Open-label Phase 3 Study With Mirabegron in Children From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity
Condition: Neurogenic Detrusor Overactivity
MeSH terms: Urinary Bladder, Overactive
Intervention: Mirabegron
Intervention description: 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.
Intervention MeSH terms: Mirabegron
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 91.0
Sex: All
Minimum age: 3 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Pediatrics; Urodynamics; Mirabegron; Phase 3; Neurogenic Detrusor Overactivity

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.
    

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.