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 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.

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).

Cognitive Function, Phase 3, Neurogenic Detrusor Overactivity, Pharmacokinetics, Ocular Accommodation, Urodynamics

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.