Open-label Phase 3 Study With Mirabegron in Children From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity

Phase 3CompletedNCT02751931

Astellas Pharma Europe B.V.91 enrolled

Overview

The objective of the study was to evaluate the efficacy, safety, tolerability and pharmacokinetics of mirabegron after multiple-dose administration in the pediatric population.

This was a phase 3, open-label, baseline-controlled, multicenter study. The study consisted of 3 periods: Pretreatment period: for a maximum of 28 days before baseline, including screening, washout (if applicable) and baseline. Efficacy treatment period: beginning the day after baseline and continuing to week 24. Long-term safety period: beginning after week 24 and continuing to week 52 (end of study \[EOS\]), or to the end of treatment (EOT).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Neurogenic Detrusor Overactivity

Interventions

MirabegronDRUG

Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were up-titrated to PED50 based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT. Participants with a body weight \>=35 kg received mirabegron tablets or body weight \<35 kg received mirabegron oral suspension. At week 24, participants on mirabegron oral suspension could switch to tablets if the body weight became \>=35 kg or participants on mirabegron tablets could switch to oral suspension if the body weight became \<35 Kg or participants could switch to either of the dosage form for acceptability reasons after sponsor's prior approval and on a case-by-case basis. Mirabegron extended-release granules were reconstituted with water to prepare a mirabegron oral suspension of 8 mg/mL. Administration was via an oral syringe with a sip of water afterwards.

Eligibility

Sex: ALLMin age: 3 YearsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Subject has a body weight of greater than or equal to 11 kg. * Subject suffers from NDO confirmed by urodynamic investigation at baseline. The diagnosis of NDO must be confirmed by the presence of at least 1 involuntary detrusor contraction \> 15 cm H2O from baseline detrusor pressure, and/or a decrease in compliance leading to an increase in baseline detrusor pressure of \> 20 cm H2O. * Subject has been using CIC for at least 4 weeks prior to visit 1/screening. * Subject has a current indication for drug therapy to manage NDO. * Subject is able to take the study drug in accordance with the protocol Exclusion Criteria: * Subject has a known genitourinary condition (other than NDO) that may cause overactive contractions or incontinence or kidney/bladder stones or another persistent urinary tract pathology that may cause symptoms. * Subject has one of the following gastrointestinal problems: partial or complete obstruction, decreased motility such as paralytic ileus, subjects at risk of gastric retention. * Subject has a urinary indwelling catheter within 4 weeks prior to visit 1/screening. * Subject has a surgically treated underactive urethral sphincter * Subject has vesico-ureteral reflux grade 3 to 5. * Subject has undergone bladder augmentation surgery. * Subject receives electrostimulation therapy, if started within 30 days before visit 1/screening or is expected to start during the study period. Subjects who are on an established regimen may remain on this for the duration of the study. * Subject suffers from a symptomatic urinary tract infection (UTI) at baseline (symptomatic is defined as pain, fever, hematuria, new onset foul-smelling urine). If present at visit 1/screening or diagnosed between visit 1/screening and visit 3/baseline, the UTI should be treated successfully (clinical recovery) prior to baseline. If a symptomatic UTI is present at baseline, all baseline assessments are allowed to be postponed for a maximum of 7 days until the UTI is successfully treated (clinical recovery). * Subject has a (mean) resting pulse rate \> 99th percentile \[Fleming et al, 2011\]. * Subject has an established hypertension and a systolic or diastolic blood pressure greater than the 99th percentile of the normal range determined by sex, age and height, plus 5mmHg \[NIH 2005\]. * Subject has a risk of QT prolongation (e.g., hypokalemia, long QT syndrome \[LQTS\]; or family history of LQTS, exercise-induced syncope). * Subject has severe renal impairment (eGFR according to Larsson equation \< 30 mL/min). * Subject's aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is greater than or equal to 2 times the upper limit of normal (ULN) or total bilirubin (TBL) greater than or equal to 1.5 times the ULN according to age and sex. * Subject has a history or presence of any malignancy prior to visit 1/screening. * Subject has known or suspected hypersensitivity to mirabegron, any of the excipients used in the current formulations or previous severe hypersensitivity to any drug. * Subject has participated in another clinical trial (and/or has taken an investigational drug within 30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is longer) prior to visit 1/screening. * Subject uses any of the following prohibited medications (after start of washout): * Any medication, other than the study drug used, for the management of NDO; * Any drugs that are sensitive CYP2D6 substrates with a narrow therapeutic index or sensitive P-glycoprotein (P-gp) substrates * Any strong CYP3A4 inhibitors if the subject has a mild to moderate renal impairment (eGFR 30 - 89 mL/min). * Subject has been administered intravesical botulinum toxin; except if given \> 4 months prior to visit 1/screening and the subject experiences symptoms comparable to those existing prior to the botulinum toxin injections.

Locations (32)

Site AU61002

Randwick, New South Wales, Australia

Outcomes

Primary Outcomes

Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 24

Change from baseline in MCC was based on filling urodynamics (volume at the end of filling). During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. Missing MCC observations at week 24 were imputed using last observation carried forward (LOCF).

Time frame: Baseline and week 24

Secondary Outcomes

Change From Baseline in Bladder Compliance (ΔV/ΔP)

Bladder compliance was 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 compliance (change in volume/change in pressure) was assessed by the independent central reviewers and reported as annotations on the urodynamic trace and in an external database. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers.

Time frame: Baseline and weeks 4 and 24

Change From Baseline in Maximum Cystometric Capacity at Week 4

Time frame: Baseline and week 4

Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cm H20) Until End of Filling

Data from ClinicalTrials.gov

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Site BE32004

Edegem, Belgium

Site BE32001

Ghent, Belgium

Site HR38501

Zagreb, Croatia

Site HR38503

Zagreb, Croatia

Site DK45001

Aarhus N, Denmark

Site DK45002

Copenhagen, Denmark

Site IL97202

Jerusalem, Israel

Site JO96202

Amman, Jordan

Site JO96201

Irbid, Jordan

...and 22 more locations

Time frame: Baseline and weeks 4 and 24

Change From Baseline in Detrusor Pressure at End of Filling

Detrusor pressure was defined as bladder pressure minus intra-abdominal pressure as assessed by urodynamics. Filling was stopped (end of filling) when the detrusor pressure exceeded 100 cm H2O or was considered dangerously high by the investigator or urodynamicist (for instance, a prolonged passive detrusor pressure \> 40 cm H2O). During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers.

Time frame: Baseline and weeks 4 and 24

Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20)

Time frame: Baseline and weeks 4 and 24

Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Wilcoxon Signed-rank Test Updated Analysis

Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. If no detrusor contraction of \> 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity. This updated analysis is presented as the original analysis of bladder volume until first detrusor contraction (\> 15 cm H2O) did not impute missing bladder volume data with the maximum cystometric capacity (MCC) value at that visit according to the statistical analysis plan (SAP). This analysis was updated to impute missing values for volume at first contraction with respective MCC values.

Time frame: Baseline and weeks 4 and 24

Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Paired T-test

Time frame: Baseline and weeks 4 and 24

Change From Baseline in Average Catheterized Volume Per Catheterization

For each participant, the average catheterized volume per catheterization was calculated as the sum of all available/non-missing catheterized volumes recorded over 2 measuring days in the weekend diary, whether or not the 2 days were consecutive divided by the number of catheterizations with non-missing volumes. If volumes were recorded on 1 single day of the weekend diary, the average catheterized volume per catheterization was calculated using all available/non-missing catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend diary, the average catheterized volume per catheterization was missing. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume \>0 mL was recorded with complete date and time.