A Study to Evaluate Mirabegron in Pediatric Participants From 5 to Less Than 18 Years of Age With Overactive Bladder (OAB) (Dolphin)

Astellas

Status and phase: Terminated; Phase 3

Conditions: Overactive Bladder (OAB); Pharmacokinetics of Mirabegron

Treatments: Drug: Placebo; Drug: Mirabegron

Study type: Interventional

Funder types: Industry

Identifiers

NCT04641975

178-CL-204

2016-001767-37 (EudraCT Number)

Details and patient eligibility

About

The purpose of this study was to evaluate the efficacy of mirabegron in children (5 to < 12 years of age) with OAB.

This study will also evaluated the safety and tolerability of mirabegron in pediatric participants with OAB and evaluated the pharmacokinetics after multiple dose administration of mirabegron in pediatric participants with OAB.

Full description

The study consisted of 3 periods (Screening period/urotherapy (4 weeks); Double-blind, placebo-controlled period (12 weeks); Follow-up period (2 weeks)) for a total duration of 18 weeks.

Enrollment: 26 patients

Sex: All

Ages: 5 to 17 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Subject has OAB defined according to the International Children's Continence Society (ICCS) criteria.

• Subject weighs at least 13 kg at screening.

• Subject is able to take the IP in accordance with the protocol.

• Subject agrees to drink an adequate fluid volume during urine collection weekends.

• Subject and subject's parent(s)/legal guardian(s) agree that the subject will not participate in another interventional study while participating in the present study.

• Subject and subject's parent(s)/legal guardian(s) are willing and able to comply with the study requirements and with the concomitant medication restrictions.

• Female subject is not pregnant and at least 1 of the following conditions apply:

  • Not a female of childbearing potential
  • Female of child bearing potential who agrees to follow the contraceptive guidance from the time of informed consent/assent through at least 30 days after final IP administration.

• Female subject must agree not to breastfeed starting at screening and throughout the study period and for 30 days after final IP administration.

• Female subject must not donate ova starting at first dose of IP and throughout the study period and for 30 days after final IP administration.

• Male subject with female partner(s) of childbearing potential (including breastfeeding partner[s]) must agree to use contraception throughout the treatment period and for 30 days after final IP administration.

• Male subject must agree not donate sperm during the treatment period and for 30 days after final IP administration.

• Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 30 days after final IP administration.

Additional Inclusion at Visit 3/Week 0 (Baseline)

• Subject must have a micturition frequency of at least 8 times (on average) per day, in the 7 days prior to visit 3/week 0 (baseline), as recorded in the bladder e-diary.
• Subject must have at least 1 daytime incontinence episode (on average) per day, during the 7-day period before visit 3/baseline, as recorded in the bladder e-diary.
• Subject whose symptoms are not satisfactorily controlled with urotherapy and still fulfills the inclusion/exclusion criteria will enter the study.

Exclusion criteria

Exclusion at Visit 1/Week -4 (Screening)

• Subject has extraordinary daytime only urinary frequency according to the ICCS definition.

  • This applies to a toilet-trained child who has the frequent need to void that is associated with small micturition volumes solely during the day.
  • The daytime voiding frequency is at least once per hour with an average voided volume of < 50% of expected bladder capacity (EBC) (typically 10% to 15%).
  • Incontinence is rare and nocturia is absent.

• Subject has an uroflow indicative of pathology other than OAB.

• Subject has monosymptomatic enuresis.

• Subject has dysfunctional voiding.

• Subject has bladder outlet obstruction, except if successfully treated.

• Subject has anatomical anomalies (surgically treated or untreated) that affect lower urinary tract function.

• Subject with hematuria on dipstick test. In the case of hematuria on dipstick test in a female during menstruation, the test can be repeated before randomization (after the end of menstruation).

• Subject with diabetes insipidus.

• Subject has kidney or bladder stones.

• Subject has suffered from chronic UTI or has had more than 3 UTIs in the 2 months prior to visit 1/week -4 (screening).

• Subject has stage 2 hypertension or subject has stage 1 hypertension that is not well controlled, as defined by the 2017 American Academy of Pediatrics Clinical Practice Guidelines.

• Subject has QT interval using Fridericia's correction formula (QTcF) > 440 msec on screening ECG, risk of QT prolongation (e.g., hypokalemia, long QT syndrome [LQTS] or family history of LQTS or exercise-induced syncope) or is currently taking medication known to prolong the QT interval.

• Subject's aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is ≥ 2 × upper limit of normal (ULN) or total bilirubin (TBL) is ≥ 1.5 × ULN according to age and sex (subjects with Gilbert's syndrome are excepted from the bilirubin threshold).

• Subject has mild or moderate renal impairment (estimated glomerular filtration rate according to the modified Schwartz of < 60 mL/min per 1.73 m^2).

• Subject has a symptomatic (symptoms can include pain, fever, hematuria, new onset foul-smelling urine) UTI. Note: if the UTI is treated successfully (clinical recovery: confirmed by dipstick test and repeated dipstick test after 14 days [both should be negative]), the subject can be rescreened.

• Subject has a history or presence of any malignancy.

• Subject uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates with a narrow therapeutic index or sensitive P-glycoprotein (P-gp) substrates, or moderate or strong cytochrome CYP3A4/5 or P-gp inhibitors or inducers after the start of washout.

• Subject is using or has used prohibited prior and/or concomitant medication(s) that cannot be discontinued.

• Subject has known or suspected hypersensitivity to mirabegron or any components of the formulations used.

• Subject has participated in another clinical study (and/or subject has received any investigational therapy within 30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is longer) prior to visit 1/week -4 (screening).

• Subject received urinary catheterization within 2 weeks prior to screening.

• Subject has constipation as defined by the Rome IV criteria that cannot be successfully treated prior to study entry.

• Female subject who has been pregnant within 6 months prior to screening or breastfeeding within 3 months prior to screening.

• Subject has any condition that makes the subject unsuitable for study participation.

Additional Exclusion at Visit 3/Week 0 (Baseline)

• Subject has extraordinary daytime only urinary frequency according to the ICCS definition based on the bladder e-diary.
• Subject has monosymptomatic enuresis confirmed by the bladder e-diary.
• Subject has a maximum voided volume (morning volume excluded) > expected bladder capacity (EBC) for age ([age +1] × 30) in mL, based on the bladder e-diary.
• Subject has polyuria defined as voided urine volumes of > 40 mL/kg baseline body weight during 24 hours or > 2.8 L urine for a child weighing ≥ 70 kg (ICCS definition), based on bladder e-diary.
• Subject has PVR volume > 20 mL (lowest PVR volume result) as measured by ultrasonography.
• Subject suffers from a symptomatic (symptoms can include pain, fever, hematuria, new onset foul-smelling urine) urinary tract infection (UTI). Note: if a symptomatic UTI is present, all visit 3/week 0 (baseline) assessments must be postponed until the UTI is successfully treated (clinical recovery: confirmed by dipstick test and repeated dipstick test after 14 days [both should be negative]), and the urotherapy should continue. The postponed visit 3/week 0 (baseline) should be within 14 days of the intended visit 3/week 0 (baseline).
• Subject with hematuria on dipstick test. In the case of hematuria on dipstick test in a female during menstruation, the test can be repeated before randomization (after the end of menstruation).
• Subject has a pulse > 99th percentile for age.
• Subject has stage 2 hypertension or subject has stage 1 hypertension that is not well controlled, as defined by the 2017 American Academy of Pediatrics Clinical Practice Guidelines.
• Any reason that makes the subject unsuitable for study participation.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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26 participants in 4 patient groups, including a placebo group

Mirabegron (5 to <12 Years)

Experimental group

Description:

Participants aged 5 to \< 12 years received initial dose of 25 milligram (mg) of mirabegron orally once daily based on weight (pediatric equivalent dose of 25 mg \[PED25\]) on day 1. Participants with a body weight ≥ 35 kilogram (kg) received tablet and participants with a body weight\< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the pediatric equivalent dose of 50 mg \[PED50\] based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

Treatment:

Drug: Mirabegron

Placebo (5 to <12 Years)

Placebo Comparator group

Description:

Participants aged 5 to \< 12 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight\< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

Treatment:

Drug: Placebo

Mirabegron (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. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight\< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

Treatment:

Drug: Mirabegron

Placebo (12 to <18 Years)

Placebo Comparator group

Description:

Participants aged 12 to \< 18 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight\< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

Treatment:

Drug: Placebo