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

Astellas

Status and phase: Completed; Phase 3

Conditions: Neurogenic Detrusor Overactivity

Treatments: Drug: Mirabegron

Study type: Interventional

Funder types: Industry

Identifiers

NCT02751931

2015-002876-25 (EudraCT Number)

178-CL-206A

Details and patient eligibility

About

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

Full 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).

Enrollment: 91 patients

Sex: All

Ages: 3 to 17 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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91 participants in 2 patient groups

Children (3 to < 12 Years)

Experimental group

Description:

Participants aged 3 to \< 12 years received initial dose of 25 milligram (mg) of mirabegron orally once daily based on weight (pediatric equivalent dose of 25 mg (milligram) \[PED25\]) on day 1. At weeks 2, 4 or 8, participant's were up-titrated to the pediatric equivalent dose of 50 mg in adults \[PED50\], orally once daily based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 end-of-study (EOS) or end-of-treatment (EOT).

Treatment:

Drug: Mirabegron

Adolescents (12 to < 18 Years)

Experimental group

Description:

Participants aged 12 to \< 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight \[PED25\] on day 1. At weeks 2, 4 or 8, participant's were up-titrated to the pediatric equivalent dose of 50 mg in adults \[PED50\] orally once daily based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT.

Treatment:

Drug: Mirabegron