E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
-neurogenic detrusor overactivity (NDO)
-overactive bladder (OAB) |
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E.1.1.1 | Medical condition in easily understood language |
-not being able to control urination (incontinence)
-strong urge to urinate |
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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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012547 |
E.1.2 | Term | Detrusor hyperreflexia |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059617 |
E.1.2 | Term | Overactive bladder |
E.1.2 | System Organ Class | 100000004857 |
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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 |
The primary objective of the trial is to evaluate the pharmacokinetics (PK) of mirabegron oral suspension after single dose administration in children with neurogenic detrusor overactivity (NDO) or overactive bladder (OAB). |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of the trial is:
- to evaluate the safety and tolerability of mirabegron oral suspension after single dose administration in children with NDO or OAB.
- to evaluate the acceptability and palatability of mirabegron oral suspension after single dose administration in children with NDO or OAB. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Screening:
1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent/Assent and privacy language as per national regulations (e.g., HIPAA Authorization for U.S. sites) must be obtained from the subject and from the subject’s parent(s) or legal guardian(s) prior to any study-related procedures (including discontinuation of prohibited medication, if applicable); assent by the subject is given as required by local law.
2. Subject is male or female from 3 to less than 12 years of age.
3. Subject has a documented diagnosis according to the International Children’s Continence Society ICCS criteria of: NDO, or Idiopathic OAB
4. Subject’s weight/height:
• Subject must have a body weight of ≥ 15.0 kg
• For NDO: subject is not suffering from malnutrition or is not grossly overweight, in the opinion of the Investigator
• For OAB: subject’s weight and height are within the normal percentiles (3rd to 97th percentile) according to Centers for Disease Control and Prevention (CDC) growth charts.
5. Subject is able to swallow the study medication in accordance with the protocol.
6. Subject and subject’s parent(s)/legal guardian agree that the subject will not participate in another interventional study while on treatment.
7. Subject and subject’s parent(s)/legal guardian are willing and able to comply with the studyrequirements and with the concomitant medication restrictions.
8. Female subject must:
• Be of non-childbearing potential: Clearly pre-menarchal or in the judgment of the Investigator is pre-menarchal
Or the following inclusion criteria are to be followed, if applicable (rare cases).
• Female subject that reached puberty must:
- Agree not to try to become pregnant during the study and for 28 days after the final study drug administration,
- And have a negative urine pregnancy test predose Day 1,
- And, if heterosexually active agree to consistently use 2 forms of highly effective form of birth control* starting at screening and throughout the study period and for 28 days after the final study drug administration |
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E.4 | Principal exclusion criteria |
1. Subject has a known history of QTc prolongation or risk of QT prolongation (e.g. hypokalemia, family history of Long QT Syndrome) and/or QTcB of > 460 ms.
2. Subject has a (mean) resting pulse rate > 99th percentile [Fleming et al, 2011].
3. Subject has any clinically significant ECG (electrocardiogram) abnormality.
4. 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 5 mmHg [NIH 2005].
5. Subject has any clinically significant or unstable medical condition or disorder which, in the opinion of the Investigator, precludes the subject from participating in the study.
6. Subject has current, untreated constipation (or fecal impaction for NDO subjects). If the constipation is being consistently treated for the last month, the subject can be included.
7. Subject has been administered intradetrusor botulinum toxin injections; except if given > 4months prior to screening and symptoms reappeared comparable to those before botulinum toxin injections.
8. Subject has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to 2 times the ULN or total bilirubin greater than or equal to 1.5 times the ULN.
9. Subject has severe renal impairment (estimated glomerular filtration rate < 30 mL/min (Larsson)).
10. Subject has any other clinically significant out of range results of urinalysis, biochemistry or hematology.
11. Subject has a history or current diagnosis of any malignancy.
12. Subject has known or suspected hypersensitivity to mirabegron, other ß3-agonists, any of the excipients used in the mirabegron oral suspension formulation or previous severe hypersensitivity to any drug.
13. Subject meets any of the contra indications or precautions for use of mirabegron listed in the Investigator’s Brochure (IB).
14. Subject has used mirabegron within 12 days of the planned Reference Day (Day -4 to Day -1).
15. Subject requires ongoing treatment with any of the following prohibited medications:
• Any anticholinergic/antimuscarinic drugs within 5 half-lives prior to planned Reference Day (Day -4 to Day -1).
• Any drugs that are sensitive CYP2D6 substrates with a narrow therapeutic index (such as thioridazine, flecainide, propafenone, imipramine, desipramine) and sensitive P-gp substrates (such as digoxin, dabigatran) within 5 half-lives prior to the planned Reference Day (Day -4 to Day -1).
• Any moderate or strong cytochrome CYP3A4/5 or P-gp inhibitors or inducers including natural and herbal remedies (such as itraconazole, rifampicin, phenytoin, carbamazepine, St.John’s Wort, grapefruit, Seville orange) within 4 weeks (inducers only) or 5 half-lives (inhibitors only) prior to the planned Reference Day (Day -4 to Day -1).
16. Subject has participated in another clinical trial and/or has taken an investigational drug within 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to the planned Reference Day (Day -4 to Day -1).
17. Subject’s parent(s)/legal guardian is an employee of the Astellas Group, any Contract Research Organization (CRO) involved, or the Investigator site executing the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetics of mirabegron:
Cmax, AUCinf, tmax, and t1/2 . Additional PK parameters may be calculated. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1, Day 2, Day 3-6, Day 4-7 |
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E.5.2 | Secondary end point(s) |
Safety:
Nature, frequency and severity of adverse events, clinical laboratory evaluations (hematology, biochemistry, urinalysis), vital signs (including 24-hr Holter HR (heart rate)), ECG (including interval measurements), post-void residual volume (PVR)
Acceptability and Palatability:
Taste and acceptance of the suspension (5-point scale) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety: Safety labs at screening and day 2 are required to be drawn. For any AE that may impact safety labs (e.g. a urinary tract infection) and occurs between Screening and Day 1, and/or Day 2 and EOS, an additional safety lab needs to be taken at Day 1 and/or the EOS visit respectively
Acceptability and Palatability: Day 1 (shortly after dosing) |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
tolerability, acceptability and palatability |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
paediatric phase I in patients |
|
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
|
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |