Clinical trial NCT04501640
Conditions: Pharmacokinetics of Mirabegron Food Effect Healthy Chinese Subjects
Keywords: mirabegron pharmacokinetics two-way crossover
Sponsor: Astellas Pharma China, Inc.
Start date: 2020-09-21; Completion date: 2020-10-27
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study determined the effect of food on the pharmacokinetics (PK) of single oral doses of mirabegron in healthy Chinese male and female participants.

This study also evaluated the safety and tolerability of single oral doses of mirabegron in healthy Chinese male and female participants.

Detailed description:
An open-label, randomized, 2-period, single oral dose crossover design at 2 dose levels in healthy Chinese male and female participants. Each participant took part in 2 periods separated by a washout of at least 10 days between investigational product (IP) administrations in each period.

Participants were screened for up to 21 days prior to IP administration on day 1 of period 1. Eligible participants were admitted to the clinical unit on day -1 of each period and were confined until the last pharmacokinetic sample had been drawn within each period. PK samples were collected predose on day 1 of each period and at multiple time points following each dose.

Arms: arm 1: Participants received single dose of 25 mg mirabegron tablet under fed condition orally, on day 1 of period 1 followed by single dose of 25 milligram (mg) mirabegron tablet under fasted condition orally, on day 1 of period 2. A washout period of 10 days was maintained between the mirabegron administrations in each period. arm 2: Participants received single dose of 25 mg mirabegron tablet under fasted condition orally, on day 1 of period 1 followed by single dose of 25 mg mirabegron tablet under fed condition orally, on day 1 of period 2. A washout period of 10 days was maintained between the mirabegron administrations in each period. arm 3: Participants received single dose of 50 mg mirabegron tablet under fed condition orally, on day 1 of period 1 followed by single dose of 50 mg mirabegron tablet under fasted condition orally, on day 1 of period 2. A washout period of 10 days was maintained between the mirabegron administrations in each period. arm 4: Participants received single dose of 50 mg mirabegron under fasted condition orally, on day 1 of period 1 followed by single dose of 50 mg mirabegron tablet under fed condition orally, on day 1 of period 2. A washout period of 10 days was maintained between the mirabegron administrations in each period.
Interventions: intervention 1: mirabegron
Intervention descriptions: intervention 1: Oral adminstration

Protocol documents:
Prot_000.pdf: 
Sponsor: ACN
ISN/Protocol 178-MA-2294
- CONFIDENTIAL -
17 Sep 2020
Astellas
Page 1 of 72
Version 1.3 Incorporating Nonsubstantial Amendment 3
A Phase 4 Open-label, Randomized, Single Oral Dose, Two-way 
Crossover Study to Investigate the Effect of Food on the 
Pharmacokinetics of Mirabegron in Healthy Chinese Subjects
ISN/Protocol 178-MA-2294
Version 1.3
Incorporating Nonsubstantial Amendment 3 [See Section 13]
17 Sep 2020
Sponsor:
Astellas Pharma China, Inc.
No. 3 Jia 6 Road 10, Shenyang Economic and Technological Development 
Zone, Shenyang City, Liaoning Province, The People’s Republic of China
Protocol History:
Version 1.0 Original [17 Feb 2020]
Version 1.1 Incorporating Nonsubstantial Amendment 1 [19 Mar 2020]
Version 1.2 Incorporating Nonsubstantial Amendment 2 [21 May 2020]
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information, which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research subject; and (4) where disclosure of such information is made to a member of the investigator’s team 
who agrees to hold this information in confidence.
NCT04501640


Sponsor: ACN
ISN/Protocol 178-MA-2294
- CONFIDENTIAL -
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Version 1.3 Incorporating Nonsubstantial Amendment 3
Table of Contents
SIGNATURES································································································ 7
CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL ······································ 9
1
PROTOCOL SUMMARY·······································································10
1.1
Synopsis························································································10
1.2
Study Schema··················································································16
1.3
Schedule of Assessments·····································································17
2
INTRODUCTION·················································································19
2.1
Background ····················································································19
Nonclinical and Clinical Data··························································20
Summary of Key Safety Information for Investigational Product(s)··············22
2.2
Study Rationale················································································23
2.3
Risk Benefit Assessment ·····································································23
3
STUDY OBJECTIVE(S) AND ENDPOINT(S)··············································23
4
STUDY DESIGN AND DOSE RATIONALE················································24
4.1
Study Design···················································································24
4.2
Dose Rationale ················································································24
4.3
End of Study Definition ······································································24
5
STUDY POPULATION··········································································25
5.1
Inclusion Criteria··············································································25
5.2
Exclusion Criteria ·············································································26
5.3
Restrictions During the Study ·······························································27
Exercise···················································································27
Smoking ··················································································28
Dietary and Fluid Restrictions ·························································28
5.4
Screen Failures ················································································28
Rescreening ··············································································28
6
INVESTIGATIONAL PRODUCT(S) ·························································29
6.1
Investigational Product(s) Administered ···················································29
6.2
Preparation/Handling/Storage/Accountability·············································29
Packaging and Labeling ································································29
Handling, Storage and Accountability ················································30


Sponsor: ACN
ISN/Protocol 178-MA-2294
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6.3
Randomization and Blinding ································································30
Blinding Method·········································································30
Assignment and Allocation·····························································30
6.3.2.1
Subject Number····································································30
6.3.2.2
Randomization Number···························································30
6.4
Investigational Product(s) Compliance·····················································31
6.5
Previous and Concomitant Treatment (Medication and Nonmedication Therapy)····31
Previous Treatment (Medication and Nonmedication Therapy)···················31
Concomitant Treatment (Medication and Nonmedication Therapy)··············31
6.6
Dose Modification ············································································32
6.7
Criteria for Continuation of Dosing·························································32
7
STUDY PROCEDURES AND ASSESSMENTS ············································32
7.1
Efficacy Assessments·········································································32
7.2
Safety Assessments ···········································································32
Adverse Events ··········································································32
Laboratory Assessments································································32
Vital Signs················································································33
Physical Examination ···································································33
Electrocardiogram·······································································33
7.2.5.1
Routine 12-lead Electrocardiogram ·············································33
Order of Assessments···································································33
7.3
Adverse Events and Other Safety Aspects ·················································34
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information···············································································34
Method of Detecting Adverse Events and Serious Adverse Events···············34
Follow-up of Adverse Events··························································34
Reporting of Serious Adverse Events·················································35
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ··········································35
Adverse Events of Special Interest ····················································35
Special Situations········································································35
Supply of New Information Affecting the Conduct of the Study··················36
Urgent Safety Measures ································································36
Reporting Urgent Safety Measures····················································36
7.4
Pharmacokinetics··············································································36


Sponsor: ACN
ISN/Protocol 178-MA-2294
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Analysis of Mirabegron in Plasma ····················································36
7.5
Pharmacodynamics | Immunogenicity······················································37
7.6
Electronic Clinical Outcome Assessment ··················································37
7.7
Other Assessments ············································································37
7.8
Total Amount of Blood·······································································37
8
DISCONTINUATION············································································37
8.1
Discontinuation of Individual Subject(s) From Study Dosing···························37
8.2
Discontinuation of Individual Subject(s) From Study ····································38
Lost to Follow-up········································································38
8.3
Discontinuation of the Study Site ···························································38
8.4
Discontinuation of the Study·································································38
9
STATISTICAL METHODOLOGY ···························································38
9.1
Sample Size····················································································39
9.2
Analysis Sets···················································································39
Safety Analysis Set······································································39
Pharmacokinetic Analysis Set ·························································39
9.3
Demographics and Baseline Characteristics ···············································39
Demographics············································································39
Subject Disposition······································································39
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ··················································································39
Medical History··········································································40
Investigational Product Exposure ·····················································40
9.4
Analysis of Efficacy ··········································································40
9.5
Analysis of Safety·············································································40
Adverse Events ··········································································40
Laboratory Assessments································································40
Vital Signs················································································40
Electrocardiogram·······································································40
9.5.4.1
Routine 12-lead Electrocardiogram ·············································40
9.6
Analysis of Pharmacokinetics ·······························································41
Plasma Concentrations··································································41
Estimation of Pharmacokinetic Parameters ··········································41


Sponsor: ACN
ISN/Protocol 178-MA-2294
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Statistical Analysis of Pharmacokinetic Parameters ································41
9.7
Analysis of Pharmacodynamics | Immunogenicity········································41
9.8
Other Analyses ················································································41
9.9
Major Protocol Deviations ···································································41
9.10
Interim Analysis (and Early Discontinuation of the Study)······························42
9.11
Additional Conventions ······································································42
10
OPERATIONAL CONSIDERATIONS·······················································42
10.1
Data Collection················································································42
10.2
Demographics and Baseline Characteristics ···············································42
Demographics············································································42
Medical History··········································································42
10.3
Major Protocol Deviations ···································································42
10.4
Study organization ············································································43
Independent Data Monitoring Committee | Data and Safety Monitoring 
Board | Monitoring Committee | Adjudication Committee | Other 
Evaluation Committee(s) ·······························································43
Other Study Organization ······························································43
11
REFERENCES ····················································································44
12
APPENDICES ·····················································································46
12.1
Ethical, Regulatory and Study Oversight Considerations ································46
Ethical Conduct of the Study···························································46
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities················································································46
Protocol Amendment and/or Revision················································46
Financial Disclosure ····································································47
Informed Consent of Subjects ·························································47
12.1.5.1
Subject Information and Consent················································47
12.1.5.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························47
Source Documents ······································································48
Record Retention ········································································48
Subject Confidentiality and Privacy···················································48
Arrangement for Use of Information and Publication of the Study ···············49
Signatory Investigator for Clinical Study Report····································49


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12.2
Procedure for Study Quality Control ·······················································50
Study Monitoring········································································50
Direct Access to Source Data/Documents············································50
Data Management ·······································································50
Quality Assurance·······································································50
12.3
Contraception Requirements·································································52
12.4
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up and Reporting ··············································································54
Definition of Adverse Events ··························································54
12.4.1.1
Abnormal Laboratory Findings ··················································54
12.4.1.2
Potential Cases of Drug-induced Liver Injury··································54
Definition of Serious Adverse Events·················································54
Criteria for Causal Relationship to Investigational Product························55
Criteria for Defining the Severity of an Adverse Event ····························56
Reporting Procedures for Serious Adverse Events··································56
Reporting Procedures for Special Situations·········································58
12.4.6.1
Pregnancy···········································································58
12.4.6.2
Medication Error, Overdose and “Off-label Use” ·····························58
12.4.6.3
Misuse/Abuse ······································································59
12.4.6.4
Occupational Exposure ···························································59
12.4.6.5
Suspected Drug-drug Interaction ················································59
12.5
Liver Safety Monitoring and Assessment ··················································60
12.6
List of Excluded Concomitant Medications················································63
12.7
Laboratory Assessments······································································64
12.8
List of Abbreviations and Definition of Key Study Terms·······························66
13
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 3····························69
14
SPONSOR’S SIGNATURES····································································72


Sponsor: ACN
ISN/Protocol 178-MA-2294
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17 Sep 2020
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SIGNATURES
1.  SPONSOR’S SIGNATURES
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 14
Sponsor’s Signatures].


Sponsor: ACN
ISN/Protocol 178-MA-2294
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2.  INVESTIGATOR’S SIGNATURE
A Phase 4 Open-label, Randomized, Single Oral Dose, Two-way Crossover Study to 
Investigate the Effect of Food on the Pharmacokinetics of Mirabegron in Healthy 
Chinese Subjects
ISN/Protocol 178-MA-2294
Version 1.3
Incorporating Nonsubstantial Amendment 3
17 Sep 2020
I have read all pages of this protocol for which Astellas is the sponsor. I agree to conduct 
the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulations. I will also 
ensure that subinvestigator(s) and other relevant members of my personnel have access to 
copies of this protocol and the ICH GCP guidelines to enable them to work in accordance 
with the provisions of these documents.
Principal Investigator:
Signature:
Date (DD Mmm YYYY)
Printed Name:
Address:


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CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL
Contact information for the Sponsor 
Corporate name: Astellas Pharma China, Inc.
Location: 27th Floor, Beijing IFC Tower, No. 8 Jianguomenwai Avenue, Chaoyang District, 
Beijing 100022, People’s Republic of China
Fax number: +86-010-85214903
Sponsor’s personnel:
Medical Manager: 
[Contact numbers during nonbusiness hours and for emergency]:
Telephone number: +
Contact information for the contract research organization
Corporate name: PAREXEL China Co., Ltd
Location: 20th Floor, Taiping Finance Tower, No. 488 Middle Yincheng Road, Pilot Free 
Trade Zone, Shanghai 200120, People’s Republic of China
Telephone number: +86-010-57631671
Fax number: +86-010-58797672
Contract research organization’s personnel: 
[Contact numbers during nonbusiness hours and for emergency]: 
Telephone number: +
PPD
PPD
PPD
PPD


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1
PROTOCOL SUMMARY
1.1
Synopsis
Date and Version of Protocol Synopsis:
17 Sep 2020 Version 1.3
Sponsor:
Astellas Pharma China, Inc. (ACN)
Protocol Number:
178-MA-2294
Compound Name:
Mirabegron
Phase of Development:
Phase 4
Title of Study:
A Phase 4 Open-label, Randomized, Single Oral Dose, Two-way Crossover Study to Investigate 
the Effect of Food on the Pharmacokinetics of Mirabegron in Healthy Chinese Subjects
Planned Study Period:
3Q2020 to 1Q2021
Study Objectives and Endpoints:
The primary, secondary and exploratory objectives and endpoints for this study are listed in the 
table below.
Study Objectives and Endpoints
Objectives
Endpoints
Primary
●
To determine the effect of food on the 
pharmacokinetics of single oral doses of 
mirabegron in healthy Chinese male and 
female subjects
●
Mirabegron plasma: AUCinf, AUClast and Cmax
Secondary
●
To evaluate the safety and tolerability of 
single oral doses of mirabegron in healthy 
Chinese male and female subjects
●
Nature, frequency and severity of AEs
●
Clinical laboratory tests (biochemistry, 
hematology and urinalysis)
●
Vital signs (blood pressure, body temperature
and pulse)
●
Routine 12-lead ECG
Exploratory
●
To evaluate the pharmacokinetics of single 
oral doses of mirabegron in healthy Chinese 
male and female subjects
●
Mirabegron plasma: AUCinf(%extrap), CL/F, 
t½, tmax, tlag and Vz/F
AE: adverse event; ECG: electrocardiogram
Planned Total Number of Study Sites and Location(s):
One study site in The People’s Republic of China
Study Population:
Healthy Chinese male and female subjects (18 to 45 years of age, inclusive)
Number of Subjects to be Enrolled/Randomized:
A total of 24 Chinese male and female subjects will be randomized within 2 dose groups (25 and 
50 mg mirabegron) of 12 subjects each.


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Study Design Overview:
The study follows an open-label, randomized, 2-period, single oral dose crossover design at 2 dose 
levels in healthy Chinese male and female subjects.  Each subject will participate in 2 periods 
separated by a washout of at least 10 days between investigational product (IP) administrations in 
each period.
Subjects will be randomized to 1 of 4 sequences according to the table below.
Sequences and Investigational Product Assignments
Dose (mg)
Sequence
n
Period 1
Period 2
25
1
6
Mirabegron (low-fat)
Mirabegron (fasted)
2
6
Mirabegron (fasted)
Mirabegron (low-fat)
50
1
6
Mirabegron (low-fat)
Mirabegron (fasted)
2
6
Mirabegron (fasted)
Mirabegron (low-fat)
The dose under fed conditions will be administered following a low-fat breakfast (total calories 
approximately 450 kcal, with approximately 70 kcal from fat).
Subjects will be screened for up to 21 days prior to IP administration on day 1 of period 1.  
Subjects who are eligible for study participation will be admitted to the clinical unit on day -1 of 
each period and will be confined until the last pharmacokinetic sample has been collected within 
each period. Subjects are to remain semirecumbent and avoid lying on either the left or right side 
for 4 hours postdose. Pharmacokinetic samples will be collected predose on day 1 of each period
and at multiple time points following each dose.
The study will be completed with an end of study visit (ESV).  The ESV will take place 5 to 9 days 
after the last pharmacokinetic sample is collected or at early discontinuation from the study.
Inclusion/Exclusion Criteria:
Inclusion Criteria:
Subject is eligible for participation in the study if all of the following apply:
1.
Institutional Review Board/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 Chinese male or female subject between 18 to 45 years of age, inclusive at 
screening.
3.
Subject has a body mass index range of 19.0 to 24.9 kg/m2, inclusive and weighs at least 50 kg 
for male subjects and 45 kg for female subjects at screening.
4.
Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at least 
1 of the following conditions apply:
a. Not a woman of childbearing potential (WOCBP) (see [Appendix 12.3 Contraception 
Requirements])
b. WOCBP who agrees to follow the contraceptive guidance (see [Appendix 12.3
Contraception Requirements]) from the time of informed consent through at least 30 days 
after final IP administration
5.
Female subject must agree not to breastfeed starting at screening and throughout the study 
period and for 30 days after final IP administration.
6.
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.
7.
Male subject with female partner(s) of childbearing potential (including breastfeeding 
partner[s]) must agree to use contraception (see [Appendix 12.3 Contraception Requirements]) 
throughout the study period and for 30 days after final IP administration.


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8.
Male subject must not donate sperm during the study period and for 30 days after final IP 
administration.
9.
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.
10. Subject agrees not to participate in another interventional study while participating in the 
present study, defined as 84 days prior screening until completion of the last study visit.
Exclusion Criteria:
Subject will be excluded from participation in the study if any of the following apply:
1.
Female subject who has been pregnant within 6 months prior to screening or breastfeeding 
within 3 months prior to screening.
2.
Subject has a known or suspected hypersensitivity to mirabegron or any components of the 
formulation used.
3.
Subject has had previous exposure with mirabegron.
4.
Subject has any of the liver function tests (alkaline phosphatase, alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase and total bilirubin 
[TBL]) > 1.5 × upper limit of normal (ULN) on day -1 of period 1.
5.
Subject has any clinically significant history of allergic conditions (including drug allergies, 
asthma, eczema or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal 
allergies) prior to first IP administration.
6.
Subject has any history or evidence of any clinically significant cardiovascular, 
gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, 
pulmonary, neurologic, dermatologic, psychiatric, renal and/or other major disease or 
malignancy, as judged by the investigator.
7.
Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory 
infection) or fungal (noncutaneous) infection within 1 week prior to day -1 of period 1.
8.
Subject has any of the following concerns with regard to tuberculosis:
●History of active tuberculosis
●Abnormalities detected in a chest X-ray on day -1 of period 1
●Contact with infectious tuberculous patients
9.
Subject has any clinically significant abnormality following the investigator’s review of the 
physical examination, electrocardiogram (ECG) and protocol-defined clinical laboratory tests 
at screening or on day -1 of period 1.
10. Subject who deviated from the following range of vital signs or routine 12-lead ECG results at 
screening or on day -1 of period 1.  If the mean blood pressure, pulse or corrected QT interval 
using Fridericia’s formula (QTcF) exceeds the limits below, 1 additional triplicate can be 
taken. The final judgment should be based on the retest results.
11. Subject has used any prescribed or nonprescribed drugs (including vitamins, natural and 
herbal remedies, e.g., St. John’s Wort and traditional Chinese medicine) in the 2 weeks prior 
to first IP administration, except for occasional use of paracetamol (up to 2 g/day), topical 
dermatological products, including corticosteroid products, hormonal contraceptives or 
hormone replacement therapy (HRT).
Blood pressure
Systolic blood pressure: ≥90 mmHg, < 140 mmHg
Diastolic blood pressure: ≥40 mmHg, < 90 mmHg
Pulse
≥45 bpm, ≤99 bpm
Body temperature
≥35.0°C, ≤37.5°C
Routine 12-lead ECG
Findings: Normal or clinically irrelevant abnormality
QTcF: < 430 msec (for male subjects)
< 450 msec (for female subjects)


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12. Subject has a history of smoking > 10 cigarettes (or equivalent amount of tobacco) per day 
within 3 months prior to day -1 of period 1.
13. Subject has a history of consuming > 21 units for male subjects or > 14 units for female 
subjects of alcohol per week within 3 months prior to day -1 of period 1 (note: 1 unit = 10 g 
pure alcohol, 250 mL of beer [5%], 35 mL of spirits [35%] or 100 mL of wine [12%]) or the 
subject has a history of alcohol-dependency, drug-dependency, chemical-dependency, or 
alcohol or drug abuse within 2 years prior to screening or the subject tests positive for alcohol 
at screening or on day -1 of period 1.
14. Subject has used any drugs of abuse (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine and/or opiates) within 3 months prior to day -1 of period 1 or the 
subject tests positive for drugs of abuse (amphetamines, benzodiazepines, cannabinoids, 
cocaine and opiates) at screening or on day -1 of period 1.
15. Subject has used any inducer of metabolism (e.g., barbiturates and rifampin) in the 3 months 
prior to day -1 of period 1.
16. Subject has had significant blood loss, donated ≥400 mL of whole blood within 90 days, 
≥200 mL of whole blood within 30 days or donated blood components within 14 days prior to 
day -1 of period 1 and/or received a transfusion of any blood or blood products within 
60 days.
17. Subject has a positive serology test for hepatitis A virus antibodies (immunoglobulin M), 
hepatitis B core antibodies, hepatitis B surface antigen, hepatitis C virus antibodies, human 
immunodeficiency virus or syphilis at screening.
18. Subject is an employee of Astellas, the study-related contract research organizations or the 
clinical unit.
19. Subject is deemed unsuitable for participating in the study by the investigator or 
subinvestigator.
Investigational Product(s):
Name/Use:
BETMIGA® (mirabegron) sustained-release tablets in 25 and 50 mg (test product)
Dose(s):
Single dose of 25 mg mirabegron (1 × 25 mg tablet)
Single dose of 50 mg mirabegron (1 × 50 mg tablet)
Mode(s) of Administration:
Fasted Conditions: Following an overnight fast of at least 10 hours, subjects will receive a single 
dose of 25 or 50 mg mirabegron with 240 mL water. Subjects are to remain semirecumbent and 
avoid lying on either the left or right side for 4 hours postdose.  No food or beverage will be 
allowed for at least 4 hours postdose.  Water can be ingested as desired except for 1 hour predose 
and 1 hour postdose.
Fed Conditions: Following an overnight fast of at least 10 hours, subjects will start a low-fat 
breakfast.  Subjects should eat the breakfast in 30 minutes or less.  Subjects will receive a single 
dose of 25 or 50 mg mirabegron with 240 mL water 30 minutes after the start of the breakfast. 
Subjects are to remain semirecumbent and avoid lying on either the left or right side for 4 hours 
postdose. No food or beverage will be allowed for at least 4 hours postdose. Water can be 
ingested as desired except for 1 hour predose and 1 hour postdose.  Except for the day 1 breakfast
in each period, subjects will receive standardized meals scheduled at the same time during the stay 
at the clinical unit. The low-fat meal (total calories approximately 450 kcal, with approximately 
70 kcal from fat) is cereal, low-fat milk, wheat bread, ham and ketchup.
Dose Modifications:
Not applicable.


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Concomitant Treatment (Medication and Nonmedication Therapy) Restrictions or 
Requirements:
All medicinal products other than the IP(s), including prescribed or nonprescribed drugs (including 
vitamins, natural and herbal remedies, e.g., St. John’s Wort and traditional Chinese medicine), used 
from first IP administration until the ESV (including washout between periods) will be considered 
concomitant medication.
Subjects will only be allowed to use the following concomitant medication, if needed, from first IP 
administration until the ESV (including washout between periods):
●
Paracetamol (up to 2 g/day)
●
Topical dermatological products, including corticosteroid products
●
Hormonal contraceptives
●
HRT
If a subject’s health condition necessitates the use of any medication other than the permitted 
medications during the study, the investigator and medical monitor, or designee(s), will discuss the 
case and determine if the subject should be withdrawn from the study and/or excluded from 
analysis sets, depending on if, and how, the medication(s) used influence(s) the study outcome. 
The nonpermitted concomitant medication will be recorded as a protocol deviation.
All concomitant treatment (medication and nonmedication therapy) will be documented.
Duration of Dosing:
Two single periods separated by a washout of at least 10 days between IP administrations in each 
period
Dosing Discontinuation Criteria:
A subject must discontinue study dosing for any of the following reasons:
●
Subject requests to stop dosing
●
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness, in the opinion 
of the investigator, indicates continued dosing is not in the best interest of the subject
●
Hepatic function parameters: ALT or AST > 3 × ULN and/or TBL > 2 × ULN
●
Cardiac repolarization dysfunction: QTcF > 500 msec and/or if QTcF change from baseline 
> 60 msec at repeat measurements
Statistical Methods:
Sample Size Justification:
A total of 24 subjects (12 subjects per dose group) will be enrolled.  Subjects who discontinue early 
from the study may be replaced at the discretion of the sponsor.
Based on data from Study 178-CL-091, a Chinese phase 1 study, the intrasubject coefficient of 
variation (CV) for pharmacokinetic parameters AUCinf, AUClast and Cmax of the 50 mg mirabegron 
dose are estimated to be between 33% and 60%.  Assuming the underlying variability is similar to 
60% and an observed ratio between fasted and fed conditions of 100%, the 90% CI will lie within 
(60, 167) with > 80% probability.
Efficacy:
Not applicable.


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Safety:
To characterize the safety profile, descriptive statistics will be presented for AEs, clinical 
laboratory tests (hematology and biochemistry) and vital signs (blood pressure, body temperature 
and pulse) by fasted/fed conditions for each dose group.
Pharmacokinetics:
To assess the effect of food on the pharmacokinetic of mirabegron, a mixed effects analysis of 
variance (ANOVA) model with fixed effects for food condition (fasted or fed) and period and 
subject as a random effect will be fitted on natural logarithm-transformed AUCinf, AUClast and Cmax.  
Within the ANOVA, the least squares (LS) mean differences between fed and fasted, along with 
90% CIs for the differences will be estimated for 25 and 50 mg mirabegron doses separately.
The LS means for AUCinf, AUClast and Cmax will be back-transformed to produce the geometric LS 
means and presented with the number of subjects for each food condition.  The geometric LS mean 
ratios and their corresponding 90% CIs for each pharmacokinetic parameter will be presented by 
back-transforming and expressed as percentages. The analysis will be repeated if all subjects did 
not complete both periods using an ANOVA with fixed effects for period, food condition and 
subject; this analysis will only include subjects with complete data in both periods.
Pharmacodynamics | Immunogenicity:
Not applicable.
Interim Analyses:
Not applicable.




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1.3
Schedule of Assessments
Table 1
Schedule of Assessments
Assessments
Screening Period
Periods 1/21
ESV
Withdrawal
Day(s)
-21 to -2
-1
1
2 to 4
5
12±2
Residential Period
X
X
X
X
Ambulant Visits
X
X
Informed Consent
X
Chest X-ray
X2
Inclusion and Exclusion Criteria
X
X2
Medical History
X
X2
Body Weight and Height
X
X3
Demographics
X
Drugs of Abuse and Alcohol Tests
X
X
Randomization4
X2
IP Administration5
X
Physical Examination
X
X2
X
X
X
X
Vital Signs (Blood Pressure, Body 
Temperature and Pulse)6
X
X
predose†, 2, 8, 24, 48, 72 and 96 hours postdose
X
X
Clinical Laboratory Tests (Serology, 
Hematology, Biochemistry and 
Urinalysis)7
X
X†
X
X
X
12-lead ECG8
X
X†
X
X
Blood Sampling for Mirabegron 
Pharmacokinetics
predose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 
72 and 96 hour(s) postdose
Serum Pregnancy Test (Female Subjects 
Only)9
X
X
FSH Test (Postmenopausal Female 
Subjects Only)
X
Adverse Event Assessment
X
Previous/Concomitant Treatment 
(Medication and Nonmedication Therapy)
X
Footnotes appear on the next page


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ECG: electrocardiogram; ESV: end-of-study visit; FSH: follicle-stimulating hormone; IP: investigational product; X: to be conducted
† Baseline
1.
Periods will be separated by a washout of at least 10 days between IP administrations in each period.  There is no washout after period 2.
2.
Period 1 only.
3.
Body weight only.
4.
Subjects will be randomized to 1 of 4 sequences.
5.
Fasted Conditions: Following an overnight fast of at least 10 hours, subjects will receive a single dose of 25 or 50 mg mirabegron with 240 mL water. Subjects are to remain 
semirecumbent and avoid lying on either the left or right side for 4 hours postdose.  No food or beverage will be allowed for at least 4 hours postdose.  Water can be ingested as 
desired except for 1 hour predose and 1 hour postdose.
Fed Conditions: Following an overnight fast of at least 10 hours, subjects will start a low-fat breakfast.  Subjects should eat the breakfast in 30 minutes or less.  Subjects will 
receive a single dose of 25 or 50 mg mirabegron with 240 mL water 30 minutes after the start of the breakfast. Subjects are to remain semirecumbent and avoid lying on either 
the left or right side for 4 hours postdose. No food or beverage will be allowed for at least 4 hours postdose. Water can be ingested as desired except for 1 hour predose and 
1 hour postdose. Except for the day 1 breakfast in each period, subjects will receive standardized meals scheduled at the same time during the stay at the clinical unit. The low-fat 
meal (total calories approximately 450 kcal, with approximately 70 kcal from fat) is cereal, low-fat milk, wheat bread, ham and ketchup.
6.
Measurements will be taken after the subject has been resting in the supine position for at least 5 minutes.  Blood pressure and pulse measurements will be taken in triplicate at 
screening and on day -1 of each period and at all other time points as single measurements.  Body temperature measurements will be taken as single measurements.
7.
Blood collection for serology tests (screening only), hematology and biochemistry; urine collection for urinalysis.
8.
Routine 12-lead ECGs will be taken after the subjects has been resting in the supine position for at least 5 minutes. Routine 12-lead ECG will be taken in triplicate at screening 
and on day -1 of each period and at all other time points as single measurements.
9.
Not for postmenopausal female subjects.


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2
INTRODUCTION
The generic name of the investigational product (IP) is mirabegron sustained-release tablets
(also called mirabegron oral controlled absorption system tablets internally) and the trade 
name is BETMIGA® [Betmiga Package Insert, Aug 2019].
Mirabegron is a selective agonist for human beta 3-adrenoceptor. It is a new chemical entity
and first-in-class compound with a distinct mechanism of action compared to the current 
standard of care (primarily antimuscarinics).
Mirabegron is indicated for the symptomatic treatment of urgency, increased micturition 
frequency and/or urgency incontinence as may occur in adult patients with overactive bladder 
(OAB) syndrome.
In the mirabegron approval letter, China National Medical Products Administration (NMPA) 
requested further investigation into the usage (before/after meal) and dosage (including 
initiation dose) of mirabegron in Chinese patients and data should be submitted when the 
Imported Drug License is renewed.
2.1
Background
OAB is a syndrome characterized by symptoms of urinary urgency with or without urge 
incontinence, often accompanied by frequency and nocturia in the absence of pathologic or 
metabolic factors that would explain these symptoms, according to the 2002 International 
Continence Society definition [Abrams et al, 2002; Charlson et al, 1987].
Several publications have studied the prevalence of OAB in developed countries. An overall 
OAB prevalence of 11.8% was observed in a population-based, cross-sectional survey of 
adults in Canada, Germany, Italy, Sweden and the UK (the European Prospective 
Investigation into Cancer and Nutrition study) [Osman & Chapple, 2013; Irwin et al, 2006; 
Abrams et al, 2002]. In the US (the National Overactive Bladder Evaluation study) reported 
an overall OAB prevalence of 16.5%.  The figure increased by age, with a similar distribution 
between the 2 sexes.
In Asia, a questionnaire-based survey conducted in adult women in China, Hong Kong, India, 
Indonesia, Malaysia, Pakistan, Philippines, Singapore, South Korea, Taiwan and Thailand 
reported an OAB prevalence of 53.1%, with only 21.1% wanting treatment [Lapitan & Chye, 
2001]. In the same 11 Asian countries, a prevalence of 29.9% was reported in adult male 
patients [Moorthy et al, 2004]. An internet-based self-administered survey was conducted 
among men and women ≥40 years of age in China, Taiwan and South Korea, reporting an 
OAB prevalence of 20.8% (19.5% in men and 22.1% in women), increasing significantly 
with age (10.8% in those 40 to 44 years of age to 27.9% in those > 60 years of age
(p = 0.001)) [Chuang & Liu, 2019].
OAB patients experience significantly greater symptom bother, worse health-related quality 
of life (HRQoL), higher rates of depression and decreased enjoyment of sexual activity [Chen 
& Li, 2016; Osman & Chapple, 2013; Coyne et al, 2008; Stewart et al, 2003]. In addition, 
the economic costs of OAB is substantial.


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The management of OAB is multimodal, including lifestyle modifications, behavioral 
therapies and pharmacological therapeutic strategies. Antimuscarinics, which exert their 
effect through the blockade of postjunctional muscarinic receptors, are currently the mainstay 
of pharmacological treatment and represent the most commonly prescribed drugs. 
Meta-analyses of several randomized controlled studies have shown that antimuscarinics 
(including propiverine, fesoterodine, tolterodine, oxybutynin, solifenacin, trospium and 
darifenacin) are efficacious, safe and well-tolerated therapies that improve HRQoL [Chapple 
et al, 2008; Novara et al, 2008]. However, the lack of persistence with antimuscarinics is a 
well-known challenge, which may occur due to the side-effects or the lack of perceived 
efficacy [Andersson, 2013]. A systematic literature review indicated high rates of 
discontinuation from 12-week randomized controlled studies, ranging from 4% to 31% in 
treatment groups and 5% to 20% in placebo groups, respectively. Findings from medical 
claims data also suggested that over half of the patients never refilled their initial prescription 
and that adherence levels were low, with mean/median medication possession ratio values 
ranging from 0.30 to 0.83 [Sexton et al, 2011].
Mirabegron, a first in class beta 3-adrenergic receptor agonist, has been approved for OAB 
treatment in the US, Europe, Canada, Japan, Australia, Hong Kong, Korea, China and 
Taiwan. A review of 6 randomized controlled studies of mirabegron concluded that 
mirabegron had clinically significant efficacy and tolerability in treating OAB symptoms. 
The tolerability profile of mirabegron provided the potential for improving patient adherence 
with OAB treatment, as dry mouth was often the reason for antimuscarinics treatment 
discontinuation [Chapple et al, 2014].
Nonclinical and Clinical Data
Mirabegron is a selective beta 3-adrenoceptor agonist showing selective agonistic activity 
and high affinity for human beta 3- as compared with beta 1- and beta 2-adrenoceptors.
The primary pharmacology studies show bladder relaxation with mirabegron during the 
filling phase and inhibition of the frequency of nonvoiding activity, without impairing 
voiding efficiency.
The nonclinical data provide proof of principle that mirabegron enhances urine storage 
function by stimulating beta 3-adrenoceptors in the bladder, without affecting voiding 
contractions.
The mirabegron clinical pharmacology program in the Chinese population consisted of 
2 studies in 48 volunteers. The results in the Chinese population showed that the exposure of 
mirabegron was largely similar among different ethnic groups (Chinese, Japanese and 
Western subjects), considering a large intersubject variability of plasma concentration of 
mirabegron.
The efficacy of mirabegron in the treatment of symptoms of OAB is well demonstrated with 
the following data.


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Study 178-CL-090 assessed the efficacy and safety of mirabegron in Asian patients (total 
1126 patients, including 344 Chinese). Mirabegron 50 mg per day for 12 weeks demonstrated 
superior efficacy to placebo in the change from baseline in the mean number of micturitions 
per 24 hours and the secondary efficacy variables (change from baseline to last visit in mean 
volume voided per micturition, mean number of urgency episodes per 24 hours, mean number 
of incontinence episodes per 24 hours and mean number of urge incontinence episodes per 
24 hours). The efficacy trend in Asian and Chinese patient was same. The clinical study
showed mirabegron was safe and well-tolerated. No clinically relevant concerns were 
identified.
The efficacy of mirabegron has also been demonstrated across 6 phase 2b and 3, 12-week 
global studies, evaluating doses of 25, 50 or 100 mg mirabegron orally once daily in a total of 
4285 patients in the full analysis set (FAS) population and 2815 patients in the 
FAS-incontinence population. Mirabegron consistently demonstrated superiority compared 
with placebo in reducing both coprimary endpoints of the mean number of incontinence 
episodes per 24 hours and the mean number of micturitions per 24 hours.
The long-term effect of mirabegron was established by a 1-year study, Study 178-CL-049. 
Improvement in incontinence episodes, micturitions and mean volume voided per micturition 
was observed for mirabegron 50 and 100 mg once daily; results were similar to tolterodine. 
Improvement was also established in subjective endpoints as well as responder analyses 
indicating that the patients had clinically meaningful benefit from treatment.
Mirabegron at the proposed therapeutic dose is well-tolerated in the OAB population studied, 
inclusive of patients with multiple comorbidities and concomitant medications. The data 
from the clinical program are generalizable to the population of patients intended for the use 
of mirabegron in the treatment of OAB.
Adverse events (AEs) of interest have been thoroughly evaluated, generally do not represent 
product-related safety concerns, and where appropriate, can be addressed in labeling and 
other routine pharmacovigilance.
Preclinical and clinical safety data, including AEs of interest, support the safety of 
mirabegron under labeled condition in the treatment of patients with OAB.
The effect of food on the pharmacokinetics of mirabegron has been evaluated in healthy 
subjects in the US and Japan [Studies 178-CL-041 and 178-CL-078]. Both low-fat and 
high-fat meals decreased the peak and systemic exposures to mirabegron (50 or 100 mg dose) 
when compared with fasting conditions, however, the magnitude of the food effect was 
greater for the low-fat than the high-fat meal. Following a low-fat meal, Cmax was reduced by 
approximately 64% to 75% and AUCinf was reduced by approximately 47% to 51% relative 
to the fasted state. Following a high-fat meal, Cmax was reduced by approximately 39% to 
53% and AUCinf was reduced by approximately 17% to 29% relative to the fasted state. No 
clear difference was observed between male and female subjects.
Refer to the [Investigator’s Brochure] for detailed information.


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Summary of Key Safety Information for Investigational Product(s)
Preclinical and clinical safety data, including AEs of interest, support the safety of 
50 mg mirabegron in the treatment of patients with OAB.
The global OAB 12-week phase 2/3 studies included 4414 patients treated with mirabegron, 
2142 patients treated with placebo and 958 patients treated with tolterodine.
One or more serious adverse events (SAEs) were reported by 1.7% of mirabegron patients, 
1.8% of placebo patients and 1.7% of tolterodine patients, with no apparent mirabegron dose 
response. The most common SAEs in the total mirabegron group were atrial fibrillation 
(mirabegron: 0.1%; placebo: < 0.1%; tolterodine: 0%), chest pain (mirabegron: 0.1%; 
placebo: 0.1%; tolterodine: 0%) and pneumonia (mirabegron: 0.1%; placebo: < 0.1%; 
tolterodine: 0%). The most common treatment-emergent adverse events (TEAEs) (by 
preferred term) reported in the total mirabegron group were nasopharyngitis 
(mirabegron: 6.7%; placebo: 6.6%; tolterodine: 5.9%), hypertension (mirabegron: 5.0%; 
placebo: 5.0%; tolterodine: 4.5%) and blood glucose increased (mirabegron: 4.7%; 
placebo: 5.4%; tolterodine: 7.6%).
Study 178-CL-090 included 366 patients treated with mirabegron, 371 patients treated with 
tolterodine and 366 patients treated with placebo. One or more SAEs were reported by 
1.4% of mirabegron patients, 1.6% of tolterodine patients and 1.9% of placebo patients. All 
SAEs were unique to a single patient in each treatment group. All SAEs were considered by 
the investigator to be not related to the IP except for headache and vomiting, which occurred 
in 1 patient in the tolterodine sustained release 4 mg group.
In the 1-year long term study, Study 178-CL-049, 1632 patients treated with mirabegron and 
812 patients treated with tolterodine were included. The most common SAEs in the total 
mirabegron group were osteoarthritis (mirabegron: 0.2%; tolterodine: 0.1%) and 
cerebrovascular accident (mirabegron: 0.2%; tolterodine: 0.1%). The most common TEAEs
(by preferred term) reported in the total mirabegron group were hypertension 
(mirabegron: 9.5%; tolterodine: 9.6%), urinary tract infection (mirabegron: 5.7%; 
tolterodine: 6.4%) and nasopharyngitis (mirabegron: 4.1%; tolterodine: 3.1%).
AEs of interest have been thoroughly evaluated in all completed studies and do not represent 
product-related safety concerns. Potential risks included QT prolongation with 
supratherapeutic doses or in high-risk populations, increased heart rate with supratherapeutic 
doses, increased blood pressure with supratherapeutic doses, nonimmediate cutaneous 
hypersensitivity reactions and exposure in utero. The potential risks of QT prolongation, 
increased heart rate or increased blood pressure are greater with increasing exposure at 
supratherapeutic doses and can be mitigated with optimal dose selection.
Detailed reference safety information (RSI) can be found in the [Investigator’s Brochure, 
Appendix 1].


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2.2
Study Rationale
This phase 4 study will be an open-label, randomized, 2-period, single oral dose crossover 
design at 2 dose levels in healthy Chinese male and female subjects. It is intended to 
determine the effect of food on the pharmacokinetics of 25 and 50 mg mirabegron tablets, 
and to evaluate the pharmacokinetics, safety and tolerability of single oral doses of 25 and 
50 mg mirabegron under fasted and fed (low-fat meal) conditions.
2.3
Risk Benefit Assessment
Subjects participating in this study will not benefit from administration of mirabegron. In 
contrast, subjects might experience AEs related to mirabegron or procedural complications 
(e.g., blood draws, slight skin irritation from the adhesive on the ECG electrodes). AEs are 
described in [Section 2.1.1 Nonclinical and Clinical Data], the package insert [Betmiga 
Package Insert, Aug 2019] and interview form of mirabegron. Unknown AEs that have not 
been reported in the past may occur in this study.
Overall, the risk associated with the participation of healthy subjects in this study is 
considered acceptable.
3
STUDY OBJECTIVE(S) AND ENDPOINT(S)
The primary, secondary and exploratory objectives and endpoints for this study are listed in 
[Table 2].
Table 2
Study Objectives and Endpoints
Objectives
Endpoints
Primary
●
To determine the effect of food on the 
pharmacokinetics of single oral doses of 
mirabegron in healthy Chinese male and female 
subjects
●
Mirabegron plasma: AUCinf, AUClast and Cmax
Secondary
●
To evaluate the safety and tolerability of single 
oral doses of mirabegron in healthy Chinese 
male and female subjects
●
Nature, frequency and severity of AEs
●
Clinical laboratory tests (biochemistry, 
hematology and urinalysis)
●
Vital signs (blood pressure, body temperature 
and pulse)
●
Routine 12-lead ECG
Exploratory
●
To evaluate the pharmacokinetics of single oral 
doses of mirabegron in healthy Chinese male 
and female subjects
●
Mirabegron plasma: AUCinf (%extrap), CL/F, 
t½, tmax, tlag and Vz/F
AE: adverse event; ECG: electrocardiogram


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4
STUDY DESIGN AND DOSE RATIONALE
4.1
Study Design
The study follows an open-label, randomized, 2-period, single oral dose crossover design at 
2 dose levels in healthy Chinese male and female subjects. Each subject will participate in 
2 periods separated by a washout of at least 10 days between IP administrations in each 
period.
Subjects will be randomized to 1 of 4 sequences according to [Table 3].
Table 3
Sequences and Investigational Product Assignments
Dose (mg)
Sequence
n
Period 1
Period 2
25
1
6
Mirabegron (low-fat)
Mirabegron (fasted)
2
6
Mirabegron (fasted)
Mirabegron (low-fat)
50
1
6
Mirabegron (low-fat)
Mirabegron (fasted)
2
6
Mirabegron (fasted)
Mirabegron (low-fat)
The dose under fed conditions will be administered following a low-fat breakfast (total 
calories approximately 450 kcal, with approximately 70 kcal from fat).
Subjects will be screened for up to 21 days prior to IP administration on day 1 of period 1. 
Subjects who are eligible for study participation will be admitted to the clinical unit on day -1 
of each period and will be confined until the last pharmacokinetic sample has been drawn 
within each period. Subjects are to remain semirecumbent and avoid lying on either the left 
or right side for 4 hours postdose. Pharmacokinetic samples will be collected predose on 
day 1 of each period and at multiple time points following each dose (see the Schedule of 
Assessments [Table 1]).
The study will be completed with an end-of-study visit (ESV).  The ESV will take place 5 to 
9 days after the last pharmacokinetic sample is collected or at early discontinuation from the 
study.
4.2
Dose Rationale
Mirabegron 50 mg is commercially available worldwide; however, the recommended starting 
dose in the US is 25 mg. In accordance with the Centre for Drug Evaluation’s request to 
continue the study on the posology of Chinese patients, including the initial dose and taking 
the drug before and after a meal, and submit the study results when the Imported Drug 
License is renewed, both 25 and 50 mg doses of mirabegron will be investigated.
4.3
End of Study Definition
The study start is defined as the date the first subject signs informed consent. End of the 
study is defined as the last visit or scheduled procedure shown in the Schedule of 
Assessments [Table 1] for the last subject in the study.


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5
STUDY POPULATION
The study population will consist of healthy Chinese male and female subjects (18 to 
45 years of age, inclusive). Eligible subjects must be able to provide written informed 
consent and meet all the inclusion criteria and none of the exclusion criteria.
All screening assessments must be completed and reviewed to confirm the potential subject 
meets all eligibility criteria. Prospective approval of protocol deviations to eligibility criteria 
(also known as protocol waivers or exemptions) is not permitted.
5.1
Inclusion Criteria
Subject is eligible for participation in the study if all of the following apply:
1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-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 Chinese male or female subject between 18 to 45 years of age, 
inclusive at screening.
3.
Subject has a body mass index (BMI) range of 19.0 to 24.9 kg/m2, inclusive and weighs 
at least 50 kg for male subjects and 45 kg for female subjects at screening.
4.
Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at 
least 1 of the following conditions apply:
a. Not a woman of childbearing potential (WOCBP) (see [Appendix 12.3
Contraception Requirements])
b. WOCBP who agrees to follow the contraceptive guidance (see [Appendix 12.3
Contraception Requirements]) from the time of informed consent through at least 
30 days after final IP administration.
5.
Female subject must agree not to breastfeed starting at screening and throughout the 
study period and for 30 days after final IP administration.
6.
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.
7.
Male subject with female partner(s) of childbearing potential (including breastfeeding
partner[s]) must agree to use contraception (see [Appendix 12.3 Contraception 
Requirements]) throughout the study period and for 30 days after final IP administration.
8.
Male subject must not donate sperm during the study period and for 30 days after final IP
administration.
9.
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.
10. Subject agrees not to participate in another interventional study while participating in the 
present study, defined as 84 days prior screening until completion of the last study visit.


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5.2
Exclusion Criteria
Subject will be excluded from participation in the study if any of the following apply:
1.
Female subject who has been pregnant within 6 months prior to screening or 
breastfeeding within 3 months prior to screening.
2.
Subject has a known or suspected hypersensitivity to mirabegron or any components of 
the formulation used.
3.
Subject has had previous exposure with mirabegron.
4.
Subject has any of the liver function tests (alkaline phosphatase, alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase 
and total bilirubin [TBL]) > 1.5 × upper limit of normal (ULN) on day -1 of period 1.
5.
Subject has any clinically significant history of allergic conditions (including drug 
allergies, asthma, eczema or anaphylactic reactions, but excluding untreated, 
asymptomatic, seasonal allergies) prior to first IP administration.
6.
Subject has any history or evidence of any clinically significant cardiovascular, 
gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, 
urologic, pulmonary, neurologic, dermatologic, psychiatric, renal and/or other major 
disease or malignancy, as judged by the investigator.
7.
Subject has/had febrile illness or symptomatic, viral, bacterial (including upper 
respiratory infection) or fungal (noncutaneous) infection within 1 week prior to day -1 of 
period 1.
8.
Subject has any of the following concerns with regard to tuberculosis:
●History of active tuberculosis
●Abnormalities detected in a chest X-ray on day -1 of period 1
●Contact with infectious tuberculous patients
9.
Subject has any clinically significant abnormality following the investigator’s review of 
the physical examination, electrocardiogram (ECG) and protocol-defined clinical 
laboratory tests at screening or on day -1 of period 1.
10. Subject who deviated from the following range of vital signs or routine 12-lead ECG 
results at screening or on day -1 of period 1. If the mean blood pressure, pulse or 
corrected QT interval using Fridericia’s formula (QTcF) exceeds the limits below, 
1 additional triplicate can be taken. The final judgment should be based on the retest 
results.
Blood pressure
Systolic blood pressure (SBP): ≥90 mmHg, < 140 mmHg
Diastolic blood pressure (DBP): ≥40 mmHg, < 90 mmHg
Pulse
≥45 bpm, ≤99 bpm
Body temperature
≥35.0°C, ≤37.5°C
Routine 12-lead ECG
Findings: Normal or clinically irrelevant abnormality
QTcF: < 430 msec (for male subjects)
< 450 msec (for female subjects)


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11. Subject has used any prescribed or nonprescribed drugs (including vitamins, natural and 
herbal remedies, e.g., St. John’s Wort and traditional Chinese medicine) in the 2 weeks 
prior to first IP administration, except for occasional use of paracetamol (up to 2 g/day), 
topical dermatological products, including corticosteroid products, hormonal 
contraceptives or hormone replacement therapy (HRT).
12. Subject has a history of smoking > 10 cigarettes (or equivalent amount of tobacco) per 
day within 3 months prior to day -1 of period 1.
13. Subject has a history of consuming > 21 units for male subjects or > 14 units for female 
subjects of alcohol per week within 3 months prior to day -1 of period 1 (note: 1 unit = 
10 g pure alcohol, 250 mL of beer [5%], 35 mL of spirits [35%] or 100 mL of wine 
[12%]) or the subject has a history of alcohol-dependency, drug-dependency, 
chemical-dependency, or alcohol or drug abuse within 2 years prior to screening or the 
subject positive for alcohol at screening or on day -1 of period 1.
14. Subject has used any drugs of abuse (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine and/or opiates) within 3 months prior to day -1 of period 1 or the 
subject tests positive for drugs of abuse (amphetamines, benzodiazepines, cannabinoids, 
cocaine and opiates) at screening or on day -1 of period 1.
15. Subject has used any inducer of metabolism (e.g., barbiturates and rifampin) in the 
3 months prior to day -1 of period 1.
16. Subject has had significant blood loss, donated ≥400 mL of whole blood within 90 days, 
≥200 mL of whole blood within 30 days or donated blood components within 14 days 
prior to day -1 of period 1 and/or received a transfusion of any blood or blood products 
within 60 days.
17. Subject has a positive serology test for hepatitis A virus (HAV) antibodies 
(immunoglobulin M [IgM]), hepatitis B core (HBc) antibodies, hepatitis B surface 
antigen (HBsAg), hepatitis C virus (HCV) antibodies, human immunodeficiency virus 
(HIV) or syphilis at screening.
18. Subject is an employee of Astellas, the study-related contract research organizations 
(CROs) or the clinical unit.
19. Subject is deemed unsuitable for participating in the study by the investigator or 
subinvestigator.
5.3
Restrictions During the Study
Exercise
Subjects will refrain from strenuous exercise from 48 hours prior to first admission to the 
clinical unit up to and including the ESV.
Subjects are encouraged to walk and stretch while in the clinical unit to avoid AEs associated 
with the sedentary environment.


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Smoking
Subjects are not allowed to smoke or use tobacco-containing products and nicotine or 
nicotine-containing products (e.g., electronic vapes) from screening up to and including the 
ESV.
Dietary and Fluid Restrictions
To avoid false-positive results of the drugs of abuse test, no food or drinks containing poppy 
seeds (e.g., specialty breads and muffins) will be allowed from 48 hours prior to first 
admission to the clinical unit up to and including the ESV.
Subjects will not be allowed to consume food and drinks, which may interact with 
circulatory, gastrointestinal, liver or renal function from at least 24 hours for alcohol or 
xanthine-containing products (including caffeine) and 72 hours for grapefruit/Seville orange 
or grapefruit/Seville orange-containing products prior to first admission to the clinical unit up 
to and including the ESV.
Subjects will be served normal balanced caloric drinks and meals at consistent times during 
their stay in the clinical unit. Total daily caloric intake will preferably not exceed normal 
daily limits (2600 kcal/male and female subjects). On day 1 of each period, when IP 
administration is under fed conditions, a low-fat breakfast (total calories approximately 
450 kcal, with approximately 70 kcal from fat) applies. Dietary and fluid restrictions apply to 
dosing conditions as specified in [Section 6.1 Investigational Product(s) Administered]. The 
menu and nutritional information, including the caloric and content breakdown 
(carbohydrates, proteins and fat), will be documented in the clinical study file and will be 
described in the clinical study report.
Standardized and identical, lunch and dinner will be served at fixed time points on day 1 of 
each period. On other days the subjects will receive standard meals.
5.4
Screen Failures
A screen failure is defined as a potential subject who signed the informed consent form (ICF)
but did not meet 1 or more criteria required for participation in the study and was not 
randomized.
For screen failures, the demographic data, date of signing the ICF, inclusion and exclusion 
criteria, AEs up to the time of screen failure and reason for screen failure will be collected in 
the electronic case report form (eCRF).
Rescreening
Rescreening is allowed only in situations in which a subject underwent the screening 
procedures and due to logistical circumstances, the allocated time window for these tests has 
expired and the subject is documented as a screen failure. In order to rescreen, a new ICF 
must be signed and a new subject screening number assigned. Rescreening is only allowed 
once for an individual subject.


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6
INVESTIGATIONAL PRODUCT(S)
6.1
Investigational Product(s) Administered
Table 4
Investigational Product(s)
Name
BETMIGA® (Mirabegron)
Use
Test product
Dosage Formulation
Sustained-release tablet
Physical Description
25 mg: oval, brown, film-coated tablet
50 mg: oval, yellow, film-coated tablet
Dose Strength
25 and 50 mg
Packaging and Labeling
10 tablets per carton
Route of Administration
Oral
Administration Instruction
Mirabegron will be administered as single oral doses under fed or fasted 
conditions on day 1 of each period.
Fasted Conditions: Following an overnight fast of at least 10 hours, 
subjects will receive a single dose of 25 or 50 mg mirabegron with 
240 mL water. Subjects are to remain semirecumbent and avoid lying 
on either the left or right side for 4 hours postdose.  No food or beverage 
will be allowed for at least 4 hours postdose.  Water can be ingested as 
desired except for 1 hour predose and 1 hour postdose.
Fed Conditions: Following an overnight fast of at least 10 hours, 
subjects will start a low-fat breakfast.  Subjects should eat the breakfast 
in 30 minutes or less.  Subjects will receive a single dose of 25 or 
50 mg mirabegron with 240 mL water 30 minutes after the start of the 
breakfast. Subjects are to remain semirecumbent and avoid lying on 
either the left or right side for 4 hours postdose. No food or beverage 
will be allowed for at least 4 hours postdose. Water can be ingested as 
desired except for 1 hour predose and 1 hour postdose.  Except for the 
day 1 breakfast in each period, subjects will receive standardized meals 
scheduled at the same time during the stay at the clinical unit. The 
low-fat meal (total calories approximately 450 kcal, with approximately 
70 kcal from fat) is cereal, low fat milk, wheat bread, ham and ketchup.
IMP or Non-IMP
IMP
Sourcing
Provided centrally by sponsor
IMP: investigational medicinal product
Refer to the product label and package insert [Betmiga Package Insert, Aug 2019] for 
detailed information regarding handling and storage of the IP.
6.2
Preparation/Handling/Storage/Accountability
Packaging and Labeling
All IP used in this study will be commercial products.  Each carton will bear a label 
conforming to regulatory guidelines, Good Manufacturing Practice (GMP) and local laws and 
regulations that identifies the contents as investigational drug.
Refer to the product label and package insert [Betmiga Package Insert, Aug 2019] for 
detailed information regarding packaging and labeling of the IP.


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Handling, Storage and Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and 
resolved before use of the IP.
2.
Only subjects enrolled in the study may receive IP and only authorized study site 
personnel may supply or administer IP. Only IP with appropriate expiry/retest dating 
may be dispensed.
3.
All IP must be stored in a secure, environmentally controlled and monitored (manual or 
automated) area in accordance with the labeled storage conditions and access must be 
limited to the investigator and authorized study site personnel.
4.
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records).
Refer to the package insert [Betmiga Package Insert, Aug 2019] for detailed information 
regarding handling and storage of the IP.
6.3
Randomization and Blinding
Blinding Method
Not applicable.
Assignment and Allocation
6.3.2.1
Subject Number
Subjects will be assigned a subject number at study entry (i.e., signing the ICF).  The subject 
numbers will be sequential and rising.
The subject number will comprise of a 5-digit clinical unit number and 5-digit screening 
number.
6.3.2.2
Randomization Number
Subjects will be randomized in a 1:1:1:1 ratio to a dosing sequence according to the 
randomization schedule. All subjects who meet the eligibility criteria will be randomized.
Prior to dosing on day 1 of period 1, subjects will be assigned a randomization number in 
accordance with the randomization code generated by the sponsor’s designee.
Once a randomization number has been allocated to a subject, it will not be assigned to 
another subject.  If a subject withdraws prematurely from the study and is replaced under the 
direction of the sponsor, then a replacement randomization number will be assigned.  A 
replacement randomization code will be generated such that replacement subjects are 
assigned to the same dosing sequence as the discontinued subject.


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6.4
Investigational Product(s) Compliance
Dosing will take place in the clinical unit. The administration of IP will be supervised to 
ensure study compliance. After IP administration, a check of the subject’s mouth and hands 
will be performed. The exact day and time of IP administration will be documented.
6.5
Previous and Concomitant Treatment (Medication and 
Nonmedication Therapy)
Previous Treatment (Medication and Nonmedication Therapy)
All medicinal products, including prescribed or nonprescribed drugs, used prior to first IP 
administration will be considered previous medication.
The subjects must abstain from use of any prescribed or nonprescribed drugs (including 
vitamins, natural and herbal remedies, e.g., St. John’s Wort and traditional Chinese medicine)
in the 2 weeks prior to first IP administration, except for:
●
Paracetamol (up to 2 g/day)
●
Topical dermatological products, including corticosteroid products
●
Hormonal contraceptives
●
HRT
At the screening, subjects will be questioned regarding the medicinal products that they have 
been taking over the past 3 months. All medication taken within 4 weeks prior to first 
admission to the clinical unit will be documented.
Concomitant Treatment (Medication and Nonmedication Therapy)
All medicinal products other than the IP(s), including prescribed or nonprescribed drugs
(including vitamins, natural and herbal remedies, e.g., St. John’s Wort and traditional 
Chinese medicine), used from first IP administration until the ESV (including washout 
between periods) will be considered concomitant medication.
Subjects will only be allowed to use the following concomitant medication, if needed, from 
first IP administration until the ESV (including washout between periods):
●
Paracetamol (up to 2 g/day)
●
Topical dermatological products, including corticosteroid products
●
Hormonal contraceptives
●
HRT
If a subject’s health condition necessitates the use of any medication other than the permitted 
medications during the study, the investigator and medical monitor, or designee(s), will 
discuss the case and determine if the subject should be withdrawn from the study and/or 
excluded from analysis sets, depending on if, and how, the medication(s) used influence(s)
the study outcome. The nonpermitted concomitant medication will be recorded as a protocol 
deviation (see [Section 9.9 Major Protocol Deviations]).


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All concomitant treatment (medication and nonmedication therapy) will be documented 
within the source.
6.6
Dose Modification
Not applicable.
6.7
Criteria for Continuation of Dosing
Not applicable.
7
STUDY PROCEDURES AND ASSESSMENTS
7.1
Efficacy Assessments
Not applicable.
7.2
Safety Assessments
Adverse Events
See [Section 7.3 Adverse Events and Other Safety Aspects] for information regarding AE 
collection and data handling.
Laboratory Assessments
Clinical laboratory tests will be performed at a local laboratory.
Blood samples will be collected via a peripherally placed intravenous cannula or by direct 
venipuncture in a suitable forearm vein.
Blood samples for hematology and biochemistry and urine samples for urinalysis will be 
collected as indicated in the Schedule of Assessments [Table 1].  The clinical laboratory tests 
to be performed in the study are listed in [Appendix 12.7 Laboratory Assessments].
A blood sample will be collected for serology tests (HAV antibodies [IgM], HBc antibodies, 
HBsAg, HCV antibodies, HIV and syphilis) at screening only.
Drugs of abuse and alcohol tests will be performed according to the clinical site’s preferred 
method. Drugs of abuse and alcohol tests will be performed as indicated in the Schedule of 
Assessments [Table 1].
Serum pregnancy tests (female subjects only) will be performed according to the clinical 
site’s preferred method.  Serum pregnancy tests will be performed as indicated in the 
Schedule of Assessments [Table 1].
A blood sample will be collected for follicle-stimulating hormone (FSH) tests 
(postmenopausal female subjects only) as indicated in the Schedule of Assessments 
[Table 1].
If any of the clinical laboratory tests results be outside the normal range at any scheduled 
time point during the study, the investigator may decide to repeat the test(s) on new samples.  
The clinical relevance of the abnormal results will be documented. Clinically relevant 


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changes will be recorded as AEs (see [Section 7.3 Adverse Events and Other Safety 
Aspects]).
Vital Signs
Blood pressure (SBP and DBP), body temperature and pulse measurements will be taken as 
indicated in the Schedule of Assessments [Table 1]. Measurements will be taken after the 
subject has been resting in the supine position for at least 5 minutes. Blood pressure and 
pulse measurements will be taken in triplicate with approximately 2-minute intervals at 
screening and on day -1 of each period (the mean will be used).  At all other time points and 
for body temperature, single measurements will be taken.
Physical Examination
Physical examination will be performed as indicated in the Schedule of Assessments 
[Table 1] and whenever there is a medical indication.
The investigator should perform physical examinations in accordance with routine 
procedures. Any abnormal finding observed at screening must be assessed and documented 
as not clinically significant if a subject is to be enrolled in the study. After IP administration, 
new clinically significant findings or a worsening of an ongoing clinically significant 
abnormal condition will be recorded as an AE (see [Section 7.3 Adverse Events and Other 
Safety Aspects]).
Electrocardiogram
7.2.5.1
Routine 12-lead Electrocardiogram
Routine (12-lead) ECGs will be taken as indicated in the Schedule of Assessments [Table 1]. 
Routine 12-lead ECGs will be taken after the subject has been resting in the supine position 
for at least 5 minutes. Routine 12-lead ECGs will be taken in triplicate at screening and on 
day -1 of each period with approximately 1-minute intervals and all 3 ECGs will be 
completed within 5 minutes. At all other time points, single measurements will be taken.
The investigator will review, sign and date the ECG after recording to ensure subject safety.
The time of the ECG, the interval measurements, as well as an overall conclusion, will be 
documented. This overall conclusion will be recorded as normal, abnormal not clinically 
significant, or abnormal clinically significant. If the overall conclusion is abnormal, the 
details must be recorded.
Per time point, the ECG will be stored electronically and reviewed in a timely manner by the 
investigator. The electronic data file with all generated ECG variables and electronic files 
with the digitized tracings will be transferred to the sponsor at the end of the study.
Order of Assessments
When time points for procedures overlap, blood sampling for pharmacokinetics will be 
collected at the nominal time point.  Blood and urine sampling for clinical laboratory tests, 
routine 12-lead ECG and vital signs are to be collected before or after the nominal blood 


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sampling for pharmacokinetics.  Vital signs are recommended to be collected before 
venipuncture or, if necessary, after venipuncture from the opposite arm.
The allowed collection windows for procedures are shown in [Table 5].
Table 5
Order of Assessments
Assessment
Time Point
Window
Blood Sampling for
Pharmacokinetics
Predose
-90 to 0 minutes
0 to < 4 hours
± 2 minutes
4 to < 12 hours
± 5 minutes
12 to < 48 hours
± 15 minutes
48 hours and thereafter
± 30 minutes
Vital Signs
Predose
-60 to 0 minutes
0 to < 12 hours
± 15 minutes
> 12 hours
± 30 minutes
7.3
Adverse Events and Other Safety Aspects
The definitions of an AE or SAE can be found in [Appendix 12.4 Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting].
The investigator and medically qualified designee(s) are responsible for detecting, 
documenting and recording events that met the definition of an AE or SAE.
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received IP. AE collection begins after the signing of the ICF and will be collected until the 
ESV or when the subject is determined to be a screen failure.
Method of Detecting Adverse Events and Serious Adverse Events
The methods of recording, evaluating and assessing seriousness, causality and severity of 
AEs and SAEs are described in [Appendix 12.4 Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up and Reporting]. Care will be taken not to introduce 
bias when detecting AEs and/or SAEs. Open-ended and nonleading verbal questioning of the 
subject is the preferred method to inquire about AE occurrences.
An AE with a change in severity is recorded as a new AE.
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator.
If after the protocol-defined AE collection period (see [Section 7.3.1 Time Period for 
Collecting Adverse Event and Serious Adverse Event Information]), an AE progresses to an
SAE, or the investigator learns of any (S)AE (serious adverse event or adverse event) 


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including death, where he/she considers there is reasonable possibility it is related to the IP or 
study participation, the investigator must promptly notify the sponsor.
Reporting of Serious Adverse Events
Prompt notification by the investigator to the sponsor of an SAE is essential, so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
intervention under clinical investigation are met.
In the case of an SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness).
Procedures for reporting SAEs to the sponsor are described in [Section 12.4.5 Reporting 
Procedures for Serious Adverse Events].
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events
Not applicable.
Adverse Events of Special Interest
AEs of special interest are AEs that the sponsor may wish to carefully monitor. These AEs 
may be serious or nonserious and should be collected on the eCRF and the SAE worksheet
and reported within 24 hours as described in [Section 12.4.5 Reporting Procedure for Serious 
Adverse Events]. These AEs are not considered SAEs unless they meet the definition of an 
SAE. AEs of special interest in this study will include:
●
Increased heart rate and tachycardia
●
Increased blood pressure
●
Hypersensitivity reactions
Special Situations 
Certain special situations observed in association with the IP, such as incorrect administration 
(e.g., wrong dose of IP or background therapy) are collected in the eCRF, as protocol 
deviations per [Section 10.3 Major Protocol Deviations] or may require special reporting, as 
described below. These special situations are not considered AEs, but are required to be 
communicated to Astellas as per the timelines defined below.
If a special situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the special situation and captured as an AE in the eCRF. If the AE meets the 
definition of an SAE, the SAE is to be reported as described in [Section 12.4.5 Reporting 
Procedures for Serious Adverse Events] and the details of the associated special situation are 
to be included in the clinical description on the special situation worksheet.
The special situations are:
●
Pregnancy
●
Medication error, overdose and “off-label” use
●
Misuse/abuse


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●
Occupational exposure
●
Suspected drug-drug interaction
Instructions and procedures for reporting special situations are provided in [Appendix 12.4.6
Reporting Procedures for Special Situations].
Supply of New Information Affecting the Conduct of the Study
When new information becomes available that is necessary for conducting the study properly, 
the sponsor will inform all investigators involved in the study as well as the appropriate 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.
The investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue in the study.
Urgent Safety Measures
An urgent safety measure (USM) is an intervention that is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant competent authorities, IRB/IEC, where applicable, in order to protect 
subjects from any immediate hazard to their health and/or safety. Either the investigator or 
the sponsor can initiate a USM. The cause of a USM can be safety-, product- or 
procedure-related.
Reporting Urgent Safety Measures
In the event of a potential USM, the investigator must contact the study physician (within 
24 hours of awareness). Full details of the potential USM are to be recorded in the subject’s 
medical records. The sponsor may request additional information related to the event to 
support their evaluation.
If the event is confirmed to be a USM, the sponsor will take appropriate action to ensure the 
safety and welfare of the subjects. These actions may include but are not limited to a change 
in study procedures or study dosing, halting further enrollment in the study, or stopping the 
study in its entirety. The sponsor or sponsor’s designee will notify the relevant competent 
authorities and concerned ethics committee within the timelines required per current local 
regulations, and will inform the investigators, as required. When required, investigators must 
notify their IRB/IEC within timelines set by regional regulations.
7.4
Pharmacokinetics
Analysis of Mirabegron in Plasma
Blood samples will be collected for pharmacokinetic analysis of mirabegron as indicated in 
the Schedule of Assessments [Table 1].
The actual date and time of pharmacokinetic blood sample collection will be captured in the 
source. Blood sample collection, handling and storage will be described in the laboratory 
manual.  Plasma samples will be analyzed using a validated method.


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7.5
Pharmacodynamics | Immunogenicity
Not applicable.
7.6
Electronic Clinical Outcome Assessment
Not applicable.
7.7
Other Assessments
Not applicable.
7.8
Total Amount of Blood
The approximate total blood volume taken per subject will be as follows:
Table 6
Blood Volume
Sample Type
Number of 
Samples
Sample Volume 
(mL)
Total Volume (mL)
Clinical Laboratory Tests
6
7.0
(12.0)†
47.0
Pregnancy Test (Female Subjects 
Only)
3
3.0
9.0
FSH Test (Postmenopausal Female 
Subjects Only)
1
3.0
3.0
Mirabegron Pharmacokinetics
34
4.0
136.0
Total
183.0 for males
192.0 for females
186.0 for postmenopausal 
females
FSH: follicle-stimulating hormone
†
Includes serology test at screening.
Additional blood may be drawn for safety reasons. The maximum amount of blood drawn 
during the study will not exceed 400 mL.
8
DISCONTINUATION
8.1
Discontinuation of Individual Subject(s) From Study Dosing
A discontinuation from dosing is defined as a subject who enrolled in the study and for whom 
study dosing is permanently discontinued for any reason.
The subject is free to withdraw from the study dosing and/or study for any reason and at any 
time without giving reason for doing so and without penalty or prejudice. The investigator is 
also free to discontinue the subject from study dosing or to terminate a subject’s involvement 
in the study at any time if the subject’s clinical condition warrants it.
The reason for discontinuation from study dosing must be documented in the subject’s 
medical records.


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A subject must discontinue study dosing for any of the following reasons:
●
Subject requests to stop dosing
●
Any clinical AE, laboratory abnormality or intercurrent illness, in the opinion of the 
investigator, indicates continued dosing is not in the best interest of the subject
●
Hepatic function parameters: ALT or AST > 3 × ULN and/or TBL > 2 × ULN; for 
additional information on hepatic parameter abnormalities, refer to [Appendix 12.5 Liver 
Safety Monitoring and Assessment]
●
Cardiac repolarization dysfunction: QTcF > 500 msec and/or if QTcF change from 
baseline > 60 msec at repeat measurements
8.2
Discontinuation of Individual Subject(s) From Study
All subjects who discontinue study dosing will remain in the study and must continue to be 
followed for protocol-specific follow-up procedures as outlined in Schedule of Assessments 
[Table 1]. The only exception to this is when the subject specifically withdraws consent for 
any further contact with him/her or persons previously authorized by the subject to provide 
this information.
Lost to Follow-up
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments and record outstanding data.
8.3
Discontinuation of the Study Site
If an investigator intends to discontinue participation in the study, the investigator must
immediately inform the sponsor.
8.4
Discontinuation of the Study
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
9
STATISTICAL METHODOLOGY
In general, all data will be summarized with descriptive statistics for continuous endpoints, 
and frequency and percentage for categorical endpoints, unless otherwise specified. 
Percentages by categories will be based on the number of subjects with no missing data (i.e., 
will add up to 100%).
Baseline will be defined as the last nonmissing observation prior to first administration of IP, 
unless otherwise specified.


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9.1
Sample Size
A total of 24 subjects (12 subjects per dose group) will be enrolled. Subjects who 
discontinue early from the study may be replaced at the discretion of the sponsor.
Based on data from Study 178-CL-091, a Chinese phase 1 study, the intrasubject coefficient 
of variation (CV) for pharmacokinetic parameters AUCinf, AUClast and Cmax of the 
50 mg mirabegron dose are estimated to be between 33% and 60%.  Assuming the underlying 
variability is similar to 60% and an observed ratio between fasted and fed conditions of 
100%, the 90% CI will lie within (60, 167) with > 80% probability.
9.2
Analysis Sets
For each sequence, the number and percentage of subjects will be characterized for all 
randomized subjects and by each analysis set.
Safety Analysis Set
The safety analysis set (SAF) consists of all subjects who receive at least 1 dose of IP.
The SAF will be used for all summaries and analyses of the safety data.
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set (PKAS) consists of all subjects who receive at least 1 dose 
of IP for which concentration data are available to facilitate derivation of at least 1 primary 
pharmacokinetic parameter. Inclusion of subjects in the PKAS with missing data or major 
protocol deviations will be considered by the pharmacokineticist on a case-by-case basis.
The PKAS will be used for all summaries and analyses of the pharmacokinetic data.
9.3
Demographics and Baseline Characteristics
Demographics
Demographics and baseline characteristics (age, sex, race, body weight, height and BMI) will 
be summarized by dose group, sequence and overall for all randomized subjects.
Subject Disposition
The number and percentage of subjects who completed and discontinued dosing and reasons 
for dosing discontinuation will be presented for all randomized subjects and for subjects in 
the SAF by dose group, sequence and overall. Similar tables for investigational period 
disposition and follow-up disposition will also be presented for all randomized subjects by 
dose group, sequence and overall. All disposition details and dates of first and last 
evaluations for each subject will be listed.
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy)
Previous and concomitant treatment (medication and nonmedication therapy) will be listed.


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Medical History
Medical history for each subject will be listed.
Investigational Product Exposure
The number and percentage of subjects exposed to IP will be summarized by dose group and 
sequence under fed and fasted conditions.
IP exposure data will be listed.
9.4
Analysis of Efficacy
Not applicable.
9.5
Analysis of Safety
Adverse Events
AEs will be coded using MedDRA. An AE with onset at any time from first dosing until last 
scheduled procedure will be classified as a TEAE for inclusion in the summary tabulations. 
An IP-related TEAE is defined as any TEAE with a causal relationship assessed as “yes” by 
the investigator, or records where the relationship is missing.
An overview and separate summaries of the number and percentage of subjects with TEAEs, 
drug-related TEAEs, TEAEs leading to withdrawal of dosing, IP-related TEAEs leading to 
withdrawal of dosing and TEAEs excluding SAEs that equal or exceed a threshold of 5% in 
any dose group under fed and fasted conditions will be presented by SOC, preferred term, by 
fed and fasted conditions for each dose group. Also included in the overview are the number 
and percentage of subjects with serious TEAEs, IP-related serious TEAEs, TEAEs leading to 
death and IP-related TEAEs leading to death.
AE data will be listed.
Laboratory Assessments
For quantitative clinical laboratory measurements (hematology and biochemistry), descriptive 
statistics will be used to summarize results and change from baseline by fed and fasted 
conditions and visit for each dose group.
Laboratory data will be listed.
Vital Signs
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects by fed and fasted conditions and time point for each dose group.
Vital signs data will be listed.
Electrocardiogram
9.5.4.1
Routine 12-lead Electrocardiogram
Routine 12-lead ECG data and interpretations will be listed.


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9.6
Analysis of Pharmacokinetics
Descriptive statistics will include n, mean, SD, CV, geometric mean, geometric CV, median, 
minimum and maximum.  For the pharmacokinetic parameters tmax and tlag, only n, median, 
minimum and maximum will be calculated.
Plasma Concentrations
Plasma concentrations under both fasted and fed conditions will be listed and summarized 
using descriptive statistics by scheduled time point for each dose group. Standard graphics 
including mean plasma concentration-time profiles, overlay (spaghetti) plots and individual 
subject plasma concentration-time profiles will be produced.
Estimation of Pharmacokinetic Parameters
Noncompartmental analysis will be used for the calculation of plasma pharmacokinetic 
parameters using Phoenix® (Certara LP, 100 Overlook Center, Suite 101, Princeton, 
NJ 08540, US).
Plasma pharmacokinetic parameters under both fasted and fed conditions will be listed and 
summarized using descriptive statistics for each dose group.
Statistical Analysis of Pharmacokinetic Parameters
To assess the effect of food on the pharmacokinetic of mirabegron, a mixed effects analysis 
of variance (ANOVA) model with fixed effects for food condition (fed or fasted) and period 
and subject as a random effect will be fitted on natural logarithm-transformed AUCinf,
AUClast and Cmax.  Within the ANOVA, the least squares (LS) mean differences between fed 
and fasted, along with 90% CIs for the differences will be estimated for 25 and 
50 mg mirabegron doses separately.
The LS means for AUCinf, AUClast and Cmax will be back-transformed to produce the 
geometric LS means and presented with the number of subjects for each food condition.  The 
geometric LS mean ratios and their corresponding 90% CIs for each pharmacokinetic 
parameter will be presented by back-transforming and expressed as percentages. The 
analysis will be repeated if all subjects did not complete both periods using an ANOVA with 
fixed effects for period, food condition and subject; this analysis will only include subjects 
with complete data in both periods.
9.7
Analysis of Pharmacodynamics | Immunogenicity
Not applicable.
9.8
Other Analyses
Not applicable.
9.9
Major Protocol Deviations
Major protocol deviations as defined in [Section 10.3 Major Protocol Deviations] will be 
listed.


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9.10
Interim Analysis (and Early Discontinuation of the Study)
Not applicable.
9.11
Additional Conventions
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of AEs and concomitant medications if they are missing on day of first IP 
administration. The imputed dates will be used to assess if the AEs or concomitant 
medications are treatment emergent or concomitant, respectively. Listings of the AEs and 
concomitant medications will present the actual partial dates; imputed dates will not be 
shown.
10
OPERATIONAL CONSIDERATIONS
10.1
Data Collection
The investigator or site designee will enter data collected using an electronic data capture 
system. In the interest of collecting data in the most efficient manner, the investigator or 
designee should record data (including clinical laboratory values, if applicable) in the eCRF 
within 10 working days after the subject’s visit. The data will be entered after HGRAC data 
filing approval if required by site.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with the source. These 
documents should be appropriately maintained by the study site.
The monitor should verify the data in the eCRFs with the source and confirm that there are no 
inconsistencies among them.
Clinical laboratory tests and ECG are performed at a local laboratory.
10.2
Demographics and Baseline Characteristics
Demographics
Demographics and baseline characteristics will be collected as indicated in the Schedules of 
Assessments [Table 1]. This will include age, sex, race, body weight, height and BMI.
Medical History
A complete medical history will be collected as indicated in the Schedules of Assessments 
[Table 1].
10.3
Major Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. All deviations from the protocol are to be 
recorded. A protocol waiver is a documented prospective approval of a request from an 
investigator to deviate from the protocol. Protocol waivers are strictly prohibited.


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The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol and must protect the rights, safety and 
well-being of subjects. The investigator should not implement any deviation from, or 
changes of, the protocol, unless it is necessary to eliminate an immediate hazard to subjects.
A major protocol deviation is one that may potentially impact the completeness, accuracy or 
reliability of data contributing to the primary endpoint or affect the rights, safety or 
well-being of a subject. Major protocol deviations will have additional reporting 
requirements.
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified. The sponsor will follow up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety 
and/or pharmacokinetic parameters of the subject to determine subject continuation in the 
study.
The major protocol deviation criteria that will be summarized at the end of the study are as 
follows:
PD1 - Entered into the study even though the subject did not satisfy entry criteria
PD2 - Developed withdrawal criteria during the study and was not withdrawn
PD3 - Received incorrect dose
PD4 - Received excluded concomitant treatment
The investigator will also assure that deviations meeting IRB/IEC and appropriate regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and appropriate regulatory authorities will be provided to the 
sponsor and maintained within the trial master file.
10.4
Study organization
Independent Data Monitoring Committee | Data and Safety Monitoring Board | 
Monitoring Committee | Adjudication Committee | Other Evaluation 
Committee(s)
Not applicable.
Other Study Organization
Not applicable.


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11
REFERENCES
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of 
terminology of lower urinary tract function: report from the Standardisation Sub-committee of 
the International Continence Society. Neurourol Urodyn. 2002;21(2):167-78.
Andersson KE. New developments in the management of overactive bladder: focus on mirabegron 
and onabotulinumtoxinA. Ther Clin Risk Manag. 2013;9:161-70.
Betmiga Package Insert, August 2019.
Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D. The effects of antimuscarinic 
treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol. 
2008;54(3):543-62.
Chapple CR, Cardozo L, Nitti VW, Siddiqui E, Michel MC. Mirabegron in overactive bladder: a 
review of efficacy, safety, and tolerability. Neurourol Urodyn. 2014;33:17-30.
Charlson ME, Pompei P, Ales KL, Mackenzie CR. A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. J Chronic Dis. 
1987;40(5):373-83.
Chen D, Li Y. The impact of overactive bladder on quality of life in south of China. J Sci Appl: 
Biomed. 2016;4(2):19-23.
Chuang YC, Liu SP, Lee KS, Liao L, Wang J, Yoo TK, et al. Prevalence of overactive bladder in 
China, Taiwan and South Korea: Results from a cross-sectional, population-based study. Low 
Urin Tract Symptoms. 2019;11(1):48-55.
Coyne KS, Elinoff V, Gordon DA, Deng DY, Brodsky M, Glasser DB, et al. Relationships between 
improvements in symptoms and patient assessments of bladder condition, symptom bother and 
health-related quality of life in patients with overactive bladder treated with tolterodine. Int J 
Clin Pract. 2008;62(6):925-31.
Investigator’s Brochure, Mirabegron, Edition 16, Jan 2020, Astellas.
Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S, et al. Population-based survey of 
urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five 
countries: results of the European Prospective Investigation into Cancer and Nutrition study. 
Eur Urol. 2006;50(6):1306-14.
Lapitan MC, Chye PL. The epidemiology of overactive bladder among females in Asia: a 
questionnaire survey. Int Urogynecol J Pelvic Floor Dysfunct. 2001;12(4):226-31.
Moorthy P, Lapitan MC, Quek PL, Lim PH. Prevalence of overactive bladder in Asian men: an 
epidemiological survey. BJU Int. 2004;93(4):528-31.
Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V et al. A systematic review and meta-
analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Eur 
Urol. 2008;54(4):740-63.


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Osman NI, Chapple CR. Overactive bladder syndrome: Current pathophysiological concepts and 
therapeutic approaches. Arab J Urol. 2013;11(4):313-18.
Sexton CC, Notte SM, Maroulis C, Dmochowski RR, Cardozo L, Subramanian D, et al. Persistence 
and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a 
systematic review of the literature. Int J Clin Pract. 2011;65(5):567-85.
Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, et al. Prevalence and 
burden of overactive bladder in the United States. World J Urol. 2003;20(6):327-36.


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12
APPENDICES
12.1
Ethical, Regulatory and Study Oversight Considerations
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing study conduct and the ethical principles that have their 
origin in the Declaration of Helsinki.
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities
Good Clinical Practice (GCP) requires that the protocol, any protocol amendments, 
Investigator’s Brochure, ICF and all other forms of subject information related to the study 
(e.g., advertisements used to recruit subjects) and any other necessary documents be reviewed 
by an IRB/IEC. The IRB/IEC will review the ethical, scientific and medical appropriateness 
of the study before it is conducted. IRB/IEC approval of the protocol, ICF and subject 
information and/or advertising, as relevant, will be obtained prior to initiation of any 
study-specific procedures.
Any substantial amendments to the protocol will require competent authority and IRB/IEC 
approval before implementation, except for changes necessary to eliminate an immediate 
hazard to subjects.
The investigator will be responsible for the following:
●
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies and procedures established by 
the IRB/IEC
●
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
●
Providing oversight of the conduct of the study at the study site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU Regulation No. 536/2014 for 
studies (if applicable), and all other applicable local regulations
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as
protocol amendments: substantial amendments and/or nonsubstantial amendments. 
Depending on the nature of the amendment, either IRB/IEC or competent authority approval 
or notification may be required. The changes will become effective only after the approval of 
the sponsor, investigator, IRB/IEC and appropriate regulatory authorities.
Amendments to this protocol must be signed by the sponsor and investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented. 
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
regulations.


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If there are changes to the ICF, written verification of IRB/IEC approval must be forwarded 
to the sponsor. An approved copy of the new ICF must also be forwarded to the sponsor.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
Informed Consent of Subjects
12.1.5.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject
and answer all questions regarding this study. Prior to any study-related screening 
procedures being performed on the subject, the ICF will be reviewed, signed and dated by the 
subject, the person who administered the ICF and any other signatories according to local 
requirements. A copy of the signed ICF will be given to the subject and the original will be 
placed in the subject’s medical record. If the subject signs 2 original ICFs, 1 of the original 
ICFs will be given to the subject and the other original ICF will be placed in the subject’s 
medical record.  An entry must also be made in the subject’s dated source documents to 
confirm that the ICF was signed prior to any study-related procedures and that the subject 
received a signed copy of the ICF.
The signed ICFs will be retained by the investigator and made available (for review only) to 
the study monitor, auditor and appropriate regulatory authorities and other applicable 
individuals upon request.
12.1.5.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject verbally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue participating in the study 
(e.g., report of serious adverse drug reaction). The communication must be documented 
in the subject’s medical records and whether the subject is willing to remain in the study 
or not must be confirmed and documented.
2.
The investigator must update the subject’s ICF and submit it for approval to the 
IRB/IEC. The investigator or his/her representative must obtain written informed 
consent from the subject on all updated ICFs throughout their participation in the study. 
The investigator or his/her designee must reconsent subjects with the updated ICF even if 
relevant information was provided verbally. The investigator or his/her representative 
who obtained the written informed consent and the subject should sign and date the ICF. 
A copy of the signed ICF will be given to the subject and the original will be placed in 
the subject’s medical record. An entry must be made in the subject’s records 
documenting the reconsent process.


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Source Documents
Source data must be available at the study site to document the existence of the subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are handwritten on paper 
or entered electronically. If source data are created (first entered), modified, maintained, 
achieved, retrieved or transmitted electronically via computerized systems (and/or other kind 
of electronic devices) as part of regulated study activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health 
records, protocol-related assessments, AE tracking, electronic clinical outcome assessment 
(eCOA) and/or drug accountability.
Paper records from electronic systems used in place of electronic format must be certified 
copies. A certified copy must be an exact copy and must have all the same attributes and 
information as the original. Certified copies must include signature and date of the individual 
completing the certification. Certified copies must be a complete and chronological set of 
study records (including notes, attachments, and audit trail information, if applicable). All 
printed records must be kept in the subject file and be available for archiving.
Record Retention
The investigator will archive all study data (e.g., subject identification code list, source data,
case report forms [CRFs] and investigator’s file) and relevant correspondence. These 
documents are to be kept on file for the appropriate term determined by local regulation. The 
investigator agrees to obtain the sponsor’s agreement prior to disposal, moving or transferring 
of any study-related records. The sponsor will archive and retain all documents pertaining to 
the study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subject’s 
medical records and/or study progress notes.
Subject Confidentiality and Privacy
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the subject provides written 
consent or approval. Additional medical information may be given only after approval of the 
subject to the investigator or to other appropriate medical personnel responsible for the 
subject’s well-being.
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the study without justifiable reasons.


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Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to a subject’s privacy due to direct access to source 
documents, or from other sources, they may not disclose the content to third parties.
The sponsor affirms the subject’s right to protection against invasion of privacy. Only a 
subject identification number will identify subject data retrieved by the sponsor. However, 
the sponsor requires the investigator to permit the sponsor, sponsor’s representative(s), the 
IRB/IEC and when necessary, representatives of the regulatory health authorities to review 
and/or to copy any medical records relevant to the study.
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and privacy laws in the US. If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then the sponsor shall serve as the controller of 
such data, as defined by the EU Data Protection Directive (DPD), and investigator and/or 
third party shall act only under the instructions of the sponsor in regard to personal data. If 
the sponsor is not based in the EEA, the sponsor must appoint a third party to act as its local
data protection representative or arrange for a co-controller established in the EU for data 
protection purposes in order to comply with the DPD.
Arrangement for Use of Information and Publication of the Study
Information concerning the test product, patent applications, processes, unpublished scientific 
data, the Investigator’s Brochure and other pertinent information is confidential and remains 
the property of the sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the sponsor will use the 
information obtained during the study in connection with the development of the drug and 
therefore may disclose it as required to other clinical investigators or to regulatory agencies. 
In order to allow for the use of the information derived from this study, the investigator 
understands that he/she has an obligation to provide the sponsor with all data obtained during 
the study.
Publication of the study results is discussed in the study agreement.
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final clinical 
study report that forms part of a marketing authorization application, be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator(s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for the 
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the sponsor prior to database hard-lock.


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12.2
Procedure for Study Quality Control
Study Monitoring
The sponsor or delegated CRO is responsible for monitoring the study to ensure that the 
rights, safety and well-being of subjects are protected, the study is properly conducted in 
adherence to the current protocol and GCP and the study data reported by the 
investigator/subinvestigator are accurate, complete and verifiable with the source. The 
sponsor is responsible for assigning the study monitor(s) to this study for proper monitoring. 
They will monitor the study in accordance with planned monitoring procedures.
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO, as well as inspections from the IRB/IEC and appropriate regulatory 
authorities. In these instances, they must provide all study-related records including source 
documents when they are requested by the sponsor monitors and auditors, the CRO, the 
IRB/IEC or appropriate regulatory authorities. The confidentiality of the subject’s identity 
shall be well protected consistent with local and national regulations when the source 
documents are subject to direct access.
Data Management
Data management will be coordinated by the Data Science department or designee of the 
sponsor in accordance with the standard operating procedures (SOPs) for data management. 
All study-specific processes and definitions will be documented by data management. eCRF 
completion will be described in the eCRF instructions. Coding of medical terms and 
medications will be performed using MedDRA and the WHO Drug Dictionary, respectively. 
Data management is accountable for eCOA.
Quality Assurance
The sponsor is implementing and maintaining quality assurance (QA) and quality control 
(QC) systems with written SOPs to ensure that studies are conducted and data are generated, 
documented, recorded, and reported in compliance with the protocol, GCP and applicable 
regulatory requirement(s). Where applicable, the QA and QC systems and written SOPs of 
the CRO will be applied.
The sponsor or sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities. The audit may include on-site review of regulatory documents, CRFs and source 
documents. Direct access to these documents will be required by the auditors.
To support quality around subject safety and reliability of study results, quality tolerance 
limits (QTLs) are defined and monitored. QTLs represent the acceptable variation of study 
data, taking into consideration the current state of medical and statistical knowledge about the 
variables to be analyzed as well as the statistical design of the study. It is a level, point, or 
value associated with a parameter that should trigger an evaluation if a deviation is detected 


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to determine if there is a possible systematic issue (i.e., a trend has occurred). The QTLs 
defined for this study are provided below.
Table 7
Quality Tolerance Limit
QTL #: Name and Parameter
Definition
Parameter Justification
QTL1: Pharmacokinetic sample 
collection compliance
% of pharmacokinetics samples 
that are not collected or collected 
outside the allowed collection 
window
A high percentage of 
pharmacokinetic samples missed 
or collected outside of the 
collection window can have an 
impact on the assessment of the 
pharmacokinetic parameters
QTL2: Time of meal intake and 
IP administration compliance
% of meal intake and IP 
administration that are conducted 
outside the allowed time window
A high percentage of food intake 
and IP administration conducted 
outside of the designated time 
window can have an impact on the 
evaluation of the food effect
IP: investigational product; QTL: quality tolerance limit
Additional information regarding the QTL and limit justification, as well as associated 
activities can be found in STL-3458 QTL monitoring plan.
QTL Management Activities:
●
For control of risks associated with QTL1: Pharmacokinetic sample collection 
compliance, refer to the Schedule of Assessments [Table 1] and [Section 7.2.6 Order of 
Assessments]
●
For control of risks associated with QTL2: Time of meal intake and IP administration 
compliance, refer to the Schedule of Assessments [Table 1]
The allowed collection window for pharmacokinetic blood samples is shown in [Table 8].
Table 8
Acceptable Collection Window for Pharmacokinetic Blood Samples
Nominal Time
Acceptable Window
(half-life < 48 hours)
Predose
-90 to 0 minutes
0 to < 4 hours
± 2 minutes
4 to < 12 hours
± 5 minutes
12 to < 48 hours
± 15 minutes
48 hours and thereafter
± 30 minutes


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12.3
Contraception Requirements
WOCBP who are eligible for participation in the study, including those who choose complete 
abstinence, must have pregnancy tests as specified in the Schedule of Assessments [Table 1]. 
Pregnancy test results must confirm that the subject is not pregnant.
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile.
Females in the following categories are not considered WOCBP
●
Premenarchal
●
Premenopausal with 1 of the following (i.e., permanently sterile):
○Documented hysterectomy
○Documented bilateral salpingectomy
○Documented bilateral oophorectomy
●
Postmenopausal
A postmenopausal state is defined as at least 12 months after last menstrual bleeding without 
an alternative medical cause.
In case the last menstrual bleeding cannot be clearly determined, confirmation with more 
than 1 FSH measurement of at least > 40 IU/L (or higher per local institutional guidelines) is 
required.
Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
nonestrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status by repeated FSH measurements before study enrollment.
Documentation of any of these categories can come from the study site personnel’s review of 
the female subject’s medical records, medical examination or medical history interview.
CONTRACEPTION GUIDANCE FOR FEMALE SUBJECTS OF CHILDBEARING 
POTENTIAL
Female subjects of childbearing potential are eligible for participation in the study if they 
agree to use 1 of the highly effective methods of contraception listed below from the time of 
signing the ICF and until the end of relevant systemic exposure, defined as 30 days after the 
final IP administration.a
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly)b:
●
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation
○
Oral


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○
Intravaginal
○
Transdermal
●
Progestogen-only hormonal contraception associated with inhibition of ovulation
○
Oral
○
Injectable
○
Implantable
●
Other combined (estrogen- and progesterone-containing) methods
○
Vaginal ring
○
Injectable
○
Implantable
○
Intrauterine hormone-releasing system or intrauterine device
●
Bilateral tubal occlusion
●
Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.
●
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the test 
product. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the subject. It is not 
necessary to use any other method of contraception when complete abstinence is elected.
aLocal laws and regulations may require use of alternative and/or additional contraception methods.
bTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.
CONTRACEPTION GUIDANCE FOR MALE SUBJECTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL
Male subjects with female partners of childbearing potential are eligible for participation in 
the study if they agree to the following during dosing and until the end of relevant systemic 
exposure defined as 30 days after final drug administration.a
●
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator
●
Use a condom
●
Female partners of male subjects who have not undergone a vasectomy with the absence 
of sperm confirmed or a bilateral orchiectomy should consider use of effective methods 
of contraception
aLocal laws and regulations may require use of alternative and/or additional contraception methods.


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12.4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting
Definition of Adverse Events
An AE is any untoward medical occurrence in a subject administered an IP, and which does 
not necessarily have to have a causal relationship with this IP. 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.
12.4.1.1 Abnormal Laboratory Findings
Any abnormal laboratory test result (e.g., hematology, biochemistry or urinalysis) or other 
safety assessment (e.g., vital signs, physical examination, ECGs or radiographic scans), 
including those that worsen from baseline, that is considered to be clinically significant in the 
medical and scientific judgment of the investigator and not related to underlying disease, is to 
be reported as an (S)AE.
Any clinically significant abnormal laboratory finding or other abnormal safety assessment,
which is associated with the underlying disease, does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition.
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be 
an error does not require reporting as an AE.
12.4.1.2 Potential Cases of Drug-induced Liver Injury
Refer to [Appendix 12.5 Liver Safety Monitoring and Assessment] for detailed instructions 
on drug-induced liver injury. Abnormal values in AST and/or ALT concurrent or with 
abnormal elevations in TBL that meet the criteria outlined in [Appendix 12.5 Liver Safety 
Monitoring and Assessment], in the absence of other causes of liver injury, are considered 
potential cases of drug-induced liver injury (potential Hy’s Law cases) and are always to be 
considered important medical events and reported per [Appendix 12.4.5 Reporting 
Procedures for Serious Adverse Events].
Definition of Serious Adverse Events
An AE is considered “serious” if, in the view of either the investigator or sponsor, the event:
●
Results in death
●
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death; it 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
●
Results in congenital anomaly, or birth defect


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●
Requires inpatient hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE)
●
Other medically important events (defined in paragraph below)
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
usually are considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
Criteria for Causal Relationship to Investigational Product
A medically qualified investigator is obligated to assess the relationship between IP and each 
occurrence of each (S)AE. This investigator will use medical judgment as well as the RSI
(see [Investigator’s Brochure, Appendix 1]) to determine the relationship. The causality 
assessment is 1 of the criteria used when determining regulatory reporting requirements.
The investigator is requested to provide an explanation for the causality assessment for each 
(S)AE and must document in the medical notes that he/she has reviewed the (S)AE and has 
provided an assessment of causality.
Following a review of the relevant data, the causal relationship between the IP and each 
(S)AE will be assessed by answering “yes” or “no” to the question “Do you consider that 
there is a reasonable possibility that the event may have been caused by the IP?”
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a “reasonable possibility” 
that an (S)AE may have been caused by the IP (rather than a relationship cannot be ruled out) 
or if there is evidence to reasonably deny a causal relationship:
●
Has the subject been administered IP? 
●
Plausibility (i.e., could the event been caused by the suspect drug? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and study data, etc.)
●
Dechallenge/dose reduction/rechallenge:
○
Dechallenge: Did the (S)AE resolve or improve after only stopping the dose of the 
suspect drug without any treatment?
○
Dose reduction: Did the (S)AE resolve or improve after reducing the dose of the 
suspect drug?
○
Rechallenge: Did the (S)AE reoccur if the suspected drug was reintroduced after 
having been stopped?


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●
Laboratory or other test results: a specific laboratory investigation supports the 
assessment of the relationship between the (S)AE and the IP (e.g., based on values pre-, 
during and post-dosing)
●
Available alternative explanations independent of IP exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc., and strength of the 
alternative explanation
●
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible 
temporal relationship between exposure to the IP and (S)AE onset and/or resolution will 
be provided. Did the (S)AE occur in a reasonable temporal relationship to the 
administration of the IP?
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that 
the investigator always assesses causality for every event before the initial transmission of the 
SAE data to the sponsor. With limited or insufficient information about the event to make an 
informed medical judgment and in absence of any indication or evidence to establish a causal 
relationship, a causality assessment of “no” is to be considered. In such instance, the 
investigator is expected to obtain additional information regarding the event as soon as 
possible and to re-evaluate the causality upon receipt of additional information. The 
medically qualified investigator may revise his/her assessment of causality in light of new 
information regarding the SAE and shall send an SAE follow-up report and update the eCRF 
with the new information and updated causality assessment.
Criteria for Defining the Severity of an Adverse Event
The investigator will use the following definitions to rate the severity of each AE:
●
Mild (Grade 1): No disruption of normal daily activities
●
Moderate (Grade 2): Affect normal daily activities
●
Severe (Grade 3): Inability to perform daily activities
Reporting Procedures for Serious Adverse Events
The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by fax or email immediately 
(within 24 hours of awareness).
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
delegation of authority log). Signature confirms accuracy and completeness of the SAE data 
as well as the investigator causality assessment including the explanation for the causality 
assessment.
The investigator must complete and submit the reports as required by local regulation, 
containing all necessary information, to the competent authority.


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For contact details, see [Contact Details of Sponsor’s Key Personnel]. Fax or email the 
SAE/special situation worksheet to:
Astellas Pharma Global Development Inc.
Global Pharmacovigilance
Fax number: +44-800-471-5263
Email: safety-us@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor’s medical monitor/study physician or their designee [Contact Details of Sponsor’s 
Key Personnel].
Follow-up information for the event should be sent promptly (as soon as available but no
longer than within 7 days of the initial notification).
Full details of the SAE should be recorded on the medical records, SAE/special situation 
worksheet and on the eCRF.
The following minimum information is required:
●
International study number/study number 
●
Subject number, sex and age
●
Date of report
●
Description of the SAE (event and seriousness criteria) 
●
Causal relationship to the IP (including reason)
●
Drug provided (if any)
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality and 
expectedness of the events (e.g., suspected unexpected serious adverse reaction [SUSAR]
reporting) according to current local/regional regulatory requirements. The sponsor or 
sponsor’s designee will submit expedited safety reports to competent authorities and 
concerned ethics committee per current local regulations and will inform the investigators of 
such regulatory reports as required. Investigators must submit safety reports as required by 
their IRB/IEC within timelines set by regional regulations (NMPA) where required. 
Documentation of the submission to and receipt by the IRB/IEC of expedited safety reports 
should be retained by the study site.
The delegated CRO will notify all investigators responsible for ongoing clinical studies with 
the test product of all SUSARs, which require submission per local requirements of IRB/IEC.
Investigators should provide written documentation of IRB/IEC notification for each report to 
the sponsor.
The investigator may contact the sponsor’s medical monitor/study physician for any other 
problem related to the rights, safety or well-being of the subject.


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Reporting Procedures for Special Situations
12.4.6.1 Pregnancy
If a female subject becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Appendix 12.4.5 Reporting Procedures for Serious Adverse 
Events] using the SAE worksheet as a special situation and in the eCRF.
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing and report the information to sponsor according to the timelines
in [Appendix 12.4.5 Reporting Procedures for Serious Adverse Events] using the SAE 
worksheet as a special situation.
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data, etc., should be included in this 
information.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
subject as an AE in the eCRF or SAE per [Appendix 12.4.5 Reporting Procedures for Serious 
Adverse Events]. For (S)AEs experienced by a female partner of a male subject, (S)AEs are 
to be reported via the SAE worksheet.
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below:
●
“Spontaneous abortion” includes miscarriage, abortion and missed abortion.
●
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the IP
●
If an infant dies more than 1 month after the birth, it is to be reported if a relationship 
between the death and intrauterine exposure to the IP is judged as “possible” by the 
investigator
●
Congenital anomaly (including anomaly in miscarried fetus)
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination or other 
means as appropriate. (S)AEs experienced by the newborn/infant should be reported via the 
pregnancy reporting form. Generally, follow up will be no longer than 6 to 8 weeks 
following the estimated delivery date.
12.4.6.2 Medication Error, Overdose and “Off-label Use”
If a medication error (defined as an unintended failure in the dosing process that leads to, or 
has the potential to lead to, harm to the subject), overdose or “off-label use” (i.e., use outside 
of what is stated in the protocol) is suspected, refer to [Section 10.3 Major Protocol 
Deviations]. Any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of an SAE, the SAE is also to be reported as described in [Appendix 12.4.5


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Reporting Procedures for Serious Adverse Events] together with the details of the medication 
error, overdose and/or “off-label use”.
In the event of suspected overdose, refer to the approved package insert, summary of product 
characteristics or local product information supplied by the manufacturer for the IP.
12.4.6.3 Misuse/Abuse
Definition of misuse: situations where the IP is/are intentionally and inappropriately used not 
in accordance with the intended use as defined in the protocol.
Definition of abuse: persistent or sporadic, intentional excessive use of medicinal products 
which is accompanied by harmful physical or psychological effects.
If misuse or abuse of the IP is suspected, the investigator must forward the special situation 
worksheet to the sponsor by fax or email immediately (within 24 hours of awareness). Any 
associated (S)AEs are to be reported in the eCRF. If the AE meets the definition of an SAE, 
the SAE is also to be reported as described in [Appendix 12.4.5 Reporting Procedures for 
Serious Adverse Events] together with details of the misuse or abuse of the IP.
12.4.6.4 Occupational Exposure
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the subject) to the IP occurs, the investigator must forward 
the special situation worksheet to the sponsor by fax or email immediately (within 24 hours 
of awareness). Any associated (S)AEs occurring to the individual associated with or 
resulting from the special situation are to be reported on the special situation worksheet.
12.4.6.5 Suspected Drug-drug Interaction
If a drug-drug interaction associated with the IP is suspected, the investigator must forward 
the special situation worksheet to the sponsor by fax or email immediately (within 24 hours 
of awareness). Any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of an SAE, the SAE is also to be reported as described in [Appendix 12.4.5
Reporting Procedures for Serious Adverse Events] together with details of the suspected 
drug-drug interaction.


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12.5
Liver Safety Monitoring and Assessment
The purpose of this appendix is to provide guidance for the monitoring of drug-induced liver 
injury during the course of the study. It should be noted that this section does not specify the 
end-of-study analyses of liver enzymes. Any subject enrolled in a study with active drug 
therapy and reveals an increase of serum aminotransferases (ATs) to > 3 × ULN or 
TBL > 2 × ULN should undergo detailed testing for liver enzymes (including at least alkaline 
phosphatase [ALP], ALT, AST and TBL). Testing should be repeated within 72 hours of 
notification of the test results. Subjects should be asked if they have any symptoms 
suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN is as 
shown below.
Table 9
Moderate and Severe Liver Abnormalities
ALT or AST
TBL
Moderate
> 3 × ULN
or
> 2 × ULN
Severe
> 3 × ULN
and†
> 2 × ULN
ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total bilirubin; ULN: upper limit of 
normal
†Samples taken simultaneously or within a maximum of 24 hours.
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks
●
ALT or AST > 3 × ULN and† TBL > 2 × ULN or international normalized ratio (INR) 
> 1.5 (if INR testing is applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)
† Samples taken simultaneously or within a maximum of 24 hours.
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and clinical laboratory tests. The study site personnel are to complete 
the liver abnormality case report form (LA-CRF). Subjects with confirmed abnormal liver 
function testing should be followed as described below.


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Confirmed moderately abnormal liver function tests should be repeated 2 to 3 times weekly, 
and then weekly or less if abnormalities stabilize or the IP has been discontinued and the 
subject is asymptomatic.
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 
sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to IP are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases are to be recorded as “AEs” within the eCRF. Illnesses and 
conditions such as hypotensive events and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic and/or diabetic subjects and may be associated with 
fluctuating AT levels. The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function.
●
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications are to be entered in the eCRF. Information on alcohol, other 
substance use and diet should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including:
○
Acute viral hepatitis (A, B, C, D, E or other infectious agents)
○
Ultrasound or other imaging to assess biliary tract disease
○
Other clinical laboratory tests, including INR and direct bilirubin
●
Consider gastroenterology or hepatology consultations
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document
Study Dosing Discontinuation
In the absence of an explanation for increased liver function tests, such as viral hepatitis, 
preexisting or acute liver disease, or exposure to other agents associated with liver injury, the 
subject may be discontinued from study dosing. The investigator may determine that it is not 
in the subject’s best interest to continue study dosing. Discontinuation of study dosing
should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks
●
ALT or AST > 3 × ULN and† TBL > 2 × ULN or INR > 1.5 (if INR testing is 
applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)


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† Samples taken simultaneously or within a maximum of 24 hours.
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study dosing should be discontinued.
Hy’s Law definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant).
The 2 “requirements” for Hy’s Law are: 
1.
Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in AT elevations > 3 × ULN (“2 × ULN elevations are too common in treated 
and untreated subjects to be discriminating”)
2.
Cases of increased TBL (at least 2 × ULN) with concurrent AT elevations at least 
3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated ALP) 
or Gilbert’s syndrome [Temple, 2006]
FDA Guidance for Industry titled, “Drug-induced Liver Injury: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009:
1.
The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold 
or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control 
drug or placebo
2.
Among subjects showing such AT elevations, often with ATs much greater than 
3 × ULN, 1 or more also show elevation of serum TBL to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP)
3.
No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another drug capable 
of causing the observed injury
References
Temple R. Hy’s Law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;15(4):241-3.


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12.6
List of Excluded Concomitant Medications
Not applicable.


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12.7
Laboratory Assessments
Laboratory tests will be performed as indicated in the Schedule of Assessments [Table 1] and 
sent to the local laboratory for analysis.
Table 10
Clinical Laboratory Tests
Panel/Assessments
Matrix
Parameters to be Analyzed
Hematology
Blood
Hemoglobin
Hematocrit
Erythrocytes 
Leukocytes
Differential leukocytes
Platelets
Biochemistry
Plasma/serum
Sodium
Potassium
Calcium
Chloride
Magnesium
Inorganic Phosphorus
Glucose
Alkaline phosphatase
Aspartate aminotransferase
Alanine aminotransferase
Gamma-glutamyl transferase
Total bilirubin
Total cholesterol
Triglycerides
Blood urea
Creatinine
Creatine kinase
Lactate dehydrogenase
Total protein
Uric acid
Albumin
FSH (postmenopausal female subjects only)
Urinalysis (Dipstick)
Urine
Protein
Glucose
pH
Occult blood
Leukocytes
Urobilinogen
Bilirubin
Ketones
Nitrite
Urinalysis (Microscopy)
Urine
Erythrocytes
Leukocytes
Table continued on next page


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Panel/Assessments
Matrix
Parameters to be Analyzed
Serology
Plasma/serum
HAV antibodies (IgM)
HBsAg
HBc antibodies
HCV antibodies
HIV antibodies
Treponema pallidum antibodies
Drugs of Abuse and 
Alcohol Test
Urine
Amphetamines
Benzodiazepines
Cannabinoids
Cocaine
Opiates
Breath test/blood/urine
Alcohol
Pregnancy Test
Serum
Human chorionic gonadotropin (female subjects 
only)
FSH: follicle-stimulating hormone; HAV: hepatitis A virus; HBc: hepatitis B core; HBsAg: hepatitis B surface 
antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; IgM: immunoglobulin M


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12.8
List of Abbreviations and Definition of Key Study Terms
List of Abbreviations
Abbreviations
Description of abbreviations
ACN
Astellas Pharma China, Inc.
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AT
aminotransferases
AUCinf
area under the concentration-time curve from the time of dosing extrapolated 
to time infinity
AUCinf (%extrap)
area under the concentration-time curve from the time of dosing extrapolated 
to time infinity as a percentage of total area under the concentration-time 
curve
AUClast
area under the concentration-time curve from the time of dosing to the last 
measurable concentration
BMI
body mass index
CL/F
apparent total systemic clearance after extravascular dosing
Cmax
maximum concentration
CRF
case report form
CRO
contract research organization
CV
coefficient of variation
DBP
diastolic blood pressure
DPD
Data Protection Directive
ECG
electrocardiogram
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form
EEA
European Economic Area
ESV
end-of-study visit
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HAV
hepatitis A virus
HBc
hepatitis B core
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
HRT
hormone replacement therapy
ICF
informed consent form


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Abbreviations
Description of abbreviations
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgM
immunoglobulin M
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
LA-CRF
liver abnormality case report form
LS
least square(s)
NMPA
National Medical Products Administration
OAB
overactive bladder
PKAS
pharmacokinetic analysis set
QA
quality assurance
QC
quality control
QTcF
corrected QT interval using Fridericia’s formula
QTL
quality tolerance limit
RSI
reference safety information
(S)AE
serious adverse event or adverse event
SAE
serious adverse event
SAF
safety analysis set
SBP
systolic blood pressure
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reactions
t½
terminal elimination half-life
TBL
total bilirubin
TEAE
treatment-emergent adverse event
tlag
time prior to the time corresponding to the first measurable (nonzero) 
concentration
tmax
time of maximum concentration 
ULN
upper limit of normal
USM
urgent safety measure
Vz/F
apparent volume of distribution during the terminal elimination phase after 
extravascular dosing
WOCBP
woman of childbearing potential


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Definition of Key Study Terms
Terms
Definition of Terms
Baseline 
Assessments of subjects as they enter a study before they receive any IP.
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a study.
Note: Not all endpoints are themselves assessments since certain endpoints 
might apply to populations or emerge from analysis of results. That is, 
endpoints might be facts about assessments (e.g., prolongation of survival).
Enroll
To register or enter a subject into a study. Note: Once a subject has received 
the IP or placebo, the protocol applies to the subject.
Intervention
The drug, device, therapy or process under investigation in a study that is 
believed to have an effect on outcomes of interest in a study (e.g., 
health-related quality of life, efficacy, safety and pharmacoeconomics).
Investigational 
period
Period of time where major interests of protocol objectives are observed, and 
where the test product or comparative drug (sometimes without 
randomization) is given to a subject, and continues until the last assessment 
after completing administration of the test product or comparative drug.
Randomization
The process of assigning subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
NOTE: Unequal randomization is used to allocate subjects into groups at a 
differential rate; for example, 3 subjects may be assigned to a treatment 
group for every 1 assigned to the control group.
Screen failure
Potential subject who signed the ICF but did not meet 1 or more criteria 
required for participation in the study and was not randomized.
Screening
A process of active consideration of potential subjects for randomization in a 
study.
Screening period
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent form until just before the test product 
or comparative drug (sometimes without randomization) is given to a 
subject. 
Study period
Period of time from the first study site initiation date to the last study site 
completing the study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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13
ATTACHMENT 1: NONSUBSTANTIAL AMENDMENT 3
I.  The purpose of this amendment is:
Nonsubstantial Changes
1. Change the planned study period 
DESCRIPTION OF CHANGE:
Change the planned study period.
RATIONALE:
This update is being made in order to take the COVID-19 impact in consideration.
2. Change the blood collection volume for PK analysis
DESCRIPTION OF CHANGE:
Change the blood collection volume for PK analysis.
RATIONALE:
The blood sample volume for mirabegron pharmacokinetics is changed due to the change 
of blood collection tube. The blood collection tube is changed because the tube which was 
planned to be used is not available in China.
3. Add data entry requirement
DESCRIPTION OF CHANGE:
Add data entry requirement into eCRF according to local regulation and site requirement.
RATIONALE:
This update is being made in order to take the local regulation and site requirement in 
consideration.
II. Amendment summary of changes:
1 Protocol Summary
1.1 Synopsis
WAS:
Planned Study Period:
3Q2020 to 4Q2020


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IS AMENDED TO:
Planned Study Period:
3Q2020 to 4Q20201Q2021
7 Study Procedures and Assessments
7.8 Total Amount of Blood
WAS:
Table 11
Blood Volume
Sample Type
Number of 
Samples
Sample Volume 
(mL)
Total Volume (mL)
Clinical Laboratory Tests
6
7.0
(12.0)†
47.0
Pregnancy Test (Female Subjects 
Only)
3
3.0
9.0
FSH Test (Postmenopausal Female 
Subjects Only)
1
3.0
3.0
Mirabegron Pharmacokinetics
34
5.0
170.0
Total
217.0 for males
226.0 for females
220.0 for postmenopausal 
females
FSH: follicle-stimulating hormone
†
Includes serology test at screening.
IS AMENDED TO:
Table 12
Blood Volume
Sample Type
Number of 
Samples
Sample Volume 
(mL)
Total Volume (mL)
Clinical Laboratory Tests
6
7.0
(12.0)†
47.0
Pregnancy Test (Female Subjects 
Only)
3
3.0
9.0
FSH Test (Postmenopausal Female 
Subjects Only)
1
3.0
3.0
Mirabegron Pharmacokinetics
34
54.0
170136.0
Total
217183.0 for males
226192.0 for females
220186.0 for 
postmenopausal females
FSH: follicle-stimulating hormone
†
Includes serology test at screening.


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10 Operational Considerations
10.1 Data Collection
WAS:
In the interest of collecting data in the most efficient manner, the investigator or designee 
should record data (including clinical laboratory values, if applicable) in the eCRF within 
10 working days after the subject’s visit.
IS AMENDED TO:
In the interest of collecting data in the most efficient manner, the investigator or designee
should record data (including clinical laboratory values, if applicable) in the eCRF within 
10 working days after the subject’s visit.  The data will be entered after HGRAC data 
filing approval if required by site.
III.
Nonsubstantial amendment rationale:
Rationale for nonsubstantial designation
All revisions made to the protocol are administrative in nature and do not impact the safety 
or scientific value of the clinical study.


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14
SPONSOR’S SIGNATURES
Astellas Signatories
(Electronic signatures are attached at the end of the document.)
Medical Affairs
Clinical Pharmacology and Exploratory 
Development
Data Science
PPD
PPD
PPD

SAP_001.pdf: 


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Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 6
2
STUDY OBJECTIVE(S) AND DESIGN······················································· 6
2.1
Study Objective(s) ············································································· 6
2.2
Study Design···················································································· 6
2.3
Randomization·················································································· 7
3
SAMPLE SIZE······················································································ 7
4
ANALYSIS SETS ·················································································· 7
4.1
Safety Analysis Set ············································································ 7
4.2
Pharmacokinetics Analysis Set ······························································· 7
5
PHARMACOKINETIC AND SAFETY ENDPOINTS ····································· 7
5.1
Pharmacokinetic Endpoint (Primary)························································ 7
5.2
Safety Endpoints (Secondary) ································································ 7
5.3
Exploratory Endpoints········································································· 8
6
STATISTICAL METHODOLOGY ···························································· 8
6.1
General Considerations········································································ 8
6.2
Study Population ··············································································· 8
6.2.1
Disposition of Subjects ·································································· 8
6.2.2
Protocol Deviations ······································································ 8
6.2.3
Demographic and Other Baseline Characteristics ···································· 8
6.2.4
Previous and Concomitant Medications ··············································· 8
6.2.5
Medical History··········································································· 9
6.2.6
Investigational Product Exposure ······················································ 9
6.3
Analysis of Efficacy ··········································································· 9
6.4
Analysis of Safety·············································································· 9
6.4.1
Adverse Events ··········································································· 9
6.4.2
Clinical Laboratory Evaluation ························································· 9
6.4.3
Vital Signs················································································· 9
6.4.4
Routine 12-lead Electrocardiogram ···················································10
6.5
Analysis of Pharmacokinetics ·······························································10
6.5.1
Plasma Concentrations··································································10


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6.5.2
Estimation of Pharmacokinetic Parameters ··········································10
6.5.3
Statistical Analysis ······································································10
6.6
Interim Analysis (and Early Discontinuation of the Clinical Study)····················10
6.7
Additional Conventions ······································································11
6.7.1
Analysis Windows ······································································11
7
REVISION AND RATIONALE································································11
8
REFERENCES ····················································································11
9
APPENDICES ·····················································································12
9.1
Appendix 1: Author and Approver Signatures ············································12


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
adverse event
ANOVA
analysis of variance
AUC
area under the concentration-time curve
AUCinf
area under the concentration-time curve from the time of dosing extrapolated
to time infinity
AUCinf (%extrap)
area under the concentration-time curve from the time of dosing extrapolated 
to time infinity as a percentage of total area under the concentration-time 
curve
AUClast
area under the concentration-time curve from the time of dosing to the last 
measurable concentration
BMI
body mass index
CI
confidence interval
CL
apparent total systemic clearance after extravascular dosing
Cmax
maximum concentration
CSR
clinical study report
ECG
electrocardiogram
ESV
end-of-study visit
IP
investigational product
LS
least square(s)
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligrams
PD
protocol deviation
PK
pharmacokinetic
PKAS
pharmacokinetic analysis set
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
t½
terminal elimination half-life
TEAE
treatment-emergent adverse event
tlag
time prior to the time corresponding to the first measurable (nonzero) 
concentration
tmax
time of maximum concentration
Vz/F
apparent volume of distribution during the terminal elimination phase after
extravascular dosing


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List of Key Terms
Terms
Definition of terms
Baseline
Assessments of subjects as they enter a study before they receive any 
dosing.
Endpoint
Variable that pertains to the efficacy or safety evaluations of a study.
Note: Not all endpoints are themselves assessments since certain 
endpoints might apply to populations or emerge from analysis of results. 
That is, endpoints might be facts about assessments (e.g., prolongation of 
survival).
Enroll
To register or enter a subject into a study. Note: Once a subject has 
received the IP or placebo, the protocol applies to the subject.
Intervention
The drug, device, therapy or process under investigation in a study that is 
believed to have an effect on outcomes of interest in a study (e.g., health-
related quality of life, efficacy, safety and pharmacoeconomics).
Investigational period
Period of time where major interests of protocol objectives are observed, 
and where the test product or comparative drug (sometimes without 
randomization) is given to a subject, and continues until the last 
assessment after completing administration of the test product or 
comparative drug.
Randomization
The process of assigning subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias. 
NOTE: Unequal randomization is used to allocate subjects into groups at a 
differential rate; for example, 3 subjects may be assigned to a treatment 
group for every 1 assigned to the control group.
Screen failure
Potential subject who signed the ICF but did not meet 1 or more criteria 
required for participation in the study and was not randomized.
Screening
A process of active consideration of potential subjects for randomization 
in a study.
Screening period
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent form until just before the test 
product or comparative drug (sometimes without randomization) is given 
to a subject.
Study period
Period of time from the first study site initiation date to the last study site 
completing the study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes procedures for 
executing the statistical analysis to fulfil the objectives of the study.
The final SAP will be approved prior to database hardlock.
Changes from the planned analyses in the final SAP that impact the statistical analyses will 
be documented in the Clinical Study Report (CSR).
2
STUDY OBJECTIVE(S) AND DESIGN
2.1
Study Objective(s)
The primary objective of this study is to determine the effect of food on the pharmacokinetics 
of single oral doses of mirabegron in healthy Chinese male and female subjects.
The secondary objective is to evaluate the safety and tolerability of single oral doses of 
mirabegron in healthy Chinese male and female subjects.
The exploratory objective is to evaluate the pharmacokinetics of single oral doses of 
mirabegron in healthy Chinese male and female subjects.
2.2
Study Design
The study follows an open-label, randomized, 2-period, single oral dose crossover design at
2 dose levels in healthy Chinese male and female subjects. Each subject will participate in
2 periods separated by a washout of at least 10 days between IP administrations in each 
period.
Dose (mg)
Sequence
n
Period 1
Period 2
25
1
6
Mirabegron (low-fat)
Mirabegron (fasted)
2
6
Mirabegron (fasted)
Mirabegron (low-fat)
50
1
6
Mirabegron (low-fat)
Mirabegron (fasted)
2
6
Mirabegron (fasted)
Mirabegron (low-fat)
The dose under fed conditions will be administered following a low-fat breakfast (total
calories approximately 450 kcal, with approximately 70 kcal from fat).
Pharmacokinetic samples will be collected predose on day 1 of each period and at multiple 
time points following each dose (see the Schedule of Assessments in the protocol.)
The study will be completed with an end-of-study visit (ESV). The ESV will take place 5 to
9 days after the last pharmacokinetic sample is collected or at early discontinuation from the
study.
Details of the schedule of clinical assessments are available in the protocol.


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2.3
Randomization
Randomization will be allocated through blocks. There will be no stratification variables. 
3
SAMPLE SIZE
A total of 24 subjects (12 subjects per dose group) will be enrolled. Subjects who discontinue 
early from the study may be replaced at the discretion of the sponsor. 
Based on data from Study 178-CL-091, a Chinese phase 1 study, the intrasubject coefficient 
of variation (CV) for pharmacokinetic parameters AUCinf, AUClast and Cmax of the 50 mg 
mirabegron dose are estimated to be between 33% and 60%. Assuming the underlying 
variability is similar to 60% and an observed ratio between fasted and fed conditions of 
100%, the 90% CI will lie within (60, 167) with > 80% probability.
4
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
The determination of whether subjects are included or excluded from the safety analysis set 
will be made prior to database hard-lock.
4.1
Safety Analysis Set
The safety analysis set (SAF) consists of all subjects who receive at least 1 dose of IP. The 
SAF will be used for all summaries and analyses of the safety data.
4.2
Pharmacokinetics Analysis Set
The pharmacokinetic analysis set (PKAS) consists of all subjects who receive at least 1 dose 
of IP for which concentration data are available to facilitate derivation of at least 1 primary 
pharmacokinetic parameter. Inclusion of subjects in the PKAS with missing data or major 
protocol deviations will be considered by the pharmacokineticist on a case-by-case basis.
The PKAS will be used for all summaries and analyses of the pharmacokinetic data.
5
PHARMACOKINETIC AND SAFETY ENDPOINTS 
5.1
Pharmacokinetic Endpoint (Primary)
The primary PK endpoints will be Mirabegron plasma PK parameters: AUCinf, AUClast and 
Cmax.
5.2
Safety Endpoints (Secondary)
Safety will be assessed by evaluation of the following endpoints:
●
Nature, frequency and severity of AEs
●
Clinical laboratory tests (biochemistry, hematology and urinalysis)


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●
Vital signs (blood pressure, body temperature and pulse)
●
Routine 12-lead ECG
5.3
Exploratory Endpoints
The exploratory PK endpoints will be Mirabegron plasma PK parameters AUCinf(%extrap), 
CL/F, t½, tmax, tlag and Vz/F.
6
STATISTICAL METHODOLOGY
6.1
General Considerations
In general, all data will be summarized with descriptive statistics (n, mean, SD, median, 
minimum and maximum) for continuous endpoints, and frequency and percentage for 
categorical endpoints, unless otherwise specified. Percentages by categories will be based on 
the number of subjects with no missing data (i.e., will add up to 100%).
For each sequence, the number and percentage of subjects will be characterized for all
randomized subjects and by each analysis set.
6.2
Study Population
6.2.1
Disposition of Subjects
The number and percentage of subjects who completed and discontinued dosing and reasons 
for dosing discontinuation will be presented for all randomized subjects and for subjects in 
the SAF by dose group, sequence and overall. Similar tables for investigational period 
disposition and follow-up disposition will also be presented for all randomized subjects by 
dose group, sequence and overall. All disposition details and dates of first and last 
evaluations for each subject will be listed.
6.2.2
Protocol Deviations
The major protocol deviations are defined as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received incorrect dose,
PD4 - Received excluded concomitant treatment.
Major protocol deviations will be listed. 
6.2.3
Demographic and Other Baseline Characteristics
Demographics and baseline characteristics (age, sex, race, body weight, height and BMI) will 
be summarized by dose group, sequence and overall for all randomized subjects.
6.2.4
Previous and Concomitant Medications
Previous and concomitant treatment (medication and nonmedication therapy) will be listed.


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6.2.5
Medical History
Medical history for each subject will be listed.
6.2.6
Investigational Product Exposure
The number and percentage of subjects exposed to IP will be summarized by dose group and
sequence under fed and fasted conditions.
IP exposure data will be listed.
6.3
Analysis of Efficacy 
Not applicable.
6.4
Analysis of Safety
6.4.1
Adverse Events
AEs will be coded using MedDRA. An AE with onset at any time from first dosing until last 
scheduled procedure will be classified as a TEAE for inclusion in the summary tabulations. 
An IP-related TEAE is defined as any TEAE with a causal relationship assessed as “yes” by 
the investigator, or records where the relationship is missing. 
An overview and separate summaries of the number and percentage of subjects with TEAEs, 
drug-related TEAEs, TEAEs leading to withdrawal of dosing, IP-related TEAEs leading to 
withdrawal of dosing and TEAEs excluding SAEs that equal or exceed a threshold of 5% in 
any dose group under fed and fasted conditions will be presented by SOC, preferred term, by 
fed and fasted conditions for each dose group. Also included in the overview are the number 
and percentage of subjects with serious TEAEs, IP-related serious TEAEs, TEAEs leading to 
death and IP-related TEAEs leading to death. 
AE data will be listed.
6.4.2
Clinical Laboratory Evaluation
For quantitative clinical laboratory measurements (hematology and biochemistry), 
descriptive statistics will be used to summarize results and change from baseline by fed and 
fasted conditions and visit for each dose group. 
Baseline will be defined as the last nonmissing observation prior to administration of IP 
within each period.
Laboratory data will be listed.
6.4.3
Vital Signs
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects by fed and fasted conditions and time point for each dose group.
Vital signs data will be listed.


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Baseline will be defined as the last nonmissing observation prior to administration of IP
within each period.
6.4.4
Routine 12-lead Electrocardiogram
Routine 12-lead ECG data and interpretations will be listed.
6.5
Analysis of Pharmacokinetics
Descriptive statistics will include n, mean, SD, CV, geometric mean, geometric CV, median, 
minimum and maximum. For the pharmacokinetic parameters tmax and tlag, only n, median, 
minimum and maximum will be calculated.
6.5.1
Plasma Concentrations
Plasma concentrations under both fasted and fed conditions will be listed and summarized 
using descriptive statistics by scheduled time point for each dose group. Standard graphics
including mean plasma concentration-time profiles, overlay (spaghetti) plots and individual
subject plasma concentration-time profiles will be produced.
6.5.2
Estimation of Pharmacokinetic Parameters
Noncompartmental analysis will be used for the calculation of plasma pharmacokinetic 
parameters using Phoenix® version 8.0 or higher(Certara LP, 100 Overlook Center, Suite 
101, Princeton, NJ 08540, US).
Plasma pharmacokinetic parameters under both fasted and fed conditions will be listed and 
summarized using descriptive statistics for each dose group.
6.5.3
Statistical Analysis
To assess the effect of food on the pharmacokinetics of mirabegron, a mixed effects analysis 
of variance (ANOVA) model with fixed effects for food condition (fed or fasted) and period 
and subject as a random effect will be fitted on natural logarithm-transformed AUCinf, 
AUClast and Cmax . Within the ANOVA, the least squares (LS) mean differences between fed 
and fasted, along with 90% CIs for the differences will be estimated. 
The LS means for AUCinf, AUClast and Cmax will be back-transformed to produce the 
geometric LS means and presented with the number of subjects for each food condition. The 
geometric LS mean ratios and their corresponding 90% CIs for each pharmacokinetic 
parameter will be presented by back-transforming and expressed as percentages. The 
ANOVA will be performed and results will be presented for 25mg and 50mg mirabegron 
doses separately.
The analysis will be repeated if all subjects did not complete both periods using an ANOVA 
with fixed effects for period, food condition and subject; this analysis will only include 
subjects with complete data in both periods.
6.6
Interim Analysis (and Early Discontinuation of the Clinical Study)
Not applicable.


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6.7
Additional Conventions
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of AEs and concomitant medications if they are missing on day of first IP 
administration. The imputed dates will be used to assess if the AEs or concomitant 
medications are treatment-emergent or concomitant, respectively.
Listings of AEs and concomitant medications will present the actual partial dates; imputed 
dates will not be shown.
6.7.1
Analysis Windows
Not applicable.
7
REVISION AND RATIONALE
Not applicable.
8
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines)




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(E-signatures are attached at the end of document.)