Dolphin: A Study to Evaluate Mirabegron in Pediatric Participants From 5 to Less Than 18 Years of Age With Overactive Bladder (OAB)
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate the efficacy of mirabegron in children (5 to < 12 years of age) with OAB.
This study will also evaluate the safety and tolerability of mirabegron in pediatric participants with OAB and evaluate the pharmacokinetics after multiple dose administration of mirabegron in pediatric participants with OAB.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
The study consists 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Mirabegron Children (5 to <12 Years) Participants aged 5 to < 12 years will receive a daily pediatric equivalent dose (PED) low dose of IP (Investigational Product) orally on day 1/week 0 and will continue on this dose until day 28/week 4. At day 28/week 4, participants will receive a dose up-titration to PED high dose of IP unless the investigator determines that the participant is adequately treated for OAB at the PED low dose or if there are safety concerns identified and considered associated with the use of PED low dose. Participants that receive a dose up-titration may remain on the PED high dose until day 84/week 12, however, down-titration from PED high dose to PED low dose can be done at any time for safety reasons. |
Drug: Mirabegron
Oral/ Oral Suspension: Participants with a body weight of ≥ 35 kg are to receive the tablet form of IP unless unable to swallow tablets and will be provided the oral suspension as an alternative. Participants with a body weight < 35 kg or those who cannot be dosed with the tablet will receive oral suspension.
Other Names:
|
| Placebo Comparator: Placebo Children (5 to <12 Years) Participants aged 5 to < 12 years will receive a daily placebo to match PED low dose of IP orally on day 1/week 0 and will continue on this dose until day 28/week 4. At day 28/week 4, participants will receive a dose up-titration to placebo to match PED high dose of IP unless the investigator determines that the participant is adequately treated for OAB at the PED low dose or if there are safety concerns identified and considered associated with the use of PED low dose. Participants that receive a dose up-titration may remain on the PED high dose until day 84/week 12, however, down-titration from PED high dose to PED low dose can be done at any time for safety reasons. |
Drug: Placebo
Oral/ Oral Suspension
|
| Experimental: Mirabegron Adolescents (12 to <18 Years) Participants aged 12 to < 18 years will receive a daily PED low dose of IP orally on day 1/week 0 and will continue on this dose until day 28/week 4. At day 28/week 4, participants will receive a dose up-titration to PED high dose of IP unless the investigator determines that the participant is adequately treated for OAB at the PED low dose or if there are safety concerns identified and considered associated with the use of PED low dose. Participants that receive a dose up-titration may remain on the PED high dose until day 84/week 12, however, down-titration from PED high dose to PED low dose can be done at any time for safety reasons. |
Drug: Mirabegron
Oral/ Oral Suspension: Participants with a body weight of ≥ 35 kg are to receive the tablet form of IP unless unable to swallow tablets and will be provided the oral suspension as an alternative. Participants with a body weight < 35 kg or those who cannot be dosed with the tablet will receive oral suspension.
Other Names:
|
| Placebo Comparator: Placebo Adolescents (12 to <18 Years) Participants aged 12 to < 18 years will receive a daily placebo to match PED low dose of IP orally on day 1/week 0 and will continue on this dose until day 28/week 4. At day 28/week 4, participants will receive a dose up-titration to placebo to match PED high dose of IP unless the investigator determines that the participant is adequately treated for OAB at the PED low dose or if there are safety concerns identified and considered associated with the use of PED low dose. Participants that receive a dose up-titration may remain on the PED high dose until day 84/week 12, however, down-titration from PED high dose to PED low dose can be done at any time for safety reasons. |
Drug: Placebo
Oral/ Oral Suspension
|
Outcome Measures
Primary Outcome Measures
- Change from baseline to week 12/EoT in mean number of micturitions per 24 hours for age group 5 to <12 years [Baseline and week 12/EoT]
Participants will complete a 7-day bladder e-diary (2-day weekend and 5-day weekday diary), at least 7 days before each visit or TC. Micturition is defined as the passing of urine, in the 2-day weekend diary this will be recorded as the number of urination episodes where the volume of pee is greater than 0, in the 5-day weekday diary this will be recorded as the number of times the toilet is used during the day or night. The mean number of micturitions per 24 hours will be calculated by taking the sum of all urination episodes recorded in the participant diary, divided by the number of valid diary days.
Secondary Outcome Measures
- Change from baseline to week 12/EoT in mean volume voided per 24 hours for age group 5 to <12 years [Baseline and week 12/EoT]
Participants will complete a 7-day bladder e-diary (2-day weekend and 5-day weekday diary), at least 7 days before each visit or TC. Mean volume voided will be derived from the 2-day weekend diary, total volume voided divided by the number of micturitions.
- Change from baseline to week 12/EoT in maximum volume voided (MVV) for age group 5 to <12 years [Baseline and week 12/EoT]
Participants will complete a 7-day bladder e-diary (2-day weekend and 5-day weekday diary), at least 7 days before each visit or TC. MVV data will be derived from the 2-day weekend diary, maximum volume voided is largest (non-zero) volume recorded over both of the 2 measuring days.
- Change from baseline to week 12/EoT in mean number of daytime incontinence episodes per 24 hours for age group 5 to <12 years [Baseline and week 12/EoT]
Participants will complete a 7-day bladder e-diary (2-day weekend and 5-day weekday diary), at least 7 days before each visit or TC. A daytime incontinence episode is defined as the complaint of any involuntary leakage of urine during daytime hours. The mean number of daytime incontinence episodes per 24 hours will be calculated by taking the sum of all daytime urinary incontinence episodes recorded in the participant diary, divided by the number of valid diary days.
- Change from baseline to week 12/EoT in mean number of nighttime incontinence episodes per 24 hours for age group 5 to <12 years [Baseline and week 12/EoT]
Participants will complete a 7-day bladder e-diary (2-day weekend and 5-day weekday diary), at least 7 days before each visit or TC. A nighttime incontinence episode is defined as the complaint of any involuntary leakage of urine during nighttime hours. The mean number of nighttime incontinence episodes per 24 hours will be calculated by taking the sum of all nighttime urinary incontinence episodes recorded in the participant diary, divided by the number of valid diary days.
- Change from baseline to week 12/EoT in mean number of daytime micturitions per 24 hours for age group 5 to <12 years [Baseline and week 12/EoT]
Participants will complete a 7-day bladder e-diary (2-day weekend and 5-day weekday diary), at least 7 days before each visit or TC. A daytime micturition is defined as the passing of urine during the daytime hours, in the 2-day weekend diary this will be recorded as the number of urination episodes during the daytime hours where the volume of pee is greater than 0, in the 5-day weekday diary this will be recorded as the number of times the toilet is used during the day. The mean number of daytime micturitions per 24 hours will be calculated by taking the sum of all daytime urination episodes recorded in the participant diary, divided by the number of valid diary days.
- Number of dry (incontinence-free) days per 7 days at week 12/EoT for age group 5 to <12 years [Baseline and week 12/EoT]
Participants will complete a 7-day bladder e-diary (2-day weekend and 5-day weekday diary), at least 7 days before each visit or TC. A dry (incontinence free) day is defined as a day where the response is "Dry" to the question "How was your Day" and to "How was your Night". For a weekend day a "Dry (incontinence free) Day" is defined a day where no "New pee or leakage" is reported. Let Ddry be the number of valid diary days where the response to both questions was "Dry". Let Dwet be the number of valid diary days where the response to one of the two questions or to both questions was "Wet". If (Ddry + Dwet) > 3, the number of dry days per 7 days was calculated as Ddry/(Ddry + Dwet) x 7, otherwise the value was missing.
- Frequency of Adverse Events (AE) [Up to 14 weeks]
AEs will be coded using MedDRA. An AE is any untoward medical occurrence in a participant administered an IP, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP whether or not considered related to the IP. A serious adverse event (SAE) is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results a congenital anomaly/birth defect or other medically important event. The time frame reflects 12 weeks of treatment and 2 weeks of follow-up, up to 14 weeks.
- Severity of Adverse Events [Up to 14 weeks]
AEs will be coded using MedDRA. An AE is any untoward medical occurrence in a participant administered an IP, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP whether or not considered related to the IP. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results a congenital anomaly/birth defect or other medically important event. The time frame reflects 12 weeks of treatment and 2 weeks of follow-up, up to 14 weeks.
- Number of participants with laboratory value abnormalities and/or AEs [Up to 14 weeks]
Number of participants with potentially clinically significant laboratory values.
- Number of participants with vital sign abnormalities and/or AEs [Up to 14 weeks]
Number of participants with potentially clinically significant vital sign values.
- Number of participants with electrocardiogram (ECG) abnormalities and/or AEs [Up to 14 weeks]
Number of participants with potentially clinically significant ECG values.
- Change from baseline in postvoid residual (PVR) volume [Baseline and up to week 14/EoS]
PVR volume will be assessed by ultrasonography.
- Acceptability and palatability score (tablet) [At week 12/EoT]
Acceptability and palatability of tablet will be assessed via a questionnaire by participants receiving the tablet. The taste and how it was to swallow will be assessed using 5-point scales ranging in score from 0=Really bad/difficult to 4=Really good/easy.
- Acceptability and palatability score (oral suspension) [At week 12/EoT]
Acceptability and palatability of oral suspension will be assessed via a questionnaire by participants receiving the oral suspension. The taste, smell, how it was to take and how it was to prepare will be assessed using 5-point scales ranging in score from 0=Really bad/difficult to 4=Really good/easy.
- PK of mirabegron in plasma: Maximum concentration (Cmax) [Weeks 4 and 12 predose]
Cmax will be recorded from the PK plasma samples collected.
- PK of mirabegron in plasma: Time of the maximum concentration (Tmax) [Weeks 4 and 12 predose]
Tmax will be recorded from the PK plasma samples collected.
- PK of mirabegron in plasma: PK of mirabegron in plasma: Area under concentration-time curve over dosing interval (AUCtau) [Weeks 4 and 12 predose]
AUCtau will be recorded from the PK samples collected.
- PK of mirabegron in plasma: Concentration immediately prior to dosing (Ctrough) [Weeks 4 and 12 predose]
Ctrough will be recorded from the PK plasma samples collected.
- PK of mirabegron in plasma: Apparent total clearance (CL/F) [Weeks 4 and 12 predose]
CL/F will be recorded from the PK plasma samples collected.
- PK of mirabegron in plasma: Apparent volume of distribution (VzF) [Weeks 4 and 12 predose]
VzF will be recorded from the PK plasma samples collected.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Site BE32005 | Gent | Belgium | ||
| 2 | Site BE32002 | Kortrijk | Belgium | 8500 | |
| 3 | Site CA15006 | London | Ontario | Canada | ON N6A 5W9 |
| 4 | Site FR33003 | Amiens | France | 80000 | |
| 5 | Site FR33004 | Nice | France | 06200 | |
| 6 | Site DE49002 | Moenchengladbach | Germany | 41063 | |
| 7 | Site KR82004 | Yangsan-Si | Gyeongsangnamdo | Korea, Republic of | 50612 |
| 8 | Site KR82002 | Seoul | Seoul Teugbyeolsi | Korea, Republic of | 3080 |
| 9 | Site KR82003 | Seoul | Seoul Teugbyeolsi | Korea, Republic of | 3772 |
| 10 | Site KR82001 | Seoul | Seoul Teugbyeolsi | Korea, Republic of | 5505 |
| 11 | Site ML60002 | Kuala Lumpur | Malaysia | 50586 | |
| 12 | Site ML60001 | Kuala Lumpur | Malaysia | 59100 | |
| 13 | Site ML60003 | Penang | Malaysia | 10990 | |
| 14 | Site NL31001 | Deventer | Overijssel | Netherlands | 7416 SE |
| 15 | Site NO47001 | Bergen | Norway | ||
| 16 | Site PH63002 | Angeles City | Philippines | 2009 | |
| 17 | Site PH63004 | Cebu City | Philippines | 6000 | |
| 18 | Site PH63007 | Davao City | Philippines | 8000 | |
| 19 | Site PH63006 | Quezon City | Philippines | 1100 | |
| 20 | Site PH63001 | Quezon City | Philippines | 1105 | |
| 21 | Site PH63005 | Quezon City | Philippines | 1113 | |
| 22 | Site PL48001 | Piaseczno | Poland | 05-500 | |
| 23 | Site RU70004 | Moscow | Moskva | Russian Federation | 117997 |
| 24 | Site RU70001 | Kazan | Tatarstan, Respublika | Russian Federation | 420138 |
| 25 | Site RU70008 | Yekaterinburg | Russian Federation | 620134 | |
| 26 | Site ZA27003 | Pretoria | Gauteng | South Africa | 0001 |
| 27 | Site ES34003 | Santiago de Compostela | Spain | ||
| 28 | Site TR90003 | Mersin | Içel | Turkey | 33343 |
| 29 | Site TR90001 | Bursa | Turkey | 16059 | |
| 30 | Site UA38007 | Ivano-Frankivsk | Ukraine | 76014 | |
| 31 | Site UA38008 | Kharkiv | Ukraine | 61075 | |
| 32 | Site GB44004 | Reading | Berkshire | United Kingdom | RG1 5AN |
Sponsors and Collaborators
- Astellas Pharma Global Development, Inc.
Investigators
- Study Director: Medical Monitor, Astellas Pharma Global Development, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 178-CL-204
- 2016-001767-37