A Clinical Study to Investigate How Solifenacin Fluid is Taken up, How Long it Stays in the Body and How Effective and Safe it is in Treating Children Aged From 6 Months to Less Than 5 Years With Symptoms of Neurogenic Detrusor Overactivity (NDO)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate long term efficacy and safety of treatment with solifenacin succinate (the study drug) in children with neurogenic detrusor overactivity after multiple dose administration.

Detailed Description
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In some children with a severe form of spina bifida (which is the consequence of a spinal cord defect), the bladder muscle (detrusor) contracts strongly and without warning (also known as neurogenic detrusor overactivity) and the urethra (the passage connecting the bladder with outside) does not relax. Though these children cannot void, urine leakage can happen when the overactive contractions are strong, and/or the pressure in the bladder is so high that it overcomes the closed urethra (overflow at high filling bladder pressure). This high bladder pressure puts these children at risk for kidney damage and can decrease the quality of the bladder. Therapy was aimed to decrease the high filling bladder pressure and the overactive detrusor contractions.

Official Title
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A Phase 3, Open-Label, Baseline-controlled, Multi-center, Sequential Dose-Titration Study to Assess the Pharmacokinetics, Long-Term Efficacy and Safety of Solifenacin Succinate Suspension in Children From 6 Months to Less Than 5 Years of Age With Neurogenic Detrusor Overactivity

Conditions
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Neurogenic Detrusor Overactivity, Pediatric

Intervention / Treatment
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* Drug: Solifenacin succinate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Myelomeningocoele Documented diagnosis of NDO, confirmed by urodynamics DSD (detrusor sphincter dyssynergia) Practicing clean intermittent catheterization (CIC) Exclusion Criteria: Know genitourinary condition (other than NDO) that may cause incontinence Bladder augmentation surgery Current faecal impaction Electro-stimulation therapy within 2 weeks prior to visit Subjects with the following gastro-intestinal problems: partial or complete obstructions, decreased motility like paralytic ileus, subjects at risk of gastric retention Reflux grade 3 to 5 Current urinary tract infection

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 4 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solifenacin succinate<br>Children aged 6 months to less than 5 years were treated with sequential titrated doses of solifenacin up to 12 weeks in the Titration period after which a fixed dose of solifenacin was given for at least 40 weeks in the Fixed-dose assessment period. Children received solifenacin once daily during these 2 periods. | Drug: Solifenacin succinate<br>* Oral suspension<br>* Other names: solifenacin succinate suspension;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Maximum Cystometric Capacity (MCC) | MCC was the volume instilled into the bladder prior to leakage or end of bladder-filling (whichever was reached first), as assessed by urodynamics (procedure: the bladder was to be filled until voiding/leakage began, or until it was stopped because either the participant experienced pain or discomfort or 135% of expected bladder capacity [EBC] was reached for participants ≥ 2 years or of maximum catheterized volume [MCV] for participants aged 6 months to < 2 years; the participants' bladder was emptied via catheterization). | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Weeks 3, 6, 9, 12 and 52 in MCC | MCC was the volume instilled into the bladder prior to leakage or end of bladder-filling (whichever was reached first) as assessed by urodynamics (procedure: the bladder was to be filled until voiding/leakage began, or until it was stopped because either the participant experienced pain or discomfort or 135% of EBC was reached for participants ≥ 2 years or of MCV for participants aged 6 months to < 2 years. The participants' bladder was emptied via catheterization). | Baseline and Weeks 3, 6, 9, 12, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Bladder Compliance | Bladder compliance gives an indication of the elasticity of the bladder wall. Bladder compliance was calculated by dividing the change in volume during the filling of the bladder by the change in detrusor pressure during that change in bladder volume using urodynamic assessments. The values for bladder volume and detrusor pressure at the beginning and end of filling were taken and used. | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Detrusor Pressure at End of Bladder-Filling | Detrusor pressure was expressed as bladder pressure minus intra-abdominal pressure as assessed by urodynamics. | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Detrusor Pressure 5 Minutes After End of Bladder-Filling | Detrusor pressure was expressed as bladder pressure minus intra-abdominal pressure as assessed by urodynamics. | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Catheterized Volume 5 Minutes After End of Bladder-Filling | Catheterized volume was measured when the bladder was emptied via catheterization 5 minutes after the end of bladder-filling. | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Bladder Volume Until First Detrusor Contraction (> 15 cmH2O) | Bladder volume as assessed by urodynamics. | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Bladder Volume at 10 cmH20 Detrusor Pressure | Bladder volume as assessed by urodynamics. | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Bladder Volume at 20 cmH20 Detrusor Pressure | Bladder volume as assessed by urodynamics. | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Bladder Volume at 30 cmH20 Detrusor Pressure | Bladder volume as assessed by urodynamics. | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24 and 52 in Number of Overactive Detrusor Contractions (> 15 cmH2O) Until Leakage or End of Bladder-Filling |  | Baseline and Weeks 3, 6, 9, 12, 24, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24, 36 and 52 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 were concurrent. Catheterized volumes were recorded for 2 days in a participant diary prior to each visit. Four to six catheterizations were performed every day. | Baseline and Weeks 3, 6, 9, 12, 24, 36, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24, 36 and 52 in Maximum Catheterized Volume (MCV) | 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 and Weeks 3, 6, 9, 12, 24, 36, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24, 36 and 52 in Average First Morning Catheterized Volume | The first morning catheterized volume was the volume associated with the first morning catheterization. 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 and Weeks 3, 6, 9, 12, 24, 36, 52 | 
| Change From Baseline to Weeks 3, 6, 9, 12, 24, 36 and 52 in Mean Number of Periods Between the Clean Intermittent Catheterizations (CICs) With Incontinence Per 24 Hours | Participants were required to have 4-6 CICs per day on a schedule fixed for the duration of the study. To calculate the number of periods between CICs with incontinence in a diary day, the diary day was divided into periods between CICs (i.e. inter-CIC periods). The hour period, rather than the exact time, of each CIC and incontinence episode was recorded in the diary. When an incontinence episode and a CIC were marked in the same hour period, the incontinence episode was counted as occurring prior to the CIC (when the bladder had not yet emptied), rather than after it (when the bladder had recently been emptied), i.e. the inter-CIC period ended with the hour in which the CIC was recorded. The mean number of periods between CICs with incontinence per 24 hours was the number of periods between CICs when incontinence occurred, divided by the total number of valid diary days. | Baseline and Weeks 3, 6, 9, 12, 24, 36, 52 | 
| Percentage of Days With Catheterizations for Each Hour of 24 Hour Day at Baseline | For each one hour period of the 24 hour day, the percentage of days with catheterization was assessed as the number of days with catheterization occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Baseline visit | 
| Percentage of Days With Catheterizations for Each Hour of 24 Hour Day During Week 3 | For each one hour period of the 24 hour day, the percentage of days with catheterization was assessed as the number of days with catheterization occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 3 visit | 
| Percentage of Days With Catheterizations for Each Hour of 24 Hour Day During Week 6 | For each one hour period of the 24 hour day, the percentage of days with catheterization was assessed as the number of days with catheterization occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 6 visit | 
| Percentage of Days With Catheterizations for Each Hour of 24 Hour Day During Week 9 | For each one hour period of the 24 hour day, the percentage of days with catheterization was assessed as the number of days with catheterization occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 9 visit | 
| Percentage of Days With Catheterizations for Each Hour of 24 Hour Day During Week 12 | For each one hour period of the 24 hour day, the percentage of days with catheterization was assessed as the number of days with catheterization occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 12 visit | 
| Percentage of Days With Catheterizations for Each Hour of 24 Hour Day During Week 24 | For each one hour period of the 24 hour day, the percentage of days with catheterization was assessed as the number of days with catheterization occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 24 visit | 
| Percentage of Days With Catheterizations for Each Hour of 24 Hour Day During Week 36 | For each one hour period of the 24 hour day, the percentage of days with catheterization was assessed as the number of days with catheterization occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 36 visit | 
| Percentage of Days With Catheterizations for Each Hour of 24 Hour Day During Week 52 | For each one hour period of the 24 hour day, the percentage of days with catheterization was assessed as the number of days with catheterization occurring within the one hour period divided by the number of valid diary days over all subjects. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 52 visit | 
| Percentage of Days With Incontinence for Each Hour of 24 Hour Day at Baseline | Incontinence was defined as leakage where a diaper is not used, or dampness where a diaper is used. For each one hour period of the 24 hour day, the percentage of days with incontinence was assessed as the number of days with incontinence occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Baseline visit | 
| Percentage of Days With of Incontinence for Each Hour of 24 Hour Day During Week 3 | Incontinence was defined as leakage where a diaper is not used, or dampness where a diaper is used. For each one hour period of the 24 hour day, the percentage of days with incontinence was assessed as the number of days with incontinence occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 3 visit | 
| Percentage of Days With Incontinence for Each Hour of 24 Hour Day During Week 6 | Incontinence was defined as leakage where a diaper is not used, or dampness where a diaper is used. For each one hour period of the 24 hour day, the percentage of days with incontinence was assessed as the number of days with incontinence occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 6 visit | 
| Percentage of Days With Incontinence for Each Hour of 24 Hour Day During Week 9 | Incontinence was defined as leakage where a diaper is not used, or dampness where a diaper is used. For each one hour period of the 24 hour day, the percentage of days with incontinence was assessed as the number of days with incontinence occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 9 visit | 
| Percentage of Days With Incontinence for Each Hour of 24 Hour Day During Week 12 | Incontinence was defined as leakage where a diaper is not used, or dampness where a diaper is used. For each one hour period of the 24 hour day, the percentage of days with incontinence was assessed as the number of days with incontinence occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 12 visit | 
| Percentage of Days With Incontinence for Each Hour of 24 Hour Day During Week 24 | Incontinence was defined as leakage where a diaper is not used, or dampness where a diaper is used. For each one hour period of the 24 hour day, the percentage of days with incontinence was assessed as the number of days with incontinence occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 24 visit | 
| Percentage of Days With Incontinence for Each Hour of 24 Hour Day During Week 36 | Incontinence was defined as leakage where a diaper is not used, or dampness where a diaper is used. For each one hour period of the 24 hour day, the percentage of days with incontinence was assessed as the number of days with incontinence occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 36 visit | 
| Percentage of Days With Incontinence for Each Hour of 24 Hour Day During Week 52 | Incontinence was defined as leakage where a diaper is not used, or dampness where a diaper is used. For each one hour period of the 24 hour day, the percentage of days with incontinence was assessed as the number of days with incontinence occurring within the one hour period divided by the number of valid diary days over all participants. Each participant contributed to up to three days of valid diary data for each visit. | 3 days prior to Week 52 visit | 
| Change From Baseline to Week 24 and 52 in Infant and Toddler Quality of Life Short Form-47 Questionnaire (ITQoL SF-47) - Overall Health Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Physical Abilities Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Growth and Development Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Pain Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Temperament and Moods Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Behaviour Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - General Health Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Change in Health Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Parent-Emotional Impact Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Parent-Time Impact Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 
| Change From Baseline to Week 24 and 52 in ITQoL SF-47 - Family Cohesion Impact Score | The ITQoL SF-47 consisted of 47 individual items and was filled in by the child's parent. The individual items are based on Likert scales with either 5 responses (coded as 1 through to 5) or 4 responses (coded as 1 through to 4). From subsets of these coded values, 11 scales are derived: overall health, physical activities, development, discomfort, moods and temperaments, perceptions of current past and future health and perception of changes. Each scale score ranges from 0 (worst possible) to 100 (best possible). | Baseline and Weeks 24, 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Efficacy, Safety, Solifenacin succinate suspension