Clinical trial NCT02751931: Open-label Phase 3 Study With Mirabegron in Children From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity
Official title: An Open-label, Baseline-controlled, Multicenter, Phase 3 Dose-titration Study Followed by a Fixed-dose Observation Period to Evaluate Efficacy, Safety and Pharmacokinetics of Mirabegron in Children and Adolescents From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity (NDO) on Clean Intermittent Catheterization (CIC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neurogenic Detrusor Overactivity
Keywords: Pediatrics
Urodynamics
Mirabegron
Phase 3
Neurogenic Detrusor Overactivity
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2016-04-26
Enrollment: 91
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 24
timeFrame: Baseline and week 24
Secondary outcomes:
measure: Change From Baseline in Bladder Compliance (ΔV/ΔP)
timeFrame: Baseline and weeks 4 and 24
measure: Change From Baseline in Maximum Cystometric Capacity at Week 4
timeFrame: Baseline and week 4
measure: Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cm H20) Until End of Filling
timeFrame: Baseline and weeks 4 and 24
measure: Change From Baseline in Detrusor Pressure at End of Filling
timeFrame: Baseline and weeks 4 and 24
measure: Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20)
timeFrame: Baseline and weeks 4 and 24
measure: Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Wilcoxon Signed-rank Test Updated Analysis
timeFrame: Baseline and weeks 4 and 24
measure: Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Paired T-test
timeFrame: Baseline and weeks 4 and 24
measure: Change From Baseline in Average Catheterized Volume Per Catheterization
timeFrame: Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
measure: Change From Baseline in Maximum Catheterized Volume
timeFrame: Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
measure: Change From Baseline in Maximum Catheterized Daytime Volume (MCDV)
timeFrame: Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
measure: Change From Baseline in Average Morning Catheterized Volume
timeFrame: Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
measure: Change From Baseline in Mean Number of Leakage Episodes Per Day
timeFrame: Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
measure: Change From Baseline in Mean Number of Leakage Episodes Per Day: Updated Analysis
timeFrame: Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
measure: Change From Baseline in Number of Dry Days Per 7 Days (Day and Night Time)
timeFrame: Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
measure: Change From Baseline in Pediatric Incontinence Questionnaire (PIN-Q) Score
timeFrame: Baseline and weeks 24 and 52
measure: Change From Baseline in Patient Global Impression of Severity Scale (PGI-S)
timeFrame: Baseline and weeks 24 and 52
measure: Number of Participants With Clinician Global Impression of Change (CGI-C)
timeFrame: Weeks 24 and 52
measure: Number of Participants With Study Drug Acceptability for Tablets at Week 4
timeFrame: Week 4
measure: Number of Participants With Study Drug Acceptability for Tablets at Week 24
timeFrame: Week 24
measure: Number of Participants With Study Drug Acceptability for Tablets at Week 52
timeFrame: Week 52
measure: Number of Participants With Study Drug Acceptability for Oral Suspension at Week 4
timeFrame: Week 4
measure: Number of Participants With Study Drug Acceptability for Oral Suspension at Week 24
timeFrame: Week 24
measure: Number of Participants With Study Drug Acceptability for Oral Suspension at Week 52
timeFrame: Week 52
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From the first dose of study drug administration up to end-of-treatment (EoT) (up to week 52)
measure: Maximum Plasma Concentration (Cmax) of Mirabegron
timeFrame: A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.
measure: Time to Reach Maximum Plasma Concentration of Mirabegron Following Drug Administration (Tmax)
timeFrame: A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) for Mirabegron
timeFrame: A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.
measure: Plasma Concentration of Mirabegron at the End of a Dosing Interval at Steady State (Ctrough)
timeFrame: A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.
measure: Apparent Total Clearance of Mirabegron From Plasma After Oral Administration (CL/F)
timeFrame: A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.
measure: Apparent Volume of Distribution After Non-intravenous Administration (Vz/F) of Mirabegron
timeFrame: A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.
Other outcomes:
Locations:
city: Randwick
country: Australia
facility: Site AU61002
state: New South Wales
city: Edegem
country: Belgium
facility: Site BE32004
city: Gent
country: Belgium
facility: Site BE32001
city: Zagreb
country: Croatia
facility: Site HR38501
city: Zagreb
country: Croatia
facility: Site HR38503
city: Aarhus N
country: Denmark
facility: Site DK45001
city: Copenhagen
country: Denmark
facility: Site DK45002
city: Jerusalem
country: Israel
facility: Site IL97202
city: Amman
country: Jordan
facility: Site JO96202
city: Irbid
country: Jordan
facility: Site JO96201
city: Seoul
country: Korea, Republic of
facility: Site KR82001
city: Seoul
country: Korea, Republic of
facility: Site KR82002
city: Riga
country: Latvia
facility: Site LV37101
city: Kaunas
country: Lithuania
facility: Site LT37002
city: Vilnius
country: Lithuania
facility: Site LT37001
city: Georgetown
country: Malaysia
facility: Site MY60001
city: Kuala Lumpur
country: Malaysia
facility: Site MY60002
city: Mexico City
country: Mexico
facility: Site MX52002
city: Bergen
country: Norway
facility: Site NO47001
city: Quezon City
country: Philippines
facility: Site PH63001
city: Gdansk
country: Poland
facility: Site PL48003
city: Gdansk
country: Poland
facility: Site PL48001
city: Warszawa
country: Poland
facility: Site PL48002
city: Bucuresti
country: Romania
facility: Site RO40002
city: Bucuresti
country: Romania
facility: Site RO40001
city: Nis
country: Serbia
facility: Site RS38102
city: Novi Sad
country: Serbia
facility: Site RS38101
city: Bratislava
country: Slovakia
facility: Site SK42101
city: New Taipei City
country: Taiwan
facility: Site TW88601
city: Ankara
country: Turkey
facility: Site TR90002
city: Bursa
country: Turkey
facility: Site TR90006
city: Mersin
country: Turkey
facility: Site TR90008
Study officials:
affiliation: Astellas Pharma Europe B.V.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Baka-Ostrowska M, Bolong DT, Persu C, Tondel C, Steup A, Lademacher C, Martin N. Efficacy and safety of mirabegron in children and adolescents with neurogenic detrusor overactivity: An open-label, phase 3, dose-titration study. Neurourol Urodyn. 2021 Aug;40(6):1490-1499. doi: 10.1002/nau.24657. Epub 2021 May 31.