Dahler E, Snijder R, Stroosma O, Verheggen F, Newgreen D, Bosman B, Vande Walle J. Long-term efficacy and safety of solifenacin in pediatric patients aged 6 months to 18 years with neurogenic detrusor overactivity: results from two phase 3 prospective open-label studies. J Pediatr Urol. 2020 Apr;16(2):180.e1-180.e8. doi: 10.1016/j.jpurol.2019.12.012. Epub 2019 Dec 27.

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 14, 2012
• Primary Completion (ACTUAL): April 28, 2016
• Study Completion (ACTUAL): April 28, 2016

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): May 6, 2019
• Last Update Submitted That Met QC Criteria: April 10, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Urodynamics; Cognitive Function; Phase 3; Neurogenic Detrusor Overactivity; Ocular Accommodation
• 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-047; 2011-000330-11 (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