A Two-week Open-label Pharmacodynamic and Pharmacokinetic Study of Multiple Doses of a Darifenacin Liquid Oral Suspension in Children (2 - 15 Years) With Neurogenic Detrusor Overactivity

Study Overview
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Brief Summary
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This study will evaluate the pharmacodynamics and pharmacokinetics of darifenacin liquid oral suspension in children, ages 2-15 years, with neurogenic detrusor overactivity. The results will support a benefit-risk based dosage recommendation for phase IIIa clinical trials.

Official Title
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A 14-day, Open-label, Multicenter, Dose-escalating, Sequential Cohort Study to Evaluate Pharmacodynamics (Urodynamics) and Pharmacokinetics, Clinical Efficacy, Tolerability and Safety Following Multiple Doses (mg/kg/Day) of a Darifenacin Liquid Oral Suspension Given BID in Children, Ages 2 - 15 Years, With Neurogenic Detrusor Overactivity

Conditions
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Neurogenic Detrusor Overactivity

Intervention / Treatment
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* Drug: Darifenacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants ages 2-15 years Documented detrusor overactivity associated with a known neurological condition such as meningomyelocele or spinal cord injury, and confirmed by urodynamics at baseline Using clean intermittent catheterization (CIC) on a regular basis Participating in a bowel program on a regular basis Able to swallow the study medication in accordance to the protocol Participants and/or parent/guardian able to complete the bladder diary and follow the study procedures Exclusion Criteria: Treatment with drugs known to significantly affect the urinary bladder and urinary bladder outlet function Fecal impaction. Participants may be included, once this condition has resolved Clinically significant anatomical abnormalities or acquired disorders of the urinary tract Previous reconstructive surgery (augmentation etc.) of the bladder or bladder outlet Symptomatic urinary tract infection unresolved at time of urodynamic study and/or completion of bladder diary. Diabetes insipidus Electro stimulation therapy or bladder training within 2 weeks prior to Visit 1 and at any time during the study Concomitant diseases, in which the use of darifenacin is contraindicated History of hypersensitivity to darifenacin or to drugs with similar chemical structures Participants with any physical and cognitive impairment or any other condition which in the opinion of the investigator makes the participants unsuitable for inclusion Female adolescent of child-bearing potential, unless using an acceptable method of contraception Pregnant or nursing (lactating) female adolescents Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 15 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (Darifenacin 0.030 mg/kg/day)<br>Following a 7-day washout period, participants received darifenacin liquid oral suspension, 0.030 milligrams/kilogram/day (mg/kg/day) dispensed per twice a day (BID) dosing, for 14 days. | Drug: Darifenacin<br>* Following a 7-day washout period, participants received darifenacin liquid oral suspension up to 14 days.<br>* Other names: Enablex®, Emselex®, DAR328;|
| Experimental: Cohort 2 (Darifenacin 0.0625 mg/kg/day)<br>Following a 7-day washout period, participants received darifenacin liquid oral suspension, 0.0625 mg/kg/day dispensed per BID dosing, for 14 days. | Drug: Darifenacin<br>* Following a 7-day washout period, participants received darifenacin liquid oral suspension up to 14 days.<br>* Other names: Enablex®, Emselex®, DAR328;|
| Experimental: Cohort 3 (Darifenacin 0.125 mg/kg/day)<br>Following a 7-day washout period, participants received darifenacin liquid oral suspension, 0.125 mg/kg/day dispensed per BID dosing, for 14 days. | Drug: Darifenacin<br>* Following a 7-day washout period, participants received darifenacin liquid oral suspension up to 14 days.<br>* Other names: Enablex®, Emselex®, DAR328;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Maximum Bladder Capacity (MBC) | MBC was defined as the volume of urine at which significant urinary leakage (i.e. leakage that prevents further volume increase) or significant discomfort/pain occurs, or a detrusor pressure at 40 centimeter (cm) H2O was reached. | Baseline (Day 0) to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Volume at First Contraction | Average volume of urine collected by catheterization at first contraction. | Baseline (Day 0) to Day 14 | 
| Change From Baseline in Detrusor Pressure at First Contraction |  | Baseline (Day 0) to Day 14 | 
| Change From Baseline in Mean Volume at First Detectable Leakage | Average volume of urine collected by catheterization at first detectable leakage. | Baseline (Day 0) to Day 14 | 
| Change From Baseline in Mean Volume at 10, 20, 30, and 40 cm H2O Detrusor Pressure |  | Baseline (Day 0) to Day 14 | 
| Change From Baseline in Mean Catheterization Volume | Average volume of urine was collected by catheterization and was recorded in a bladder diary. Bladder volume was assessed by urodynamics. The bladder diary entries completed on any 2 consecutive days after completing wash-out and prior to the baseline urodynamic examination on Visit 2 was used to calculate the baseline (Day-1) i.e. Visit 2 values. Similarly, the bladder diary entries completed on any 2 consecutive days during the week prior to the final study visit on Day 14 i.e. Visit 4 was used to calculate the Visit 4 values. The positive change from baseline indicates improvement. | Baseline (Day -1) to 2 consecutive days during the week prior to final study Day 14 | 
| Change From Baseline in Total Pad Weight In-between Catheterizations | Urodynamic test was used to assess the total pad weight in-between catheterizations. The change in total pad weight in-between catheterizations was recorded in the bladder diary. The bladder diary entries completed on any 2 consecutive days after completing wash-out and prior to the baseline urodynamic examination on Visit 2 was used to calculate the baseline (Day-1) i.e. Visit 2 values. Similarly, the bladder diary entries completed on any 2 consecutive days during the week prior to the final study visit on Day 14 i.e. Visit 4 was used to calculate the Visit 4 values. The positive change from baseline indicates improvement. | Baseline (Day -1) to 2 consecutive days during the week prior to final study Day 14 | 
| Change From Baseline in Mean Catheterization Volume at First Awakening | The change in urine volume at first awakening catherization was recorded by the participant in a bladder diary. Bladder volume was assessed by urodynamics. The bladder diary entries completed on any 2 consecutive days after completing wash-out and prior to the baseline urodynamic examination on Visit 2 was used to calculate the baseline (Day-1) i.e. Visit 2 values. Similarly, the bladder diary entries completed on any 2 consecutive days during the week prior to the final study visit on Day 14 i.e. Visit 4 was used to calculate the Visit 4 values. The positive change from baseline indicates improvement. | Baseline (Day -1) to 2 consecutive days during the week prior to final study Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, Children, Urodynamics, Oral Suspension, Overactive bladder, Dose-finding, Neurogenic Detrusor Overactivity, Meningomyelocele, Spinal cord injury