Clinical Trials Register

Summary
EudraCT Number:	2014-001446-24
Sponsor's Protocol Code Number:	178-CL-201
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-08-06
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2014-001446-24

A.3

Full title of the trial

A Phase 1, Single Dose, 4-Period Crossover Study to Assess the Bioavailability of an Mirabegron Oral Suspension Relative to the Mirabegron Prolonged Release Tablet and to Assess the Effect of Food on the Pharmacokinetics of Mirabegron Oral Suspension in Healthy Young Male and Female Subjects

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to compare the mirabegron concentrations in blood after administration of mirabegron as tablet and oral suspension in healthy subjects and to evaluate the food effect

A.4.1

Sponsor's protocol code number

178-CL-201

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/11/2014

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Astellas Pharma Europe B.V.
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Astellas Pharma Europe B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Astellas Pharma Europe B.V.
B.5.2	Functional name of contact point	Service Desk -Global Clinical Dev't
B.5.3	Address:
B.5.3.1	Street Address	Sylviusweg 62
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 BE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31715455050
B.5.5	Fax number	+31715455501
B.5.6	E-mail	contact@nl.astellas.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Betmiga
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Betmiga
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mirabegron
D.3.9.1	CAS number	223673-61-8
D.3.9.3	Other descriptive name	mirabegron
D.3.9.4	EV Substance Code	SUB32690
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Mirabegron (YM178)
D.3.4	Pharmaceutical form	Oral suspension
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mirabegron
D.3.9.1	CAS number	223673-61-8
D.3.9.3	Other descriptive name	mirabegron
D.3.9.4	EV Substance Code	SUB32690
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

No medical indication will be investigated as only healthy subjects will be included.

E.1.1.1

Medical condition in easily understood language

No medical indication will be investigated as only healthy subjects will be included.

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10059617
E.1.2	Term	Overactive bladder
E.1.2	System Organ Class	100000004857

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the bioavailability of 50 mg mirabegron oral suspension relative to that of the 50 mg mirabegron modified release tablet when dosed under fasted conditions.

E.2.2

Secondary objectives of the trial

- To assess the effect of food on the pharmacokinetics of 50 mg mirabegron oral suspension.
- To evaluate the safety and tolerability of single doses of 50 mg mirabegron oral suspension under fed and fasted conditions.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Independent Ethics Committee-approved written informed consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures(including withdrawal of prohibited medication, if applicable).
2. Subject is a healthy male or female subject aged 18 to less than 26 years of age at screening.
3. Subject has a body mass index of 18.5 to 29.9 kg/m2 inclusive.
4. Female subject must:
a) Agree not to try to become pregnant during the study and for 28 days after the final study drug administration.
b) Have a negative serum pregnancy test at day -1.
c) And, if heterosexually active, agree to consistently use 2 forms of highly effective birth control† starting at screening and throughout the clinical study period, and for 28 days after the final study drug administration. ††
5. Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 28 days after the final study drug administration.
6. Female subject must not donate ova starting at screening and throughout the study period, and for 28 days after the final study drug administration.
7. Subject agrees not to participate in another interventional study while participating in the present study, defined as signing the informed consent form until completion of the last study visit.
† Highly effective forms of birth control include:
- Consistent and correct usage of established oral contraception.
- Injected or implanted hormonal methods of contraception.
- Established intrauterine device or intrauterine system.
- Any male partner that has undergone effective surgical sterilization.
- Any female partner that has undergone effective surgical sterilization.
†† Barrier methods of birth control includes:
- Condom with spermicidal foam/gel/film/cream/suppository.
- Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/ cream/suppository.
Note: the combination of condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository is not considered as a highly effective form of birth control.

E.4

Principal exclusion criteria

1. Female subject who has been pregnant within 6 months prior to screening assessment or breastfeeding within 3 months prior to screening.
2. Subject has a known or suspected hypersensitivity to mirabegron or any components of the formulations used.
3. Subject has any of the liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], gamma glutamyl transferase [GGT], total bilirubin [TBL]) above 1.5 times the upper limit of normal. In such a case the assessment may be repeated once [day -1 of the first treatment period].
4. Subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
5. Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrine, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal, and/or other major disease or malignancy, as judged by the Investigator.
6. Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (noncutaneous) infection within 1 week prior to admission to the clinical unit [day -1 of the first treatment period].
7. Subject has any clinically significant abnormality following the Investigator’s review of the physical examination, electrocardiogram (ECG) and clinical study protocol-defined clinical laboratory tests at screening or day -1 of the first treatment period.
8. Subject has a mean heart rate (HR) < 50 or > 90 beats per minute; mean systolic blood pressure > 140 mmHg; mean diastolic blood pressure (DBP) > 90 mmHg (vital sign measurements taken in triplicate after subject has been resting in supine position for 5 minutes; HR will be measured automatically). If the mean HR, SBP or DBP exceeds the limits above, 1 additional assessment can be taken [day -1 of the first treatment period).
9. Subject has a mean QTc(F) interval of > 430 ms (for males) and > 450 ms (for females) at day -1 of the first period. If the mean QTc(F) exceeds the limits above, 1 additional triplicate ECG can be taken [day -1 of the first treatment period].
10. Subject uses any prescribed or non-prescribed drugs (vitamins, natural and herbal remedies [e.g., St. John’s Wort]) in the 2 weeks (or 5 elimination half-lives, whichever is longer) prior to study drug administration, except for occasional use of paracetamol (up to 2 g/day), oral contraceptives or hormone replacement therapy.
11. Subject consumes products containing grapefruit or Seville orange in the 2 weeks prior to study drug administration.
12. Subject has a history of smoking more than 10 cigarettes (or equivalent amount of tobacco) per day within 3 months prior to admission to the clinical unit.
13. Subject has a history of drinking more than 21 units of alcohol per week (1 unit = 10 g pure alcohol = 250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine [12%]) (> 14 units of alcohol for female subjects) within 3 months prior to admission to the clinical unit.
14. Subject uses any drugs of abuse within 3 months prior to admission to the clinical unit.
15. Subject has significant blood loss, donated one unit (500 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to admission to the clinical unit.
16. Subject has a positive serology test for hepatitis B surface antigen [HBsAG], hepatitis A virus antibodies (immunoglobulin M) [anti-HAV (IgM)], hepatitis C virus antibodies [anit-HCV], or antibodies to human immunodeficiency virus type [1 HIV-1) and/or type 2 [HIV-2) at screening.
17. Subject participated in any study or has been treated with any investigational drugs within 90 days or 5 half-lives whichever is longer, prior to screening.
18. Subject is unable to communicate, read and understand German, or any other condition which, in the Investigator’s opinion, makes the subject unsuitable for study participation.
19. Subject is a vulnerable subject (e.g., subject kept in detention).
20. Subject is an employee of the Astellas Group or clinical research organization involved in the study.

E.5 End points

E.5.1

Primary end point(s)

Pharmacokinetic parameters for mirabegron (plasma) after administration of mirabegron as modified release tablet or oral suspsension under fasted condition:
AUCinf, AUClast, Cmax

E.5.1.1

Timepoint(s) of evaluation of this end point

starting at 30min post-dose up to 240 h post-dose

E.5.2

Secondary end point(s)

Pharmacokinetics:
Pharmacokinetic parameters for mirabegron (plasma) after administration of mirabegron as oral suspsension under fed or fasted condition:
AUC(%extrap), CL/F, lambdaz, MRTinf, t½, tlag, tmax, Vz/F

Safety:
● Nature, frequency and severity of AEs
● Vital signs (blood pressure, pulse rate, body temperature)
● Safety laboratory tests (biochemistry, hematology and urinalysis)
● Routine ECG

Palatability
● Questionnaire including VAS

E.5.2.1

Timepoint(s) of evaluation of this end point

Pharmacokinetics: starting at 30min post-dose up to 240h post-dose

Safety: specific timepoints, as well as ongoing throughout the study.

Palatability: Day 1 after administration of oral suspension

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

food effect, bioavailability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

food effect, bioavailability

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-10-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-08-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-01-22

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