Clinical Trial Results:
A Multicentre, Open-label, Single Dose, Phase 1 Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Mirabegron Oral Suspension in Pediatric Subjects from 3 to
Less than 12 Years of Age with Neurogenic Detrusor Overactivity (NDO) or Overactive Bladder (OAB)
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Summary
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EudraCT number |
2015-000700-26 |
Trial protocol |
DK |
Global end of trial date |
30 Sep 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Apr 2017
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First version publication date |
05 Apr 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
178-CL-203
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Astellas Pharma Europe B.V.
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Sponsor organisation address |
Sylviusweg 62, Leiden, Netherlands, 2333 BE
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Public contact |
Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com
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Scientific contact |
Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000597-PIP02-10 EMEA-000597-PIP03-15 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Sep 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Sep 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the pharmacokinetics of mirabegron oral suspension after single dose
administration in children with NDO or OAB.
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Protection of trial subjects |
This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the fed ral, national and/or regional legislation related to the privacy and protection of personal information.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 Dec 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 5
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Country: Number of subjects enrolled |
Poland: 4
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Worldwide total number of subjects |
9
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EEA total number of subjects |
9
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
9
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Children were enrolled in sites in Denmark and Poland. | ||||||
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Pre-assignment
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Screening details |
Children with NDO aged 3 to less than 12 years of age and with OAB aged 5 to less than 12 years of age who gave assent or whose parents/legal guardians consented to enter this study and fulfilled all the eligibility criteria were enrolled. A wash-out of prohibited medication for 5 half-lives was performed if a participant was using them. | ||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Total (All participants) | ||||||
Arm description |
Participants received a single, weight-based dose of mirabegron on day 1. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Mirabegron
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Investigational medicinal product code |
YM178
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Other name |
Myrbetriq®, Betmiga™
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Pharmaceutical forms |
Granules for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received a single, weight-based dose of mirabegron, resulting in an exposure equivalent to steady state exposure to 50 mg prolonged-release tablets given once daily to adults. Participants were dosed under fed conditions (within 1 hour after completion of the light breakfast and were allowed to have a light lunch > 2 hours after dosing). Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL.
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Baseline characteristics reporting groups
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Reporting group title |
Total (All participants)
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Reporting group description |
Participants received a single, weight-based dose of mirabegron on day 1. | |||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Total (All participants)
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Reporting group description |
Participants received a single, weight-based dose of mirabegron on day 1. | ||
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End point title |
Maximum Concentration (Cmax) of Mirabegron [1] | ||||||||
End point description |
The analysis population was the Pharmacokinetic Analysis Set (PKAS) which consisted of participants from the Safety Analysis Set (SAF; consisted of all participants who took the dose of study medication) population for whom sufficient plasma concentration data were available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom date and time of dosing and sampling were known.
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End point type |
Primary
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End point timeframe |
Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Concentration-time Curve from Time Zero to Infinity (AUCinf) for Mirabegron [2] | ||||||||
End point description |
The analysis population was the PKAS.
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End point type |
Primary
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End point timeframe |
Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time After Dosing When Cmax Occurs (tmax) for Mirabegron [3] | ||||||||
End point description |
The analysis population was the PKAS.
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End point type |
Primary
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End point timeframe |
Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Terminal Elimination Half-life (t1/2) of Mirabegron [4] | ||||||||
End point description |
The analysis population was the PKAS.
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End point type |
Primary
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End point timeframe |
Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Concentration-time Curve from the Time of Dosing (Time Zero) to 24 Hours (AUC24) for Mirabegron [5] | ||||||||
End point description |
The analysis population was the PKAS.
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End point type |
Primary
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End point timeframe |
Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Concentration-time Curve from Time Zero to Last Measurable Concentration (AUClast) for Mirabegron [6] | ||||||||
End point description |
The analysis population was the PKAS.
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End point type |
Primary
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End point timeframe |
Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Oral Clearance (CL/F) for Mirabegron [7] | ||||||||
End point description |
The analysis population was the PKAS.
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End point type |
Primary
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End point timeframe |
Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent volume of Distribution (Vz/F) of Mirabegron [8] | ||||||||
End point description |
The analysis population was the PKAS.
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End point type |
Primary
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End point timeframe |
Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants with Adverse Events | ||||||||||||||||
End point description |
Safety was assessed by collecting AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, PVR volume, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A serious AE (SAE) was an event resulting in death, persistent or significant disability/incapacity or congenital anomaly or birth defect, was life-threatening, required or prolonged hospitalization or was considered medically important A treatment-emergent adverse event (TEAE) was defined as an AE observed after starting administration of the test drug, and no later than 7 days after the last dose of study drug received over the whole investigational period. The analysis population was the SAF.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug up to 30 days after last dose of study drug (up to 37 days)
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Taste | ||||||||||||||||||
End point description |
Acceptability (drug intake) and palatability (taste and smell) of mirabegron (oral suspension) was assessed using a 5-point VAS questionnaire, which was completed by the participant (or by parent/guardian based on input from the participant). The taste assessment scales ranged from "really bad" to "really good". Not available was regarded as response not available. The analysis population was the SAF.
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End point type |
Secondary
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End point timeframe |
Day 1
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Smell | ||||||||||||||||||
End point description |
Acceptability (drug intake) and palatability (taste and smell) of mirabegron was assessed using a 5-point VAS questionnaire, which was completed by the participant (or by parent/guardian based on input from the participant). The smell assessment scales ranged from "really bad" to "really good". Not available was regarded as response not available. The analysis population was the SAF.
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End point type |
Secondary
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End point timeframe |
Day 1
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Drug Intake | ||||||||||||||||||
End point description |
Acceptability (drug intake) and palatability (taste and smell) of mirabegron was assessed using a 5-point VAS questionnaire, which was completed by the participant (or by parent/guardian based on input from the participant). The smell assessment scales ranged from "really bad" to "really good". Not available was regarded as response not available. The analysis population was the SAF.
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End point type |
Secondary
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End point timeframe |
Day 1
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| No statistical analyses for this end point | |||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From first dose of study drug up to 30 days after last dose of study drug (up to 37 days)
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Assessment type |
Systematic | ||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||
Dictionary version |
16.0
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Reporting groups
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Reporting group title |
Total (All participants)
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Reporting group description |
Participants received a single, weight-based dose of mirabegron on day 1. | ||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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24 Nov 2015 |
In this global amendment, changes include: (1) The exclusion criterion for pulse rate has been amended to exclude subjects with a (mean) resting pulse rate > 99th percentile. The age-specific centiles used for heart rate in children were based on a systematic review of all studies, which measured these vital signs in healthy children. Taking into account the high variability in pulse rate in children, inclusion would become more feasible if this criterion was followed; (2) The exclusion criteria on systolic blood pressure (SBP) and diastolic blood pressure (DBP) have been combined and amended to exclude subjects with established hypertension and a SBP or DBP greater than the 99th percentile of their normal range determined by sex, age and height, plus 5 mmHg. The previous criteria on blood pressure rates were based on normal ranges in healthy children. However, children with spina bifida have a higher prevalence of hypertension. Therefore, the exclusion criteria had to be amended to allow inclusion of NDO subjects, but still exclude subjects with established hypertension; (3) It was amended that a serious adverse event (SAE) had to be reported to INC Research LCC and not to Astellas Pharma Europe BV; (4) The contact details for the Medical Monitor and the Medical Expert were updated; (5) The list of references was updated; (6) Minor administrative-type changes were implemented. |
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08 Jul 2016 |
In this global amendment, changes include: (1) The age range for the study population was expanded to include male and female children with NDO from 3 years to less than 12 years of age to enter the study, in order to fulfill the FDA Written Request requirement regarding age range for this study; (2) The protocol was amended to allow a total of 6 subjects with NDO in the study to fulfill an FDA Written Request stipulating that Study 178-CL-203 should include a total of 6 subjects with NDO. By allowing a total of 6 subjects with NDO (adding 3 NDO subjects to the already recruited group of subjects [3 NDO and 3 OAB]), this study was designed to fulfill both the Pediatric Investigation Plan and the FDA Written Request, without the need to setup a new study and expose more subjects. The total number of 9 subjects as indicated in the initially approved protocol was not exceeded. A subgroup analysis for the 6 subjects with NDO was added to the protocol to allow for separate reporting of the NDO data. Because subjects with NDO are more difficult to recruit, the planned study period was also prolonged; (3) The calculation of the estimated glomerular filtration rate (eGFR) according to the modified Schwartz formula was added to the protocol in line with the Advice/Information Request, dated 14 Mar 2016, which was received a few days before the FDA Written Request. The eGFR calculated using the Larsson equation was erroneously not listed amongst the laboratory parameters, but only mentioned in the exclusion criterion for the determination of the eGFR. This omission was corrected; (4)The procedure of reporting of expedited safety reports was updated to reflect the actual process. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
