| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language | | a sudden and uncontrollable urge to urinate (urinary incontinence) | |
| E.1.1.2 | Therapeutic area | Body processes [G] - Biological Phenomena [G16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10059617 | | E.1.2 | Term | Overactive bladder | | E.1.2 | System Organ Class | 100000004857 | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To evaluate the efficacy of mirabegron in children (5 to < 12 years of age) with OAB | |
| E.2.2 | Secondary objectives of the trial | ● To evaluate the efficacy of mirabegron in children (5 to < 12 years of age) with OAB
● To evaluate the safety and tolerability of mirabegron in pediatric subjects with OAB
● To evaluate the pharmacokinetics after multiple dose administration of mirabegron in pediatric subjects with OAB | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Inclusion at Visit 1/Week -4 (Screening)
2. Subject has OAB defined according to the ICCS criteria.
4. Subject weighs at least 13 kg at screening.
5. Subject is able to take the IP in accordance with the protocol.
6. Subject agrees to drink an adequate fluid volume during urine collection weekends, as instructed by the investigator.
7. 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.
8. 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.
9. At least 1 of the following conditions apply:
a. Not a female of childbearing potential
b. Female of childbearing potential who agrees to follow the contraceptive guidance from the time of informed consent/assent through at least 30 days after final IP administration.
10. Female subject must agree not to breastfeed starting at screening and throughout the study period and for 30 days after final IP administration.
11. 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.
12. 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.
13. Male subject must agree not to donate sperm during the treatment period and for 30 days after final IP administration.
14. 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)
15. 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.
16. 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.
17. Subject whose symptoms are not satisfactorily controlled with urotherapy and still fulfills the inclusion/exclusion criteria will enter the study. | |
| E.4 | Principal exclusion criteria | Exclusion at Visit 1/Week -4 (Screening)
1 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
2 an uroflow indicative of pathology other than OAB
3 monosymptomatic enuresis
4 dysfunctional voiding
5 bladder outlet obstruction, except if successfully treated
6 anatomical anomalies (surgically treated or untreated) that affect lower urinary tract function
7 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)
8 Subject with diabetes insipidus
9 kidney or bladder stones
10 suffered from chronic UTI or has had more than 3 UTIs in the 2 months prior to visit 1/week -4 (screening)
11 removed.
12 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
13 QTcF > 440 msec on screening ECG, a 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
14 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)
15 mild or moderate renal impairment (estimated glomerular filtration rate according to the modified Schwartz of < 60 mL/min per 1.73 m2)
16 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
17 a history or presence of any malignancy
18 uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates with a narrow therapeutic index, sensitive P-glycoprotein (P-gp) substrates, or moderate or strong cytochrome CYP3A4/5 or P-gp inhibitors or inducers after the start of washout
19 is using or has used prohibited prior and/or concomitant medication(s) that cannot be discontinued
20 known or suspected hypersensitivity to mirabegron or any components of the formulations used
21 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)
22 Subject received urinary catheterization within 2 weeks prior to screening
23 Constipation as defined by the Rome IV criteria that cannot be successfully treated prior to study entry
24 Female subject who has been pregnant within 6 months prior to screening or breastfeeding within 3 months prior to screening
25 any condition which makes the subject unsuitable for study participation
Additional Exclusion at Visit 3/Week 0 (Baseline)
26 extraordinary daytime only urinary frequency according to the ICCS definition based on the bladder e-diary
27 monosymptomatic enuresis confirmed by the bladder e-diary
28 a maximum voided volume (morning volume excluded) > EBC for age ([age +1] × 30) in mL, based on the bladder e-diary
29 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) [Austin et al, 2014], based on bladder e-diary
30 PVR volume > 20 mL (lowest PVR volume result) as measured by ultrasonography
31 Subject suffers from a symptomatic (symptoms can include pain, fever, hematuria, new onset foul-smelling urine) 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)
32 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)
33 a pulse > 99th percentile for age
34 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
35 Any reason that makes the subject unsuitable for study participation | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Change from baseline at the end of the 12-week treatment period: Mean number of micturitions per 24 hours | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | at the end of the 12-week treatment period | |
| E.5.2 | Secondary end point(s) | ● Change from baseline at the end of the 12-week treatment period:
○ Mean volume voided per 24 hours
○ Maximum volume voided
○ Mean number of daytime incontinence episodes per 24 hours
○ Mean number of nighttime incontinence episodes per 24 hours
○ Mean number of daytime micturitions per 24 hours
● Number of dry (incontinence-free) days per 7 days at the end of the 12-week treatment
● Nature, frequency and severity of AEs
● Clinical laboratory tests (hematology, biochemistry and urinalysis)
● Vital signs (blood pressure and pulse)
● Routine 12-lead ECG
● PVR volume
● Acceptability and palatability questionnaire
● Steady-state Cmax, AUCtau, Ctrough, Tmax, CL/F, and Vz/F. Additional parameters may be calculated based on the population
pharmacokinetic model used | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | throughout and at the end of the 12-week treatment period | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description | | sequential dose titration | |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Malaysia | | Philippines | | Ukraine | | Belgium | | Canada | | Denmark | | France | | Germany | | Italy | | Korea, Republic of | | Mexico | | Netherlands | | Norway | | Poland | | Russian Federation | | Serbia | | South Africa | | Spain | | Turkey | | United Kingdom | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
