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

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

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.

Study Overview

• Status: Terminated
• Conditions: Neurogenic Detrusor Overactivity
• Intervention / Treatment: Drug: Darifenacin

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Colombia
  • Bogota, Colombia
    • Fundacion Hospital Infantil, Universitario De San Jose
  • Cali, Colombia
    • Fundación Valle de Lili
  • Medellín, Colombia
    • Hospital Pablo Tobon Uribe
• United States
  • California
    • San Diego, California, United States, 92123
      • University of California at San Diego
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital, Karp 8210
  • Michigan
    • Detroit, Michigan, United States, 48201-2119
      • Children's Hospital of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Pediatric Urology
  • New York
    • Lake Success, New York, United States, 11042
      • Pediatric Urology Associates, PC
    • Tarrytown, New York, United States, 10591
      • Pediatric Urology Associates PC
  • Ohio
    • Akron, Ohio, United States, 44302
      • Pediatric & Adolescent Urology, Inc Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (Darifenacin 0.030 mg/kg/day); 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; Following a 7-day washout period, participants received darifenacin liquid oral suspension up to 14 days.; Other Names: Enablex®, Emselex®, DAR328
Experimental: Cohort 2 (Darifenacin 0.0625 mg/kg/day); 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; Following a 7-day washout period, participants received darifenacin liquid oral suspension up to 14 days.; Other Names: Enablex®, Emselex®, DAR328
Experimental: Cohort 3 (Darifenacin 0.125 mg/kg/day); 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; Following a 7-day washout period, participants received darifenacin liquid oral suspension up to 14 days.; Other Names: Enablex®, Emselex®, DAR328

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Warner Chilcott
• Investigators: Study Director: Herman Ellman, MD, Warner Chilcott (US) LLC

Study record dates

Study Major Dates

• Study Start (Actual): October 7, 2008
• Primary Completion (Actual): May 23, 2013
• Study Completion (Actual): May 23, 2013

Study Registration Dates

• First Submitted: July 3, 2008
• First Submitted That Met QC Criteria: July 3, 2008
• First Posted (Estimate): July 9, 2008

Study Record Updates

• Last Update Posted (Actual): June 9, 2022
• Last Update Submitted That Met QC Criteria: May 13, 2022
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Pediatric, Children, Urodynamics, Oral Suspension, Overactive bladder, Dose-finding, Neurogenic Detrusor Overactivity, Meningomyelocele, Spinal cord injury
• 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; Darifenacin
• Other Study ID Numbers: CDAR328B2201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No