Conditions: Duchenne Muscular Dystrophy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate the efficacy after 24-week repeated oral doses of TAS-205 in patients with Duchenne Muscular Dystrophy (DMD) in an exploratory manner.

Detailed description:
Duchenne Muscular Dystrophy (DMD) is the most common fatal genetic disorder diagnosed in childhood, affecting approximately 1 in 3,500 lives male births. DMD patients suffer from a relentless decline in muscle strength that impairs the ability of walking and breathing, resulting in their lives with wheelchairs and then loss of upper body function. The main objective of this study is to evaluate the efficacy after 24-week repeated oral doses of TAS-205 in patients with DMD in an exploratory manner. The objective of this study is also to evaluate the safety, the dose-response and the urinary excretion of pharmacodynamic (PD) marker after 24-week repeated oral doses of TAS-205 in DMD patients.

Arms:
arm 1: Low dose group：Oral administration of tablets for 24 weeks, bis in die (BID) after meal The number of tablets of the study drug corresponding to the dosage (6.67-13.33 mg/kg/dose) by body weight within 14 days before enrollment was to be administered within 30 minutes after breakfast and dinner. arm 2: High dose group: Oral administration of tablets for 24 weeks, bis in die (BID) after meal The number of tablets of the study drug corresponding to the dosage (13.33-26.67 mg/kg/dose) by body weight within 14 days before enrollment was to be administered within 30 minutes after breakfast and dinner. arm 3: Placebo group: Oral administration of tablets for 24 weeks, BID after meal

Interventions: intervention 1: TAS-205 intervention 2: Placebo
Intervention descriptions: intervention 1: 2 groups: Low dose group, High dose group. Oral administration for 24 weeks, bis in die (BID) after meal intervention 2: 1 group: Placebo group. Oral administration for 24 weeks, BID after meal

Protocol document:
Prot_000.pdf: 
 
Early Phase II Randomized Study of TAS-205 in Patients with 
Duchenne Muscular Dystrophy 
 
 
TAS-205 
Protocol No.:
Creation date:
10053040 Ver.P02 
April 7, 2016 
 
 
 
Sponsor: 
Taiho Pharmaceutical Co., Ltd. 
1-27 Kandanishikicho, Chiyoda-ku, Tokyo, 101-8444 Japan 
 
Medical Expert: 
 
 
 
 
Coordinating Investigator: 
 
 
 
 
This study will be conducted in accordance with the Guideline for Good Clinical Practice (GCP) of the 
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals 
for Human Use (ICH), as well as applicable regulatory requirements in Japan. 
 
Confidentiality Statement 
The information in this protocol is confidential and the property of Taiho Pharmaceutical Co., Ltd. 
The information therefore may not be published or disclosed to third parties without the written consent 
of Taiho Pharmaceutical Co., Ltd., except when required by the regulatory authorities or required for 
obtaining consent from the patients willing to participate in this study. 
 
1 


Table of Contents 
Table of Contents ...................................................................................................................... 2 
List of Abbreviations ................................................................................................................ 9 
Synopsis .................................................................................................................................... 11 
1. 
Background Information ................................................................................................ 21 
1.1 
Introduction ............................................................................................................. 21 
1.2 
TAS-205 .................................................................................................................. 22 
1.2.1 
Mechanism of Action .................................................................................... 22 
1.3 
Overview of Risks and Benefits ............................................................................. 22 
1.3.1 
TAS-205 ........................................................................................................ 22 
1.3.2 
Risks and Benefits Expected in the Study .................................................... 23 
1.4 
Major Study Results ................................................................................................ 23 
1.4.1 
Nonclinical Studies ....................................................................................... 23 
1.4.2 
Clinical Studies ............................................................................................. 23 
1.4.2.1 
Study 10053010 (Phase I Study in Healthy Adult Subjects) .............. 23 
1.4.2.2 
Study 10053030 (Phase I Study in Patients with DMD) .................... 24 
1.5 
Rationale for the Study and Study Population ........................................................ 25 
1.5.1 
Study Population ........................................................................................... 25 
1.5.2 
Study Design ................................................................................................. 25 
1.5.3 
Dosage of TAS-205 ....................................................................................... 26 
1.5.4 
Selection of TAS-205 Placebo ...................................................................... 27 
2. 
Study Objectives .............................................................................................................. 28 
2.1 
Primary Objective ................................................................................................... 28 
2.2 
Secondary Objective ............................................................................................... 28 
2.3 
Exploratory Objectives ........................................................................................... 28 
2.4 
Endpoints ................................................................................................................ 28 
2.4.1 
Primary Endpoint .......................................................................................... 28 
2.4.2 
Secondary Endpoints .................................................................................... 28 
2.4.3 
Pharmacodynamic Endpoints ........................................................................ 29 
2.4.4 
Exploratory Endpoints .................................................................................. 29 
3. 
Study Design .................................................................................................................... 30 
3.1 
Study Period ............................................................................................................ 30 
3.1.1 
Definitions of Periods in the Study for Individual Subjects ......................... 30 
3.2 
Subject Randomization and Blinding ..................................................................... 32 
3.2.1 
Randomization Method ................................................................................. 32 
3.2.2 
Allocation of the Investigational Product Number ....................................... 33 
3.2.2.1 
Allocation of the Investigational Product Number at Enrollment ...... 33 
3.2.2.2 
Second and Subsequent Allocation of the Investigational Product 
Number (at Visit 4 and Thereafter) ..................................................... 33 
3.2.3 
Blinding ......................................................................................................... 34 
2 


4. 
Patient Inclusion/Exclusion and Subject Discontinuation Criteria ............................ 35 
4.1 
Inclusion Criteria .................................................................................................... 35 
4.2 
Exclusion Criteria ................................................................................................... 35 
4.3 
Discontinuation Criteria for Individual Subjects .................................................... 36 
5. 
Evaluations and Tests in the Study ................................................................................ 38 
5.1 
Study Procedures .................................................................................................... 39 
5.1.1 
Informed Consent .......................................................................................... 39 
5.1.2 
Subject ID Code Assignment ........................................................................ 39 
5.1.3 
Subject Characteristics .................................................................................. 39 
5.1.4 
Motor Function/Muscle Volume/Lean Body Mass/Muscle Strength 
Evaluations and Pulmonary Function Test .................................................... 39 
5.1.5 
Pregnancy Test .............................................................................................. 39 
5.1.6 
Drug Accountability ...................................................................................... 39 
5.1.7 
Blood Pressure, Pulse Rate, Body Temperature, Height, and Body 
Weight ........................................................................................................... 40 
5.1.8 
ECG, Cardiac Ultrasonography (Echocardiography) ................................... 40 
5.1.9 
Laboratory Values ......................................................................................... 40 
5.1.9.1 
Hematology ......................................................................................... 40 
5.1.9.2 
Biochemistry ....................................................................................... 40 
5.1.9.3 
Endocrinology ..................................................................................... 40 
5.1.9.4 
Urinalysis ............................................................................................ 41 
5.1.10 
Timing for Individual Evaluations/Tests ....................................................... 41 
5.1.11 
Concomitant Medication/Therapy ................................................................ 41 
5.1.12 
Report of Adverse Events ............................................................................. 41 
5.1.13 
Sampling for Pharmacokinetic and Pharmacodynamic Analyses ................. 41 
5.2 
Evaluation/Test Parameters for Individual Visits .................................................... 42 
5.2.1 
Screening Period ........................................................................................... 42 
5.2.1.1 
Before Enrollment (Day -14 to Day -1) .............................................. 42 
5.2.2 
Baseline Period ............................................................................................. 42 
5.2.3 
Evaluation During the Investigational Product Administration Period 
(Excluding Hospitalization Period) ............................................................... 42 
5.2.4 
Evaluation During (Hospitalization Period) and at the End of the 
Investigational Product Administration Period ............................................. 43 
5.2.5 
Evaluation in the Follow-up Period (Follow-up Test, Discontinuation 
Test) ............................................................................................................... 43 
6. 
Investigational Product ................................................................................................... 45 
6.1 
Name of the Investigational Product, etc. ............................................................... 45 
6.2 
Packaging and Labeling of the Investigational Product.......................................... 45 
6.3 
Management of the Investigational Product ........................................................... 46 
6.4 
Instruction to Subjects Regarding the Handling of the Investigational Product ..... 46 
3 


7. 
Method of Administration .............................................................................................. 48 
7.1 
Administration Procedures ...................................................................................... 48 
7.1.1 
Method of Administration ............................................................................. 48 
7.1.2 
Criteria for Changing the Administration Plan ............................................. 49 
7.1.2.1 
Dose Suspension/Resumption Criteria ............................................... 49 
7.1.2.2 
Dose Reduction Criteria ...................................................................... 50 
7.1.3 
Time of Dose Resumption ............................................................................ 51 
7.2 
Volume of Blood Collected During the Study Period ............................................. 52 
7.3 
Restrictions ............................................................................................................. 52 
7.3.1 
Physical Activity ........................................................................................... 52 
7.3.2 
Fasting ........................................................................................................... 52 
7.3.3 
Foods and Beverages .................................................................................... 52 
7.4 
Concomitant Medication/Therapy .......................................................................... 52 
7.4.1 
Prohibited Concomitant Medications/Therapies ........................................... 52 
7.4.2 
Concomitant Medications/Therapies Requiring Precaution ......................... 53 
7.4.3 
Restricted Concomitant Medications/Therapies ........................................... 53 
8. 
Pharmacokinetic/Pharmacodynamic and Exploratory Evaluations .......................... 54 
8.1 
Blood Sampling ...................................................................................................... 54 
8.2 
Urine Sampling ....................................................................................................... 54 
8.3 
Pharmacokinetic Analysis of TAS-205 ................................................................... 54 
8.4 
Pharmacodynamic Analysis of TAS-205 ................................................................ 54 
8.4.1 
Calculation of Pharmacodynamic and Exploratory Endpoints ..................... 55 
8.4.2 
Pharmacodynamic and Exploratory Evaluations .......................................... 55 
8.4.3 
Bioanalytical Method in the Pharmacodynamic Analysis ............................ 55 
9. 
Pharmacogenomics ......................................................................................................... 56 
10. Early Termination or Completion of the Study............................................................ 57 
10.1 
Criteria for Discontinuation of Participation of the Study Site ............................... 57 
10.2 
Criteria for Discontinuation of the Study ................................................................ 57 
10.3 
Investigations for Individual Subjects at Discontinuation ...................................... 57 
11. Efficacy Evaluation ......................................................................................................... 58 
11.1 
Training and Prior Certification of Evaluators for Individual Study Sites 
Before Study Initiation ............................................................................................ 58 
11.2 
Order of the Efficacy Evaluations ........................................................................... 58 
11.3 
Evaluation of Motor Function ................................................................................. 58 
11.3.1 
6MWD Test ................................................................................................... 59 
11.3.2 
Time to Rise from the Floor Test .................................................................. 59 
11.3.3 
Timed Up & Go Test ..................................................................................... 59 
11.3.4 
Timed 10-m walk/run test ............................................................................. 59 
11.4 
Evaluation of Muscle Volume ................................................................................. 60 
11.4.1 
Skeletal Muscle CT ....................................................................................... 60 
4 


11.4.2 
BIA ................................................................................................................ 60 
11.5 
Lean Body Mass ..................................................................................................... 60 
11.6 
Evaluation of Muscle Strength ................................................................................ 60 
11.6.1 
Quantitative Muscle Strength Assessments .................................................. 60 
11.7 
Other Efficacy Evaluations ..................................................................................... 61 
11.7.1 
Serum CK Concentration .............................................................................. 61 
11.7.2 
Pulmonary Function Test .............................................................................. 61 
12. Safety Evaluation ............................................................................................................ 62 
12.1 
Adverse Events ....................................................................................................... 62 
12.1.1 
Definition of Adverse Event ......................................................................... 62 
12.1.2 
Severity of Adverse Events ........................................................................... 62 
12.1.3 
Causal Relationship to the Investigational Product ...................................... 63 
12.1.4 
Definition of Adverse Drug Reaction ........................................................... 63 
12.1.5 
Outcome of Adverse Events .......................................................................... 63 
12.1.6 
Reporting of Adverse Events ........................................................................ 64 
12.1.7 
Follow-up of Adverse Events ........................................................................ 64 
12.2 
Serious Adverse Events ........................................................................................... 64 
12.2.1 
Definition of Serious Adverse Event ............................................................ 64 
12.2.2 
Reporting of Serious Adverse Events ........................................................... 65 
12.2.3 
Follow-up of Serious Adverse Events ........................................................... 65 
12.3 
Worsening of Underlying Disease .......................................................................... 66 
12.4 
Reporting of Death .................................................................................................. 66 
12.5 
Adverse Events of Special Interest ......................................................................... 66 
12.5.1 
Definition of Adverse Events of Special Interest .......................................... 66 
12.6 
Predictability ........................................................................................................... 66 
12.7 
Other Information ................................................................................................... 66 
12.7.1 
Follow-up of Pregnancy ................................................................................ 66 
12.7.2 
Medication Errors ......................................................................................... 66 
12.7.3 
Misuse ........................................................................................................... 67 
12.7.4 
Drug Interaction ............................................................................................ 67 
13. Statistical Analysis .......................................................................................................... 68 
13.1 
Analysis Plan .......................................................................................................... 68 
13.1.1 
Timing of Statistical Analysis ....................................................................... 68 
13.1.2 
Analysis Sets and Criteria for Handling Subject Data .................................. 68 
13.1.2.1 
Analysis Sets ....................................................................................... 68 
13.1.2.2 
Criteria for Handling Subject Data ..................................................... 68 
13.1.3 
Statistical Analysis Methods ......................................................................... 69 
13.1.3.1 
Subject Disposition and Characteristics .............................................. 69 
13.1.3.2 
Analysis of the Primary Endpoint ....................................................... 69 
13.1.3.3 
Analysis of the Secondary Endpoints ................................................. 70 
5 


13.1.3.4 
Analyses of Pharmacodynamic and Exploratory Endpoints ............... 72 
13.1.3.5 
Current Administration ....................................................................... 72 
13.1.4 
Target Sample Size and Rationale for the Sample Size ................................ 72 
14. Rationale .......................................................................................................................... 73 
14.1 
Rationale for the Endpoints .................................................................................... 73 
14.2 
Rationale for the Method of Administration ........................................................... 74 
14.3 
Rationale for the Inclusion Criteria ......................................................................... 74 
14.4 
Rationale for the Exclusion Criteria........................................................................ 74 
14.5 
Rationale for Randomization Adjustment Factors .................................................. 75 
14.6 
Rationale for the Prohibited Concomitant Medications/Therapies ......................... 76 
14.7 
Rationale for the Concomitant Medications Requiring Precaution ........................ 76 
14.8 
Rationale for the Restricted Concomitant Medications .......................................... 76 
14.9 
Rational for the Dose Suspension Criteria .............................................................. 76 
14.10 Rationale for the Dose Reduction Criteria .............................................................. 77 
14.11 Rationale for the Contraception Period ................................................................... 78 
14.12 Rationale for the Restrictions on Foods and Beverages ......................................... 78 
15. Case Report Forms ......................................................................................................... 79 
15.1 
Recording of CRFs ................................................................................................. 79 
15.2 
Changes to or Correction of the Case Report Forms .............................................. 79 
15.3 
Instructions for Completing Case Report Forms .................................................... 79 
16. Compliance with, Deviations from, and Amendments to the Protocol ...................... 81 
16.1 
Compliance with the Protocol ................................................................................. 81 
16.2 
Deviations from the Protocol .................................................................................. 81 
16.3 
Amendments to the Protocol ................................................................................... 81 
17. Direct Access to Source Documents ............................................................................... 82 
17.1 
Source Documents .................................................................................................. 82 
17.2 
Direct Access .......................................................................................................... 82 
18. Study Quality Control and Quality Assurance ............................................................. 83 
18.1 
Study Quality Control ............................................................................................. 83 
18.2 
Audits by the Sponsor and Inspection by the Regulatory Authorities .................... 83 
19. Data Handling and Record Retention ........................................................................... 84 
19.1 
Data Handling ......................................................................................................... 84 
19.2 
Record Retention .................................................................................................... 84 
19.2.1 
Investigator/Study Site .................................................................................. 84 
19.2.2 
Sponsor ......................................................................................................... 84 
20. Compensation for Injury ................................................................................................ 85 
21. Publication and Secondary Use of Data ........................................................................ 85 
21.1 
Publication .............................................................................................................. 85 
21.2 
Secondary Use of Data ............................................................................................ 85 
22. Ethics ................................................................................................................................ 85 
6 


22.1 
Ethical Matters ........................................................................................................ 85 
22.2 
Approval of the Institutional Review Board (IRB) ................................................. 85 
22.3 
Procedure for Obtaining Informed Consent ............................................................ 86 
22.4 
Administration of the Investigational Product After the Study Period ................... 86 
23. Clinical Study Organization ........................................................................................... 86 
24. References ........................................................................................................................ 86 
 
 
 
7 


List of Figures 
Figure 3-1 Study Design ........................................................................................................ 30 
Figure 3.1-1 Study Participation Period for Individual Subjects ........................................... 32 
 
 
List of Tables 
Table 1 Clinical Assessment Schedule ................................................................................... 19 
Table 3.2-1 Allocation of the Investigational Product Number (at Enrollment and Visit 4 and 
thereafter) ............................................................................................................................... 34 
Table 5-1 Medical Evaluations/Tests ..................................................................................... 38 
Table 6.1-1 Overview of TAS-205 [Study Drug]................................................................... 45 
Table 6.1-2 Overview of Control (Placebo) ........................................................................... 45 
Table 7.1.1-1 Dosage of the Investigational Product by Body Weight (Within 14 Days 
Before Enrollment) ................................................................................................................ 49 
Table 7.1.2.1-1 Dose Suspension/Resumption Criteria ......................................................... 50 
Table 7.1.2.2-1 Dose Reduction Criteria ............................................................................... 51 
Table 7.2-1 Volume of Blood Collected During the Study Period ......................................... 52 
Table 13.1.2-1 Definition of Analysis Sets ............................................................................ 68 
 
 
8 


List of Abbreviations 
Abbreviation 
Full expression 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
Ae 
cumulative amount of drug excreted in urine 
A/G 
albumin/globulin ratio 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-t 
area under the concentration-time curve from 0 to t hours (AUC0-∞ or AUC0-inf: area 
under the concentration-time curve extrapolated to infinity) 
BIA 
bioelectrical impedance analysis 
BUN 
blood urea nitrogen 
Cmax 
maximum plasma concentration 
CK 
creatine kinase 
Cre 
creatinine 
CRP 
C-reactive protein 
CT 
computed tomography 
CYP 
cytochrome P450 
DMD 
duchenne muscular dystrophy 
DP 
D-type prostanoid 
EF 
ejection fraction 
FAS 
full analysis set 
FEV 1.0 
forced expiratory volume 1.0 
FS 
fractional shortening 
FVC 
forced vital capacity 
GCP 
good clinical practice 
γ-GTP 
γ-glutamyl transpeptidase 
HBs 
hepatitis B surface 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
HIV 
human immuno deficiency virus 
HPGDS 
hematopoietic-type prostaglandin D synthase 
IRB 
institutional review board 
IWRS 
interactive Web Response System 
LC/MS/MS 
liquid chromatography / tandem mass spectrometry 
LDH 
lactate dehydrogenase 
LOCF 
last observation carried forward 
MedDRA 
medical dictionary for regulatory activities 
MMRM 
mixed-effect models for repeated measures 
9 


Abbreviation 
Full expression 
PGD2 
prostaglandin D2 
PGDM 
prostaglandin D2 metabolite 
PGE2 
prostaglandin E2 
PGEM 
prostaglandin E2 metabolite 
P-gp 
p-glycoprotein 
POC 
Proof of Concept 
PPS 
per protocol set 
QTc 
corrected QT 
SOP 
standard operating procedure 
t1/2 
half life of elimination 
VC 
vital capacity 
6MWD 
6-minute walk distance 
 
 
 
10 


Synopsis 
Sponsor: 
Taiho Pharmaceutical Co., Ltd. 
Investigational product: 
TAS-205 
Generic name: 
Not yet confirmed. 
Study title: 
Early Phase II Randomized Study of TAS-205 in Patients with Duchenne Muscular Dystrophy  
Protocol No.: 
10053040 
Development phase: 
Early Phase II 
Indication: 
Duchenne muscular dystrophy (DMD) 
Background/Rationale: 
DMD affects approximately 1 in 3500 male births worldwide, and the 
number of patients with DMD in Japan is estimated to be approximately 5000. 
DMD is caused by a mutation in the dystrophin gene resulting in the absence 
of dystrophin protein, while involvement of immunity and inflammatory 
responses in the development of the disease is also suggested. Prostaglandin 
D2 (PGD2) is one of the major prostaglandins involved in inflammation. It is 
produced from arachidonic acid, a cell membrane constituent, via 
phospholipase A2, cyclooxygenase, and then prostaglandin D synthase. There 
are 2 types of prostaglandin D synthase: lipocalin-type, primarily located in 
the central nervous system,1, 2) and hematopoietic type, primarily expressed in 
mast cells, type 2 T helper cells, and microglial calls.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 In the Phase I single- and repeated-dose 
study of TAS-205 in patients with DMD (hereinafter referred to as Study 
10053030), TAS-205 was demonstrated to be highly safe and tolerable at 
doses of 1.67 to 13.33 mg/kg. 
Given these results, the present early Phase II study was planned to evaluate 
the efficacy of TAS-205 in patients with DMD. 
11 


Study 
objectives/endpoints: 
Primary objective: 
To evaluate the efficacy of TAS-205 administered orally twice daily for 24 
consecutive weeks compared with placebo in patients with DMD in an 
exploratory manner 
Primary endpoint: 
Efficacy: 
• 
Evaluation of motor function: Change from baseline in the measured 
6-minute walk distance (6MWD) at Week 24 
Secondary endpoints: 
Efficacy: 
• 
Evaluation of motor function: (1) Measured 6MWD and the change from 
baseline in the measured 6MWD at Week 12, (2) Time measured in the 
time to rise from the floor test, Timed 10-m walk/run test, and Timed Up 
& Go test, as well as the change from baseline in each measured value 
• 
Evaluation of muscle volume: Measured values in skeletal muscle 
computed tomography (CT) and bioelectrical impedance analysis (BIA), 
as well as the change from baseline in each measured value 
• 
Measured lean body mass and the change from baseline in each measured 
value 
• 
Evaluation of muscle strength: Quantitative muscle strength assessments 
with a hand-held dynamometer (hip flexion/extension, knee 
flexion/extension, ankle extension/flexion) and the change from baseline 
in each measured value 
• 
Measured serum creatine kinase (CK) concentration and the change from 
baseline in the measured value 
• 
Pulmonary function test (non-invasive vital capacity measurement using 
a spirometer): Measured vital capacity (VC), forced vital capacity (FVC), 
forced expiratory volume in 1.0 second (FEV1.0), and the percent ratio of 
FEV1.0 to forced vital capacity (FEV1.0%), as well as the change from 
baseline in each measured value 
Safety: 
• 
Safety evaluation by cardiac ultrasonography (echocardiography), 
12-lead ECG, blood pressure, pulse rate, body temperature, and 
laboratory tests (incidences of adverse events and adverse drug reactions, 
etc.) 
Pharmacodynamic endpoints: 
• 
Urinary tetranor-PGDM/creatinine concentration ratio 
• 
Total urinary tetranor-PGDM excretion 
• 
Urinary tetranor-PGEM/creatinine concentration ratio 
• 
Total urinary tetranor-PGEM excretion 
Exploratory endpoints: 
• 
Urinary creatinine excretion 
• 
Urinary creatine excretion 
• 
Creatine in urine (%)*1 
*1 Creatine in urine (%) = urinary creatine excretion (g/day) / [urinary creatine excretion 
(g/day) + urinary creatinine excretion (g/day)] × 100 (the value shall be rounded to 2 
decimal places)5) 
12 


Study design: 
This study is a double-blind randomized study to evaluate the efficacy of 
TAS-205 for deterioration of physical function (e.g., motor function, muscle 
volume, muscle strength) compared with placebo in patients with DMD; that 
is, the study is designed as an exploratory efficacy study. The target total 
sample size of 33 patients will be obtained through central registration. 
Patients enrolled as subjects will be randomized to one of 3 groups (low-dose 
group: 6.67 to 13.33 mg/kg/dose, high-dose group: 13.33 to 26.67 mg/kg/dose, 
and placebo group) (randomization ratio: 1:1:1), and receive the 
investigational product orally twice daily, once after breakfast and once after 
dinner, for 24 consecutive weeks starting after dinner on Day 1 (subjects will 
be hospitalized on Day -2 within 12 days after enrollment and start Day 1 
within 14 days after enrollment) to evaluate the efficacy in a double-blind 
manner. Subjects will be administered the number of tablets per dose specified 
based on their body weights measured within 14 days before enrollment.  
Study status: 
Study start day (planned): February, 2016 
Study completion day (planned): August, 2017 
Patient enrollment period (planned): May, 2016 to October, 2016 
Implementing countries: Japan only 
Number of patients 
planned: 
In this study, a total of 33 patients will be enrolled through central registration. 
Patient eligibility: 
Inclusion criteria: 
Patients who meet all of the following criteria at the enrollment are eligible to 
participate in this study: 
(1) A legal guardian (legal representative) of a male pediatric patient with the 
ability to give consent provides written informed consent to participate in 
the study (whenever possible, informed voluntary assent should also be 
obtained personally from the patient after all information has been given 
in a way that suits the patient's level of understanding). 
(2) Patients with a diagnosis of dystrophinopathy as determined by a 
dystrophin genetic test or muscle pathology findings, symptoms or signs 
characteristic to DMD (e.g., proximal muscular weakness, waddling gait, 
Gowers sign), and progressive walking difficulty at the time of informed 
consent. 
(3) Patients aged 5 years or more at the time of informed consent 
(4) Patients weighing ≥ 7.5 kg and < 60 kg within 14 days before enrollment 
(5) Patients who can rise from the floor or a chair and walk by themselves at 
the screening test (confirmed by medical interview, actual performance, 
etc.), with 6MWD of more than 75 m (use of wheelchair in daily 
activities is permissible) 
(6) Patients who can stay in the hospital for the time period specified in the 
13 


study 
(7) Patients who can continue with administration of the specified number of 
tablets 
(8) If the patient is receiving oral steroids for DMD treatment, he had begun 
the treatment more than 6 months before informed consent, and his 
symptoms remain stable with no change in the prescription-based dosage 
regimen of steroids within 3 months 
Exclusion criteria: 
Patients who meet any of the following criteria at the enrollment will be 
excluded from the study: Patients who meet any of the following criteria 
(except for criterion (2)) during the baseline period after enrollment cannot 
receive the administration of the investigational product during the period: 
(1) Patients who have serious concomitant drug hypersensitivity 
(2) Patients with FVC of < 50% of the predicted value*1 based on the 
spirometric reference value in Japanese children (developed by the Lung 
Function Review Committee of the Japanese Society of Pediatric 
Pulmonology in 2008)6) within 14 days before enrollment 
*1 FVC will be predicted using the following formula: 
FVC prediction: 2.108+(-0.1262) × age (years)+0.00819 × age (years)2+(-3.118) × 
height (m)+2.553 × height (m)2 
(3) Patients who continuously use mechanical ventilation (except for use 
while sleeping) 
(4) Patients with a left ventricular ejection fraction (EF) of < 40% or left 
ventricular fractional shortening (FS) of < 25% on the cardiac 
ultrasonography (echocardiography) performed within 14 days before 
enrollment 
(5) Patients who have been confirmed to have clinically significant 
symptoms of cardiac failure or respiratory failure 
(6) Patients receiving immunosuppressive medications (other than 
corticosteroids for DMD treatment) 
(7) Patients who have used cyclooxygenase (COX)-1 or COX-2 inhibitors, or 
nonsteroidal anti-inflammatory drugs (NSAIDs) during 7 days before the 
6MWD test in the screening period 
(8) Patients who have a history of surgery that may affect muscle strength or 
motor function within 6 months before enrollment or who will undergo 
surgery during the study 
(9) Patients who have incurred an injury (trauma/damage) that may affect 
muscle strength or motor function within 3 months before enrollment or 
who have an uncured injury (trauma/damage) that may affect muscle 
strength or motor function at the enrollment 
(10) Patients with systemic allergic disease, chronic inflammatory disease, or 
14 


other diseases that may prevent correct interpretation of efficacy or safety 
data (excluding allergic rhinitis, localized or mild atopic dermatitis, 
eczema, etc.) 
(11) Patients who have received gene-/cell-based therapy or stop-codon 
readthrough therapy with antisense oligonucleotides, or who have 
participated in another clinical trial and received an investigational 
product within 90 days before investigational product administration in 
the present study 
(12) Participants of another clinical trial or participants of other clinical 
research or another study in which they may undergo a motor function 
test during 7 days before a motor function test scheduled in the present 
study 
(13) Patients who have been confirmed to be hepatitis B surface (HBs) 
antigen-, hepatitis C virus (HCV) antibody-, or human immunodeficiency 
virus (HIV) antigen- or antibody-positive before enrollment 
(14) The patient's legal representative is unwilling to agree that the patient 
will use appropriate contraception throughout the study period and for 
180 days after the end of the study. 
1) 
The investigator or subinvestigator will discuss appropriate 
contraception with the patient and his legal representative, and 
instruct the patient to avoid pregnancy of a partner without fail 
using a double barrier method (condom plus diaphragm) or 
intrauterine contraceptive device throughout the study 
participation or contraception period if applicable. 
(15) Patients who are judged by the investigator or subinvestigator to have 
brain dysfunction, including intellectual disability, tendency of autism, 
and attention deficit hyperactivity disorder, that may affect the evaluation 
of motor function 
(16) Patients with a corrected QT interval (QTc) of 450 msec or more on the 
12-lead ECG performed within 14 days before enrollment (corrected by 
Fridericia’s formula) 
(17) Patients who are deemed not eligible for the study by the investigator or 
subinvestigator for any other reason 
Study participation 
period: 
From the day of written informed consent by the patient’s legal representative 
to the end day of the follow-up period. 
Efficacy evaluation 
criteria: 
For the evaluation of motor function, muscle volume, and muscle strength, a 
separately prepared written evaluation procedure will be followed. There are 
no standard evaluation criteria established for DMD. 
 
 
15 


Safety evaluation 
criteria: 
Definition of adverse event: 
An adverse event is defined as any unfavorable medical event that occurs in a 
subject participating in the study, regardless of whether it is considered related 
to the investigational product. A diagnosis will be recorded as an adverse 
event wherever possible. If no definite diagnosis can be established, signs or 
symptoms will be recorded. Symptoms associated with DMD or concurrent 
illness and abnormal laboratory or other test findings that have been present 
since before the study initiation will not be assessed as adverse events. 
However, any new symptoms or worsening of concurrent illness will be 
assessed as adverse events. 
All clinically or medically significant abnormal test values will be reported as 
adverse events. Symptoms derived from a diagnosis already reported as an 
adverse event by the investigator or subinvestigator will not be assessed as 
adverse events. 
Abnormal laboratory test values assessed as adverse events are: 
• 
those requiring medical treatment 
• 
those requiring prolonged administration, discontinuation, or 
dose reduction of the investigational product 
• 
those deemed medically significant by the investigator or 
subinvestigator for any other reason 
Severity of adverse events: 
One of the following severities will be selected and evaluated: 
Mild: Mild; no symptom or mild symptom; only clinical or test finding; 
requiring no treatment 
Moderate: Moderate; requiring minimum/local/non-invasive treatment; 
limiting age-appropriate activities of daily living except for self-care* 
Severe: Severe or medically significant, but not immediately life-threatening; 
requiring hospitalization or prolongation of existing hospitalization; disability; 
limiting self-care activities.** An event leading to life-threatening 
consequences or requiring emergency intervention, or death due to adverse 
event (AE) is also assessed as severe. 
* “Activities of daily living except for self-care” refers to meal preparation, 
shopping for daily goods and clothing, use of a telephone, financial 
management, etc. 
** “Self-care activities” refers to bathing, dressing/undressing, food intake, 
use of a bathroom, and oral drug intake without being bedridden. 
 
 
16 


Analytical methods: 
Analysis sets: 
The analysis sets in this study are defined as below. 
Analysis set 
Definition 
Enrolled subjects 
All subjects enrolled in the study 
Subjects 
administered the 
investigational 
product 
All enrolled subjects who received at least 1 dose of 
the investigational product 
Full Analysis Set 
(FAS) 
All subjects administered the investigational 
product who were evaluated for at least 1 efficacy 
endpoint (regardless of whether primary or 
secondary endpoint) after initiation of 
investigational product administration 
Per Protocol Set 
(PPS) 
All subjects in the FAS, excluding those who met 
any of the following conditions: 
• Subjects who were found to fail to meet any of 
the inclusion criteria after enrollment 
• Subjects who were found to meet any of the 
exclusion criteria after enrollment 
• Subjects who did not receive sufficient doses of 
the investigational product (administration rate at 
Week 24 < 70%) 
• Subjects who used prohibited concomitant 
medications/therapies 
• Subjects who failed to comply with the dosage 
regimen of restricted concomitant medications 
• Subjects who were not evaluated for the primary 
endpoint 
 
Primary endpoint: 
The following analyses will be performed for the primary endpoint, defined as 
the change from baseline in 6MWD at Week 24: 
(1) Primary analysis 
- To evaluate the efficacy of TAS-205 appropriately, summary statistics 
will be calculated for each treatment group in the PPS. 
(2) Sensitivity analysis for the primary analysis 
- The analysis described in (1) will be performed in the FAS. 
(3) Secondary analyses of the primary endpoint 
The following analyses will be performed in the PPS and FAS: 
- A 2-sample t-test will be performed between each treatment group and 
17 


placebo group. This analysis will be performed with and without the Last 
Observation Carried Forward (LOCF) imputation. 
- The treatment effect will be estimated using the Mixed effect Models for 
Repeated Measures (MMRM). The changes from baseline in 6MWD 
measured at other time points will also be included in this analysis. 
- Using the MMRM, the dose relationship will be analyzed with treatment 
contrasts of (placebo group, low-dose group, high-dose group) = (-2 1 1), 
(-1 0 1), and (-1 -1 2). The changes from baseline in 6MWD measured at 
other time points will also be included in this analysis. 
 
For the analytical methods of the secondary, pharmacodynamic, and 
exploratory endpoints, refer to Sections 13.1.3.3 and 13.1.3.4. 
Rationale for sample 
size: 
Given that DMD is a rare disease that allows only limited recruitment of 
subjects and that this study is primarily intended to evaluate the efficacy of 
TAS-205 in an exploratory manner, the sample size was determined not 
statistically, but based on feasibility. 
18 


Table 1 Clinical Assessment Schedule 
Clinical assessment item 
Screening 
period*12 
Enroll
ment 
Baseline 
period 
 
 
Administration period 
 
Follow-up period*16, 
18 
Follow-up, 
discontinuation 
Visit (n) 
1 
– 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
Within 2 weeks before 
enrollment 
– 
Within 2 weeks 
after enrollment 
0 
0.57 
0.86 
2 
4 
8 
11 
12 
18 
23 
24 
27 
Day*1 (standard day) 
Within 14 days before 
enrollment 
– 
-2 *13 
-1 
1 *14 
4 
6 
15 
29 
57 
83 
85 
127 
167 
169 *16 
190  
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject ID code entry*2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigation of subject characteristics 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight*3 
X 
 
 
 
X *15 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization*4 
 
 
X 
 
 
 
X 
 
X 
 
Investigational product (TAS-205/placebo) 
administration*5 
 
 
Prescription 
X *5 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X *5 
 
Medical examination 
X 
 
 
 
X *15 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Blood pressure, pulse rate, body temperature*6 
X 
 
 
 
X *15 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Hematology/biochemistry*6 
X 
 
 
 
X *15 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Endocrinology*6 
 
 
 
 
X *15 
 
X 
 
 
 
 
X 
 
 
X 
(X) *19 
Urinalysis*6 
X 
 
 
 
X *15 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
12-lead ECG*7 
X 
 
 
 
X *15 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Cardiac ultrasonography (echocardiography)*7 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Pulmonary function test 
X 
 
 
 
X *15 
 
X 
 
X 
 
 
X 
 
 
X *17 
 
Motor function: 6MWD 
X 
 
 
 
X *15 
 
 
 
 
 
 
X 
 
 
X *17 
 
Motor function: time to rise from the floor, Timed 
10-m walk/run test, Timed Up & Go test 
 
 
 
 
X *15 
 
 
 
 
 
 
X 
 
 
X *17 
 
Measurement of muscle volume: skeletal muscle 
CT 
 
 
 
 
X *15 
 
 
 
 
 
 
 
 
 
X *17 
 
Measurement of muscle volume: BIA*8 
 
 
 
 
X *15 
 
X 
X 
X 
X 
 
X 
X 
 
X *17 
 
Lean body mass*8 
 
 
 
 
X *15 
 
X 
X 
X 
X 
 
X 
X 
 
X *17 
 
Quantitative muscle strength assessments 
 
 
 
 
X *15 
 
 
 
 
 
 
X 
 
 
X *17 
 
Urinary tetranor-PGDM/PGEM concentrations, 
urinary creatinine and creatine concentrations, urine 
weight, and urine specific gravity (pooled urine)*9 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
Subject medication diary (investigation of 
treatment compliance, etc.)*10 
 
 
 
Supply 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
(X) 
Concomitant medication/therapy*11 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
Evaluation of adverse events*11 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
19 


1. 
Permissible range for clinical assessments: After Day 1 (except for the follow-up and discontinuation tests), clinical assessments will be performed as specified in Section 5.1.10. The permissible range for the 2nd (Week 12) and 
3rd hospitalization (Week 24) will be the standard hospitalization day ± 7 days. For hospitalization on any day other than the standard hospitalization day, pooled urine will also be started on the day after hospitalization, and the 
efficacy evaluation including that of motor function (hereinafter referred to as the efficacy evaluation), will be performed on the end day of pooled urine. However, if the efficacy evaluation cannot be performed on the end day of 
pooled urine due to an adverse event or any other reason, the efficacy evaluation may be performed within the end day of pooled urine + 2 days (this permissible range for the efficacy evaluation will also apply to the baseline 
evaluation). The increase in the number of hospitalization days due to the delay of the efficacy evaluation (excluding prolonged hospitalization due to inpatient treatment) will not be assessed as a serious adverse event. 
For hospitalization within the permissible range of standard hospitalization day at Week 24 (Day 167) ± 7 days (Day 160 to Day 174), the investigational product will not be administered after the efficacy evaluation. 
2. 
Subject ID code entry: A unique subject ID code will be provided to each patient whose legal representative has received an explanation of informed consent (the patient should also receive an explanation of informed 
consent/assent whenever possible). 
3. 
Body weight: No dose increase/decrease will be considered according to body weight increase/decrease during the study. 
4. 
Hospitalization: In principle, the duration of the initial hospitalization (Day -2 to Day 6) will be 8 days and 7 nights. In principle, the discharge day for the 2nd hospitalization (hospitalized on Day 83 and discharged on Day 85) and 
the 3rd hospitalization (hospitalized on Day 167 and discharged on Day 169) will be the day of the efficacy evaluation; however, subjects who visit the site from afar may be discharged on the day after the efficacy evaluation. 
Subjects will be appropriately instructed before hospitalization to bring all the prescribed investigational products (managed by their legal representatives) and subject medication diary at each hospitalization. 
5. 
Investigational product administration: The first dose will be administered after dinner on Day 1, and the last dose will be administered after breakfast on the efficacy evaluation day at Week 24. Any suspended or missed dose 
during the administration period will not be administered later than administration after breakfast on the efficacy evaluation day at Week 24. The investigational product will be additionally prescribed in accordance 
withTable 3.2-1. 
6. 
Blood pressure, pulse rate, body temperature, hematology/biochemistry/endocrinology, and urinalysis: The subject will be kept at rest and fasted wherever possible for 3 to 4 hours (standard) before blood collection for laboratory 
tests. The measurement on the efficacy evaluation day will be performed before the evaluation. Blood pressure and pulse rate will be measured after the subject is confirmed to be at rest in a supine or sitting position for several 
minutes, and the measurement will be immediately repeated if any abnormality is observed. Since cortisol is subject to diurnal variation, the endocrinological parameters, including adrenocorticotropic hormone (ACTH), will be 
measured at 8:00 to 10:00 am (standard) only during the hospitalization period. 
7. 
12-lead ECG, cardiac ultrasonography (echocardiography): The measurement will be performed after the subject is confirmed to be at rest for several minutes. The measurement on the efficacy evaluation day will be performed 
before the evaluation. 
8. 
BIA, lean body mass: The measurement will be performed using a body composition monitor (TANITA BC-622). 
9. 
Urinary tetranor-PGDM and tetranor-PGEM concentrations, urinary creatinine and creatine concentrations, urine weight, and urine specific gravity: During the baseline and administration periods, urine will be pooled (under 
refrigeration) for approximately 24 hours from immediately after waking on the day after hospitalization. Urine will also be pooled for approximately 24 hours from immediately after waking on Day 4 to immediately 
after waking on Day 5 (initiation of pooled urine within Day 4 ±1 day is permissible as shown in Section 5.1.10). For urinary tetranor-PGDM and tetranor-PGEM concentrations, frozen samples will be collected by an 
external contractor and analyzed at the Pharmacokinetics Research Laboratories of Taiho Pharmaceutical Co., Ltd. Urinary creatinine and creatine concentrations, urine weight, and urine specific gravity will be measured at the 
study site. Urine volume (mL) will be calculated from the measured urine weight (g) and urine specific gravity (g/mL) at the study site. 
10. 
Subject medication diary: The subject and his legal representative will bring the subject medication diary at each visit and submit it during the medical examination. The subject medication diary will be collected at each visit for 
ongoing drug accountability check and appropriate instruction. If the subject medication diary is left behind at home, it may be collected at the subsequent visit. Drug accountability to facilitate additional prescription of the 
investigational product is described in Note 5, above. 
11. 
Assessments of concomitant medication/therapy and adverse events: Investigated from the time of informed consent to the end of the follow-up period (follow-up or discontinuation test) 
12. 
Data from any evaluation/test performed as specified within 14 days before enrollment can be used as screening data, even if obtained before informed consent. 
13. 
Initial hospitalization: The subject will be hospitalized (on Day -2) within 12 days after enrollment. 
14. 
Administration start day (Day 1): The administration of the investigational product will be started after dinner on the end day of pooled urine (within 14 days after enrollment); however, if it is not possible to perform the efficacy 
evaluation (corresponding to Note 1) due to an adverse event or any other reason, or to start the investigational product administration on the end day of pooled urine, the administration may be started after dinner within the end 
day of pooled urine + 2 days (within up to 16 days after enrollment) (the actual administration start day will be designated as Day 1). The increase in the number of hospitalization days due to the delay of the administration start 
day (excluding prolonged hospitalization due to inpatient treatment) will not be assessed as a serious adverse event. 
15. 
Clinical assessments in the baseline period: Performed no later than administration on the investigational product administration start day (administration after dinner on Day 1), in principle 
16. 
Discontinuation test: Performed at the first visit after discontinuation whenever possible (safety endpoints will be evaluated) 
17. 
Efficacy endpoints on the end day of administration: Evaluated after the last dose of the investigational product (standard: administration after breakfast on Day 169) 
18. 
Follow-up test: Performed 21 days after the last day of the investigational product administration (standard day ± 7 days is permissible). 
19. 
Endocrinology at the follow-up test: Performed only if an abnormal change (adverse event) is observed in the test on the discharge day for the 3rd hospitalization (standard: Day 169). Such an endocrinological test will be 
performed around 8:00 to 10:00 am on the follow-up test day. For subjects who visit the study site from afar, a stay at night before the follow-up test day (stay at or outside the study site; planned hospitalization or stay at a nearby 
facility) will be considered to collect blood within the specified time window whenever possible.
20 


1. Background Information 
1.1 
Introduction 
Duchenne Muscular Dystrophy (DMD) affects approximately 1 in 3500 male births worldwide, and the 
number of patients with DMD in Japan is estimated to be approximately 5000. DMD is caused by a 
mutation in the dystrophin gene resulting in the absence of dystrophin protein, which is normally located 
immediately beneath the muscle sarcolemma. The clinical course of DMD is characterized by maximal 
motor function between the ages of 4 and 5 years, followed by progressive muscle weakness and then loss 
of the ability to walk at approximately 10 years of age. The gene mutations include exon deletions, 
duplications, and micro mutations such as point mutations, which account for approximately 60%, 10%, 
and 30%, respectively. 
While the cause of DMD is the lack of dystrophin protein due to a mutation in the dystrophin gene, the 
mechanism for development of DMD is not fully understood. It is suggested that immunity and 
inflammatory responses may be involved in the development of the disease. Prostaglandin D2 (PGD2) is 
one of the major prostaglandins involved in inflammation, and is produced from arachidonic acid, a cell 
membrane constituent, by phospholipase A2, cyclooxygenase, and then prostaglandin D synthase. There are 
2 types of prostaglandin D synthase: one is known as lipocalin-type and primarily located in the central 
nervous system1, 2) and produces PGD2, which centrally acts via the prostaglandin D2 receptor 1 (DP1) to 
induce sleep, regulate pain response, etc.6); and the other is hematopoietic prostaglandin D synthase, which 
is known to be primarily expressed in mast cells, type 2 T helper cells, and microglial calls.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients with DMD, no effective treatments are available except for oral steroids, but oral steroids 
require dose reduction, change in regimen, and even dose suspension in order to manage associated adverse 
reactions; therefore, a new treatment is highly needed. While no clinical studies to evaluate the efficacy of 
TAS-205 have been conducted in patients with allergic rhinitis, development of a new treatment for DMD 
is considered to be highly valuable, and thus a Phase I single- and repeated-dose study in patients with 
DMD was conducted. In this study, TAS-205 was demonstrated to be highly safe and tolerable in patients 
with DMD when given at 1.67 to 13.33 mg/kg as a single dose and at repeated doses twice daily for 7 days. 
TAS-205 also decreased urinary excretion of tetranor-PGDM (total excretion of tetranor-PGDM and 
tetranor-PGDM/Cre concentration ratio), a marker of PGD2 production, with increasing dose. Significantly 
increased urinary excretion of tetranor-PGDM in nonambulatory subjects compared with ambulatory 
subjects when analyzed by ambulatory function as the subject characteristic, as well as higher urinary 
excretion in patients with DMD aged 8 years or older compared with healthy subjects of the same age and 
reportedly increased urinary excretion with age10) suggest involvement of PGD2 production in the 
development of DMD. In conclusion, it was considered of great significance to evaluate the efficacy of 
TAS-205 in patients with DMD, and an early Phase II study in these patients was therefore planned. 
1.2 
TAS-205 
1.2.1 
Mechanism of Action 
TAS-205 inhibits HPGDS selectively and competitively. 
1.3 
Overview of Risks and Benefits 
1.3.1 
TAS-205 
Since only Phase I studies have been conducted with TAS-205 to investigate the tolerability, 
pharmacokinetics, and pharmacodynamics in healthy adult male subjects and patients with DMD, and only 
22 


limited information is available on the efficacy, benefits of TAS-205 has not been confirmed yet at the 
initiation of the present study. 
1.3.2 
Risks and Benefits Expected in the Study 
This study is expected to provide information on the efficacy of TAS-205 (high and low doses) for 
deterioration of physical function (motor function, muscle volume, and muscle strength) and the dose 
relationship of TAS-205 in patients with DMD. In addition, the study is expected to provide information on 
the long-term safety of TAS-205 administered twice daily for 24 consecutive weeks. Since no significant or 
potentially significant risks have been identified with TAS-205, no risks are expected in the present study; 
however, the high dose of TAS-205 has never been administered in clinical studies, and thus the tolerability 
of TAS-205 at the high dose has not been demonstrated yet at the initiation of the present study. 
1.4 
Major Study Results 
1.4.1 
Nonclinical Studies 
Refer to the Investigator's Brochure DMD Ver. 3 (revised on March 24, 2016). 
1.4.2 
Clinical Studies 
1.4.2.1 
Study 10053010 (Phase I Study in Healthy Adult Subjects) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
23 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.2.2 
Study 10053030 (Phase I Study in Patients with DMD) 
A Phase I single- and repeated-dose clinical study of TAS-205 was conducted in patients with DMD 
(hereinafter referred to as Study 10053030) to evaluate the safety and pharmacokinetics of TAS-205, as 
well as the effects of TAS-205 on urinary excretion of tetranor-PGDM and tetranor-PGEM in an 
exploratory manner after a single oral dose and repeated oral doses twice daily for 7 days (Steps 1 and A: 
1.67 - 3.33 mg/kg/dose, Steps 2 and B: 3.33 - 6.67 mg/kg/dose, Steps 3 and C: 6.67 - 13.33 mg/kg/dose). 
24 


In the single dose period, a total of 15 subjects in the TAS-205 group, with 5 subjects per step, and a 
total of 6 subjects in the placebo group were treated with the investigational product. Pharmacokinetics was 
evaluated only in 15 subjects in the TAS-205 group. Pharmacodynamics was evaluated in 15 subjects in the 
TAS-205 group and 6 subjects in the placebo group. 
In the repeated dose period, a total of 14 subjects in the TAS-205 group (in Steps A to C) and a total of 5 
subjects in the placebo group were treated with the investigational product. Pharmacokinetics was 
evaluated only in the 14 subjects in the TAS-205 group administered the investigational product, and all 
subjects in the placebo group were excluded from the pharmacokinetic evaluation. Pharmacodynamics was 
evaluated in the 14 subjects in the TAS-205 group and 5 subjects in the placebo group were treated with the 
investigational product. 
The pharmacokinetics of TAS-205 was linear in the dose range studied and reached steady state after 
repeated doses for 4 days. In addition, it was suggested that TAS-205 decreased urinary excretion of 
tetranor-PGDM (total excretion of tetranor-PGDM and tetranor-PGDM/Cre concentration ratio) with 
increasing dose at each measurement time point, without affecting urinary excretion of tetranor-PGEM. 
In the safety evaluation in this study, no deaths or other serious adverse events were reported in any 
subjects. No subjects were withdrawn from the study due to adverse events in any dosing period. In the 
TAS-205 group as compared with the placebo group, adverse events occurred, and adverse drug reactions 
also occurred in the single dose period, but not in the repeated dose period. None of the adverse events 
reported in the TAS-205 group were common to all steps or tended to increase dose-dependently in any 
dosing period; all adverse events were mild in severity and resolving or resolved. In addition, no clinically 
significant abnormal changes were observed in laboratory values, 12-lead ECG, blood pressure, or pulse 
rate. In the repeated dose period, an abnormal change in body temperature was observed in 1 subject in 
Step B in the TAS-205 group; however, this was associated with nasopharyngitis. Other measured values 
were comparable to those in the placebo group, with no clinically significant changes post-/pre-dose . 
In conclusion, TAS-205 was demonstrated to be highly safe and tolerable in patients with DMD when 
given at 1.67 to 13.33 mg/kg/dose as a single oral dose and repeated oral doses twice daily for 7 days. 
1.5 
Rationale for the Study and Study Population 
1.5.1 
Study Population 
This study is an early Phase II study to evaluate the efficacy of TAS-205 (low dose and high dose) 
administered orally twice daily for 24 consecutive weeks in patients with DMD. The study will also be 
conducted to evaluate the safety of TAS-205 as well as the relationship between the pharmacodynamic or 
exploratory endpoints and the efficacy in an exploratory manner. Since the efficacy for deterioration of 
physical function will be primarily evaluated, this study will include ambulatory patients with DMD aged 5 
years or older who meet all of the inclusion criteria and none of the exclusion criteria. 
1.5.2 
Study Design 
 
 
 
 
25 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5.3 
Dosage of TAS-205 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
26 


 
 
 
 
 
Since a marked increase in body weight during the 24-week evaluation period is unlikely and dose 
increase/decrease according to body weight increase/decrease during the study may be unnecessary based 
on the dose setting in 7.5-kg or 15-kg increments of body weight in the present study, the dose for each 
subject during the evaluation period will be fixed based on the body weight data in the screening period 
(within 14 days before enrollment). In summary, the subjects assigned to the active drug groups will 
receive the number of TAS-205 tablets per dose specified by the body weight measured within 14 days 
before enrollment, as shown in Table 7.1.1-1, orally twice daily, within 30 minutes after breakfast and 
dinner, for 24 consecutive weeks. 
1.5.4 
Selection of TAS-205 Placebo 
In this study, a placebo group will be included to evaluate the efficacy of TAS-205 for deterioration of 
physical function (e.g., motor function, muscle volume, muscle strength) after oral administration twice 
daily for 24 consecutive weeks as well as the safety after repeated administration for 24 weeks, in an 
appropriate and objective manner. In order to maintain blindness of the low-dose and high-dose groups, in 
which different numbers of TAS-205 50 mg tablets (active drug) will be administered, the subjects assigned 
to the low-dose group will receive the active drug tablets with the same number of placebo tablets. In 
summary, the subjects assigned to the placebo and the low-dose groups will receive the number of tablets 
per dose specified based on the body weight measured within 14 days before enrollment, as shown in Table 
7.1.1-1, orally twice daily, within 30 minutes after breakfast and dinner, for 24 consecutive weeks. Since 
this study is designed to permit subjects who had been using steroid before informed consent to continue 
their steroid therapy as far as no changes are made to their dosage regimen after informed consent, 
inclusion of a placebo group is considered ethically acceptable. 
27 


2. Study Objectives 
2.1 
Primary Objective 
To evaluate the efficacy of TAS-205 administered orally twice daily for 24 consecutive weeks compared 
with placebo in patients with DMD in an exploratory manner. 
2.2 
Secondary Objective 
To evaluate the safety and dose relationship of TAS-205 administered orally twice daily for 24 
consecutive weeks compared with placebo in patients with DMD. 
2.3 
Exploratory Objectives 
To evaluate the effect of TAS-205 on the urinary excretion of tetranor-PGDM and tetranor-PGEM in 
pooled urine samples after twice-daily oral administration for 24 consecutive weeks, as well as the 
relationship between the urinary excretions and efficacy of TAS-205 in patients with DMD, and also to 
evaluate the change in the urinary excretion of creatinine and creatine in pooled urine samples after 
twice-daily oral administration of TAS-205 for 24 consecutive weeks in patients with DMD in an 
exploratory manner. 
2.4 
Endpoints 
2.4.1 
Primary Endpoint 
Efficacy: 
Evaluation of motor function: Change from baseline in the measured 6MWD at Week 24 
2.4.2 
Secondary Endpoints 
Efficacy: 
• 
Evaluation of motor function: (1) Measured 6MWD and the change from baseline in the 
measured 6MWD at Week 12, (2) Time measured in the time to rise from the floor test, Timed 
10-m walk/run test, and Timed Up & Go test, as well as the change from baseline in the time 
measured in each test 
• 
Evaluation of muscle volume: Measured values in skeletal muscle CT and BIA as well as the 
change from baseline in each the measured value 
• 
Measured lean body mass and the change from baseline in each measured value 
• 
Evaluation of muscle strength: Quantitative muscle strength assessments with a hand-held 
dynamometer (hip flexion/extension, knee flexion/extension, ankle extension/flexion) and the 
change from baseline in each measured value 
• 
Measured CK concentration and the change from baseline in the measured value 
• 
Pulmonary function test (non-invasive vital capacity measurement using a spirometer): 
Measured VC, FVC, FEV1.0, and FEV1.0%, as well as the change from baseline in each 
measured value 
 
 
28 


 
Safety: 
• 
Safety evaluation by cardiac ultrasonography (echocardiography), 12-lead ECG, blood 
pressure, pulse rate, body temperature, and laboratory tests (incidence of adverse events and 
adverse drug reactions, etc.) 
2.4.3 
Pharmacodynamic Endpoints 
• 
Urine tetranor-PGDM/Cre concentration ratio 
• 
Total urinary tetranor-PGDM excretion 
• 
Urine tetranor-PGEM/Cre concentration ratio 
• 
Total urinary tetranor-PGEM excretion 
2.4.4 
Exploratory Endpoints 
• 
Urinary creatinine excretion 
• 
Urinary creatine excretion 
• 
Creatine in urine (%)*1 
*1 Creatine in urine (%) = urinary creatine excretion (g/day) / [urinary creatine excretion (g/day) + urinary 
creatinine excretion (g/day)] × 100 (the value shall be rounded to 2 decimal places)5) 
 
29 


3. Study Design 
This study is a double-blind, randomized study to evaluate the efficacy of TAS-205 for deterioration of 
physical function (e.g., motor function, muscle volume, muscle strength) compared with placebo in patients 
with DMD; that is, the study is designed as an exploratory efficacy study. 
The target total sample size of 33 patients will be obtained through central registration. 
Subjects will be enrolled and randomized to low-dose group (6.67 to 13.33 mg/kg/dose), high-dose 
group (13.33 to 26.67 mg/kg/dose), or placebo group (randomization ratio: 1:1:1), and receive the 
investigational product orally twice daily, once after breakfast and once after dinner, for 24 consecutive 
weeks starting after dinner on Day 1 (subjects will be hospitalized on Day -2 within 12 days after 
enrollment and start Day 1 within 14 days after enrollment) to evaluate the efficacy in a double-blind 
manner. Subjects will receive the number of tablets per dose specified based on their body weights 
measured within 14 days before enrollment, as shown in Table 7.1.1-1. 
The study design is shown in Figure 3-1 below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3-1 Study Design 
 
3.1 
Study Period 
Study start day (planned): February, 2016 
Study completion day (planned): August, 2017 
Patient enrollment period (planned): May, 2016 to October, 2016 
Implementing countries: Japan only 
3.1.1 
Definitions of Periods in the Study for Individual Subjects 
The periods described in this protocol will be defined as follows: 
R 
Enrollment 
<Central 
registration> 
Screening 
Within 14 days before 
enrollment 
Placebo tablet × number specified by body 
weight before enrollment 
Repeated oral administration twice daily, once 
after breakfast and once after dinner 
Day 1 
Start 
administration 
TAS-205 50 mg tablet and placebo tablet × number 
specified by body weight before enrollment 
Repeated oral administration twice daily, once after breakfast 
and once after dinner 
Week 24 
Study Period 
Low-dose group (6.67 to 13.33 mg/kg/dose, N = 11) 
Placebo group (N = 11) 
Informed consent/assent 
High-dose group (13.33 to 26.67 mg/kg/dose, N = 11) 
Follow-up period 
TAS-205 50 mg tablet × number specified by body 
weight before enrollment 
Repeated oral administration twice daily, once after 
breakfast and once after dinner 
30 


Study period: 
Period from the day of written informed consent by the legal representative 
of the patient to the end of the follow-up period 
Screening period: 
Period from the day of written informed consent until before enrollment 
(within 14 days before enrollment) 
Baseline period: 
Period from after enrollment to the first dose of the investigational product 
(after dinner on Day 1) (in principle, within 14 days after enrollment) 
Administration period: 
Period from after the first dose of the investigational product (after dinner on 
Day 1) to the end of the last dose of the investigational product (standard: 
after breakfast on Day 169) or discontinuation 
Follow-up period: 
21 days from the day of last dose of the investigational product (permissible 
range: standard ± 7 days). Safety follow-up test will be performed. 
Hospitalization period*1: 
 
- Initial hospitalization period*1Period from the hospitalization on Day -2 to 
the discharge on Day 6 (8 days and 7 nights; in principle, the end day of 
pooled urine initiated on Day -1 will be Day 1) 
- 2nd hospitalization period*1 
Period from the hospitalization on Day 83 ± 7 days (Day 76 to Day 90) to the 
discharge after 3 days and 2 nights (subjects who visit the site from afar may 
be discharged on the day after the efficacy evaluations [4 days and 3 nights]) 
- 3rd hospitalization period*1 
Period from the hospitalization on Day 167 ± 7 days (Day 160 to Day 174) to 
the discharge after 3 days and 2 nights (subjects who visit the site from afar 
may be discharged on the day after the efficacy evaluations [4 days and 3 
nights]) 
*1 In view of the conditions of pediatric subjects, if it is not possible due to an adverse 
event or other reasons to perform the efficacy evaluations or to start the investigational 
product administration on the end day of pooled urine, the efficacy evaluations may be 
started within the end day of pooled urine + 2 days or the administration may be started 
on Day 1. In such case, the increase in the number of hospitalization days (excluding 
prolonged hospitalization due to inpatient treatment) will not be assessed as a serious 
adverse event. 
 
 
31 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3.1-1 Study Participation Period for Individual Subjects 
3.2 
Subject Randomization and Blinding 
3.2.1 
Randomization Method 
This study is a randomized study. 
After providing due explanation to each prospective patient and his legal representative, the investigator 
or subinvestigator will obtain written informed consent/assent, and then prepare a screening log of patients 
whose legal representative consented to participate in the study in order to check the patient enrollment in 
the study. After confirming that the prospective patient is deemed eligible by meeting all of the inclusion 
criteria and none of the exclusion criteria, all necessary information will be entered the Interactive Web 
Response System (IWRS) and submitted to the Enrollment Center. 
Upon completion of enrollment after confirmation of subject eligibility, the subjects will be randomly 
assigned to the low-dose group, high-dose group, or placebo group in a ratio of 1:1:1 via IWRS based on a 
dynamic randomization method (minimization method). 
Data will be entered in accordance with the description in the IWRS procedure. 
The subjects will be stratified by the following randomization adjustment factors: 
• 
Age (between 5 and 6 years, 7 years or older) 
• 
Presence or absence of concomitant steroid use 
The above-mentioned enrollment and randomization will be centrally managed; after completion of the 
enrollment procedure, each subject will be assigned to a treatment group and given an investigational 
product number to be initially prescribed (for 6-week administration) by the enrollment system. 
The investigational product numbers corresponding to subject randomization will be given and reported 
to the study site with instructions on the investigational product prescription via IWRS. For more detailed 
information, refer to the IWRS procedure. 
If an investigational product not corresponding to the number given via IWRS is prescribed to a subject 
in error, the IWRS help desk must be notified immediately. In addition, the cause of the erroneous 
prescription of the investigational product must be recorded at the study site. 
Study participation period 
Within 14 
days 
Written 
informed 
consent 
Assent 
Day 1 
After dinner 
Start of 
administration 
Enrollment 
<Central 
registration> 
Within 14 
days 
 
Screening  
period 
Baseline 
 period 
Administration period 
Day -2 
Hospitalization 
Initial hospitalization 
period 
Day 6 
Discharge 
Follow-up 
period 
Day 169 
After breakfast 
End of 
administration 
24 weeks (168 days) 
Day 190 
Follow-up 
test 
6MWD 
evaluation, etc. 
(before 
administration) 
6MWD evaluation, etc. 
(evaluation at Week 12) 
6MWD evaluation, etc. 
(evaluation at Week 24) 
6MWD evaluation 
(Selection criteria: ≥ 75 m) 
Day 83 
Hospitalization 
2nd 
Hospitalization 
period 
Day 85 
Discharge 
Pooled urine 
Day 167 
Hospitalization 
3rd 
Hospitalization 
period 
Day 169 
Discharge 
21 ± 7 
 days 
Day 4 
Pooled urine 
Pooled urine 
Pooled urine 
Pooled urine 
32 


If a subject receives the investigational product for a different treatment group due to an error in the 
investigational product number allocation or prescription, the subject will continue to receive the 
investigational product for the rest of the study period. 
If any of the discontinuation criteria for individual subjects specified in Section 4.3 is met, the condition 
related to the discontinuation will be entered in the IWRS promptly. In addition, any dose suspension or 
reduction will be promptly recorded in the IWRS with the start and end days of the suspension, the start 
day of the reduction, etc. 
3.2.2 
Allocation of the Investigational Product Number 
3.2.2.1 
Allocation of the Investigational Product Number at Enrollment 
After enrollment, each subject will be assigned to a treatment group and provided an investigational 
product number (boxes) to be initially prescribed (for 6-week administration) via IWRS (1st allocation). 
The first dose after enrollment will start within 14 days after enrollment. 
3.2.2.2 
Second and Subsequent Allocation of the Investigational Product Number 
(at Visit 4 and Thereafter) 
At the 2nd allocation of the investigational product number, the study site staff will enter necessary 
information into the IWRS after confirming that there are no problems for continuous administration of the 
investigational product after medical examination at Visit 4 (Week 4). Based on the information entered, the 
investigational product numbers (boxes) necessary for a total of 8 weeks of administration from Week 7 to 
Week 14 should be given to the study site via IWRS (2nd allocation). 
Similarly, at the 3rd allocation, the study site staff will enter necessary information into the IWRS after 
confirming that there are no problems for continuous administration of the investigational product during 
hospitalization (after medical examination) at Visit 6 (Weeks 11 to 12), and then, based on the information 
entered, the investigational product numbers (boxes) necessary for a total of 6 weeks of administration 
from Week 15 to Week 20 should be given to the study site via IWRS. 
At the 4th allocation, the study site staff will enter necessary information into the IWRS after 
confirming that there are no problems for continuous administration of the investigational product after 
medical examination at Visit 7 (Wees 18), and then, based on the information entered, the investigational 
product numbers (boxes) necessary for a total of 6 weeks of administration from Week 21 to the day of last 
dose [taking into consideration the 3rd hospitalization on Day 174 (the latest permissible hospitalization 
day) and the end day of pooled urine (Day 176) + 2 days (Day 178: the latest permissible day of the 
efficacy evaluations)] should be given to the study site via IWRS. 
 
 
33 


 
 
Table 3.2-1 Allocation of the Investigational Product Number (at Enrollment and Visit 4 and 
thereafter) 
Allocation of the 
investigational product 
number 
1st 
2nd 
3rd 
4th 
Number of tablets prescribed 
to subjects*1 
For a total of 6 weeks of 
administration 
For a total of 8 weeks of 
administration 
For a total of 6 weeks of 
administration 
For a total of 4 weeks + 
2 weeks*2 of 
administration 
Prescription time point 
Before administration after 
the 1st hospitalization 
(Day -2 to Day 1  
before first dose) 
Visit 4 
(Week 4) 
Visit 6 
(Weeks 11 to 12;  
at the 2nd hospitalization) 
Visit 7 
(Week 18) 
Duration of administration 
period of the investigational 
product prescribed 
(planned) 
Day 1 to 
Week 6 
Week 7 to 
Week 14 
Week 15 to 
Week 20 
Week 21 to 
Week 24 (+ 2 weeks*2) 
Timing of IWRS completion 
and 
the investigational product 
number allocation  
Enrollment 
Visit 4 
(after medical 
examination) 
During hospitalization at 
Visit 6 
(after medical 
examination) 
Visit 7 
(after medical 
examination) 
*1:  Since the investigational product will be supplied in boxes, the subjects will be prescribed at least the number of boxes 
that include necessary number of tablets. 
*2:  2 weeks are added in consideration of the permissible range of the 3rd hospitalization (± 7 days) as well as the efficacy 
evaluation day at Week 24 (end day of pooled urine + 2 days). 
 
The investigational product numbers given at the 1st (at enrollment) and subsequent allocation will be 
the same as the numbers corresponding to the treatment group assigned at enrollment at the 1st allocation. 
If a subject is administered the investigational product for a different treatment group during the 
administration period due to an error in the 2nd (Visit 4) or subsequent investigational product number 
allocation or prescription, the medical expert and the sponsor will discuss the action to be taken promptly. 
3.2.3 
Blinding 
This study is a double-blind study. During the study, all subjects, the investigator, the subinvestigator, 
the trial collaborator, and the sponsor will be blinded to the treatment groups. According to the 
investigational product allocation procedure, the key codes will be prepared, broken, and managed by the 
investigational product allocation manager. 
The codes will not be broken unless otherwise needed for the management of the medical condition of 
the subject. If the investigational product has to be identified in case of emergency to manage the medical 
condition of a subject, the investigator or subinvestigator will discuss the condition of the applicable 
subject with the sponsor before code breaking via IWRS. If discussion before code breaking is not possible, 
the investigator will notify the sponsor of the code breaking as soon as possible. In case the code breaking 
occurs, the investigator or subinvestigator must record the date of and reason for the code breaking. 
The codes will be broken to identify the investigational product group after completion of the study 
period and the analysis data lock. 
 
 
34 


 
4. Patient Inclusion/Exclusion and Subject Discontinuation Criteria 
4.1 
Inclusion Criteria 
Patients who meet all of the criteria below at the enrollment will be included in the study. 
The rationale is described in Section 14.3. 
(1) A legal guardian (legal representative) of a male pediatric patient with the ability to give 
consent provides written informed consent to participate in the study (whenever possible, 
informed voluntary assent should also be obtained personally from the patient after all 
information has been given in a way that suits the patient's level of understanding). 
(2) Patients with a diagnosis of dystrophinopathy as determined by a dystrophin genetic test or 
muscle pathology findings, symptoms or signs characteristic to DMD (e.g., proximal 
muscular weakness, waddling gait, Gowers sign), and progressive walking difficulty at the 
time of informed consent. 
(3) Patients aged 5 years or more at the time of informed consent 
(4) Patients weighing ≥ 7.5 kg and < 60 kg within 14 days before enrollment 
(5) Patients who can rise from the floor or a chair and walk by themselves at the screening test 
(confirmed by medical interview, actual performance, etc.), with 6MWD of 75 m or more 
(use of wheelchair in daily activities is permissible) 
(6) Patients who can stay in the hospital for the time period specified in the study 
(7) Patients who can continue with administration of the specified number of tablets 
(8) If the patient is receiving oral steroids for DMD treatment, he had begun the treatment more 
than 6 months before informed consent, and his symptoms remain stable with no change in 
the prescription-based dosage regimen of steroids within 3 months 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria at the enrollment will be excluded from the study. 
Patients who meet any of the following criteria (except for criterion (2)) during the baseline period after 
enrollment cannot receive the administration of the investigational product during the period. 
The rationale is described in Section 14.4. 
(1) Patients who have serious concomitant drug hypersensitivity 
(2) Patients with FVC of < 50% of the predicted value*1 based on the spirometric reference 
value in Japanese children (developed by the Lung Function Review Committee of the 
Japanese Society of Pediatric Pulmonology in 2008)6) within 14 days before enrollment 
*1 FVC will be predicted using the following formula: 
FVC prediction: 2.108+ (-0.1262) × age (years)+ 0.00819 × age (years)2+(-3.118) × height (m)+2.553 × height (m)2 
(3) Patients who continuously use mechanical ventilation (except for use while sleeping) 
(4) Patients with a left ventricular EF of < 40% or left ventricular FS of < 25% on the cardiac 
ultrasonography (echocardiography) performed within 14 days before enrollment 
(5) Patients who have been confirmed to have clinically significant symptoms of cardiac failure 
or respiratory failure 
35 


(6) Patients receiving immunosuppressive medications (other than corticosteroids for DMD 
treatment) 
(7) Patients who have used COX-1 or COX-2 inhibitors, or NSAIDs during 7 days before the 
6MWD test in the screening period 
(8) Patients who have a history of surgery that may affect muscle strength or motor function 
within 6 months before enrollment or who will undergo surgery during the study 
(9) Patients who have incurred an injury (trauma/damage) that may affect muscle strength or 
motor function within 3 months before enrollment or who have an uncured injury 
(trauma/damage) that may affect muscle strength or motor function at the enrollment 
(10) Patients with systemic allergic disease, chronic inflammatory disease, or other diseases that 
may prevent correct interpretation of efficacy or safety data (excluding allergic rhinitis, 
localized or mild atopic dermatitis, eczema, etc.) 
(11) Patients who have received gene-/cell-based therapy or stop-codon readthrough therapy with 
antisense oligonucleotides, or who have participated in another clinical trial and received an 
investigational product within 90 days before investigational product administration in the 
present study 
(12) Participants of another clinical trial or participants of another clinical research or another 
study in which they may undergo a motor function test during 7 days before a motor 
function test scheduled in the present study 
(13) Patients who have been confirmed to be HBs antigen-, HCV antibody-, or HIV antigen- or 
antibody-positive before enrollment 
(14) The patient's legal representative is unwilling to agree that the patient will use appropriate 
contraception throughout the study period and for 180 days after the end of the study. 
1) The investigator or subinvestigator will discuss appropriate contraception with the patient 
and his legal representative, and instruct the patient to avoid pregnancy of a partner 
without fail using a double barrier method (condom plus diaphragm) or intrauterine 
contraceptive device throughout the study participation or contraception period if 
applicable. 
(15) Patients who are judged by the investigator or subinvestigator to have brain dysfunction, 
including intellectual disability, tendency of autism, and attention deficit hyperactivity 
disorder that may affect the evaluation of motor function 
(16) Patients with QTc of 450 msec or more on the 12-lead ECG performed within 14 days 
before enrollment (corrected by Fridericia’s formula) 
(17) Patients who are deemed not eligible for the study by the investigator or subinvestigator for 
any other reason 
 
4.3 
Discontinuation Criteria for Individual Subjects 
Subjects who meet any of the following conditions will be withdrawn from investigational product 
administration: 
36 


• 
An adverse event that, in the opinion of the investigator, requires discontinuation of 
investigational product administration occurs. 
• 
The subject or his legal representative requests to discontinue participation in the study 
(investigational product administration) (e.g., withdrawal of consent). 
• 
There is a significant deviation from the study procedures. 
• 
The subject cannot remain in the study because of residence change, hospital change, 
commitment to other tasks, etc. 
• 
The subject requires persistent use of mechanical ventilation. 
• 
The subject must use walking aids during the efficacy evaluations, including that of motor 
function. 
• 
The dose was suspended for more than a total of 50 days during the specified administration 
period (missed dose*1 will also be included; missed dose in a morning or evening will be 
counted as 0.5 days of dose suspension). 
*1 Only the missed dose of all tablets per dose will be counted. 
• 
The investigator deems it necessary to discontinue the subject from the study for any other 
reason. 
37 


5. Evaluations and Tests in the Study 
Evaluations and tests to be performed in the study are listed in Table 5-1. In addition, a detailed 
implementation schedule for clinical assessments at each visit is shown in Table 1. 
All information specified in the protocol shall be recorded. Data from any evaluation/test performed as 
specified within 14 days before enrollment can be used as screening data, even if obtained before informed 
consent. 
Table 5-1 Medical Evaluations/Tests 
Written informed consent and assent 
 
Consent to study participation 
Legal guardian (legal representative): required, patient: whenever possible 
Subject ID code assignment 
Day of diagnosis of DMD determined 
• Day of diagnosis of dystrophinopathy determined 
(Day of diagnosis determined based on dystrophin genetic test or muscle pathology) 
• Clinical symptoms or signs characteristic to DMD and symptoms of progressive walking difficulty 
(e.g., proximal muscular weakness, waddling gait, Gowers sign) 
Subject characteristics 
 
Gender 
Date of birth (age) 
Height 
 
Body weight 
Motor function (6MWD) 
History of surgery 
 
Current medication 
Previous/present participation in 
clinical researches 
Previous participation in clinical 
trials 
 
History of steroid use 
Previous medical history 
Concurrent illness 
 
Rehabilitation status 
 
 
Patient enrollment 
Investigational product accountability (subject 
medication diary) 
Medical examination (medical interview, inspection, auscultation, palpation) 
Blood pressure (systolic, diastolic), pulse rate, body temperature (axilla) 
ECG 
 
12-lead ECG (at rest) 
Heart rate, QTcF interval, findings 
Hematology 
 
Red blood cell count 
Hemoglobin 
Hematocrit 
Platelet count 
 
White blood cell count 
 
 
Neutrophils 
 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Biochemistry 
 
Total protein 
Albumin 
A/G  
Total bilirubin  
 
Direct bilirubin 
AST 
ALT 
ALP 
 
LDH 
CK 
γ-GTP 
BUN 
 
Cystatin C  
Creatinine (Cre) 
Glucose (blood sugar) 
Uric acid 
 
Triglycerides 
Total cholesterol 
HDL-C 
CRP 
 
Sodium (Na) 
Potassium (K) 
Chlorine (Cl) 
Calcium (Ca) 
 
Magnesium (Mg) 
Phosphate (P) 
 
 
Endocrinology 
 
Cortisol 
ACTH 
Urinalysis 
 
Protein 
Glucose 
Urobilinogen 
 
Cardiac ultrasonography (echocardiography) 
EF,FS 
Concomitant medication/therapy 
Evaluation of adverse events 
Motor function 
 
6MWD test, time to rise from the floor test, Timed 10-m walk/run test, Timed Up & Go test 
Evaluation of muscle volume 
Skeletal muscle CT  
 
BIA 
Lean body mass 
Quantitative muscle strength assessments 
Measured with a hand-held dynamometer (hip flexion/extension, knee flexion/extension, ankle extension/flexion) 
Pulmonary function test 
Measured with a spirometer (measured VC, FVC,* FEV1.0, and FEV1.0%) 
*Only FVC (including measured value, predicted value, and % of predicted value) will be measured during the screening period. 
Pharmacodynamic and exploratory evaluations (pooled urine) 
Urine tetranor-PGDM and tetranor-PGEM concentrations, urine creatinine and creatine concentrations [Creatine in urine 
(%) *1], urine volume (urine specific gravity and urine weight)*2 
*1 Creatine in urine (%) will be calculated by the sponsor based on the urine creatinine concentration, urine creatine concentration, and urine 
volume described on the case report form (CRF). 
*2 Urine volume (mL) will be calculated from the urine specific gravity (g/mL) and urine weight (g) measured at the study site and recorded 
on the CRF at the study site. 
 
38 


5.1 
Study Procedures 
The results of the evaluations/tests in Sections 5.1.1 to 5.1.13 must be recorded in the source documents 
of subjects. The muscle volume in the skeletal muscle CT and the urine tetranor-PGDM and 
tetranor-PGEM concentrations in the pharmacodynamic evaluation will be measured and recorded by the 
muscle volume evaluation committee and the Pharmacokinetics Research Laboratories, respectively. 
5.1.1 
Informed Consent 
Informed consent will be obtained from the legal representative of the patient, and assent from the 
patient whenever possible, within 14 days before enrollment (screening period), followed by eligibility 
confirmation. 
5.1.2 
Subject ID Code Assignment 
Subject ID code will be assigned after obtaining written informed consent at the study site. Subject ID 
code shall be composed of the study site number (2 digits) - order of informed consent obtained at each site 
(2 digits) (e.g., study site number 0X and order of informed consent obtained 1st: 0X-01). 
5.1.3 
Subject Characteristics 
The necessary items for subject characteristics shown in Table 5-1 will be entered in the CRF within 14 
days before enrollment. 
5.1.4 
Motor Function/Muscle Volume/Lean Body Mass/Muscle Strength Evaluations 
and Pulmonary Function Test 
Motor function, muscle volume, and muscle strength evaluations and pulmonary function test will be 
performed for all subjects at the time points specified in the clinical assessment schedule in Table 1. 
Skeletal muscle CT will be performed as a muscle volume evaluation. Diagnostic radiology central 
review (measurement and evaluation) will be performed by the muscle volume evaluation committee in 
accordance with a separately specified procedure. 
5.1.5 
Pregnancy Test 
This test is not applicable, because the target population is male pediatric patients. 
5.1.6 
Drug Accountability 
The investigator or subinvestigator will collect the subject medication diary at each visit and confirm 
the accountability of TAS-205 by medical interview, checking medication records in the subject medication 
diary, etc., from the start to end of the administration. If the subject medication diary is left behind at home, 
it may be collected at the subsequent visit. Confirmed drug accountability will be recorded on the CRF in 
reference to the “Instructions for Completing the CRFs and Making Changes or Corrections to the CRFs.” 
Any subject who consults another department or hospital for other diseases will inform his treating 
physician of his participation in this study. Any subject who is required to use other medications after the 
consultation will be instructed to inform the investigator or subinvestigator. 
39 


5.1.7 
Blood Pressure, Pulse Rate, Body Temperature, Height, and Body Weight 
Data on blood pressure, pulse rate, body temperature, and body weight will be collected at the time 
points specified in Table 1 and Section 5.1.10. Height will measured only during the screening period to 
calculate predicted FVC, an exclusion criterion. 
Blood pressure and pulse rate will be measured after the subject is confirmed to be at rest in a supine or 
sitting position for several minutes, and the measurement on the efficacy evaluation day will be performed 
before the evaluation. Pulse rate, blood pressure, and body temperature will always be measured at the 
same site of the same arm whenever possible. The measurement will be immediately repeated if any 
abnormality is observed. Any clinically significant change from baseline will be recorded as an adverse 
event specified in Section 12.1. 
5.1.8 
ECG, Cardiac Ultrasonography (Echocardiography) 
The investigator or subinvestigator will be responsible for assessment of the result of ECG and cardiac 
ultrasonography (echocardiography). 
The measurement will be performed after the subject is confirmed to be at rest for several minutes. The 
measurement on the efficacy evaluation day will be performed before the evaluation. Any clinically 
significant change from baseline must be recorded as an adverse event specified in Section 12.1. Data on 
12-lead ECG at rest will be collected at the time points specified in Table 1 and Section 5.1.10. 
5.1.9 
Laboratory Values 
The investigator or subinvestigator must evaluate all laboratory values to determine whether they are 
clinically significant events. 
Laboratory tests will be performed while subjects are at rest and fasted whenever possible. The 
measurement on the efficacy evaluation day will be performed before the evaluation. 
Any laboratory value determined to be clinically significant shall be followed up and reported as an 
adverse event specified in Section 12.1. In addition, the laboratory value will be repeatedly evaluated until 
the value resolves to baseline level or becomes resolving, or is determined to be difficult to follow-up due 
to a reason described in Section 12.1.7, “Follow-up of Adverse Events.” 
Outline of the laboratory parameters is shown in Table 5-1. 
As shown in Section 11.7.1, only the serum CK concentration during the hospitalization period will be 
used for the efficacy evaluation. 
5.1.9.1 
Hematology 
Blood samples for hematology will be collected at the time points specified in Table 1 and Section 
5.1.10. 
5.1.9.2 
Biochemistry 
Blood samples for biochemistry will be collected at the time points specified in Table 1 and Section 
5.1.10. 
5.1.9.3 
Endocrinology 
Blood samples for endocrinology will be collected at the time points specified in Table 1 and Section 
5.1.10 (during the hospitalization only). 
40 


5.1.9.4 
Urinalysis 
Urine samples for qualitative urinalysis will be collected at the time points specified in Table 1 and 
Section 5.1.10. 
5.1.10 
Timing for Individual Evaluations/Tests 
 
Screening period (for eligibility confirmation): Performed within 14 days before enrollment 
 
Baseline period (for baseline evaluation): Performed within 14 days after enrollment 
 
Administration period:  
- 
Day 4: Performed within ± 1 day (pooled urine may also be started on Day 4 ± 1 day) 
- 
Day 6: Performed on the day  
- 
Day 15: Performed within + 5 days*1 
*1 If all the days in the permissible range are holidays/national holidays and clinical assessments cannot be 
performed, the first working day after the holidays/national holidays is permitted. 
- 
Day 29: Performed within ± 5 days 
- 
Day 57, 127: Performed within ± 7 days 
- 
Day 85, 169: Performed within ± 7 days (if hospitalization is within the permissible range of 
± 7 days) 
 
Follow-up period: Follow-up test (21 days after the end of investigational product 
administration): Performed within ± 7 days 
5.1.11 
Concomitant Medication/Therapy 
Information on all medications (prescribed and over-the-counter drugs) and therapies concomitantly 
used during the time from the informed consent to the end of the follow-up test will be collected. This will 
include information on the medications used for treatment of adverse events or serious adverse events. Test 
or diagnostic agents, or solvents or solutions for injections need not to be recorded on the CRF. The current 
concomitant medications will be recorded in the source documents. 
5.1.12 
Report of Adverse Events 
As shown in Table 1, at each visit from the informed consent to the end of the follow-up test and during 
the hospitalization period, presence of any unfavorable medical event (adverse event or serious adverse 
event), including adverse drug reaction, will be confirmed. Any serious adverse event developed will be 
reported in accordance with the procedure presented in Section 12.2.2. 
The investigator or subinvestigator will report to the sponsor after the end of the follow-up period any 
serious medical event reported or observed, including adverse event and death, for which relationship with 
the investigational product cannot be ruled out. 
5.1.13 
Sampling for Pharmacokinetic and Pharmacodynamic Analyses 
The pharmacokinetics of TAS-205 will not be evaluated in this study. Details of sampling for 
pharmacodynamic analysis are provided in Section 8.2. 
41 


5.2 
Evaluation/Test Parameters for Individual Visits 
5.2.1 
Screening Period 
5.2.1.1 
Before Enrollment (Day -14 to Day -1) 
• 
Informed consent/assent 
• 
Subject ID code assignment 
• 
Subject characteristics (evaluation items are shown in Table 5-1 Medical Evaluations/Tests) 
• 
Day of diagnosis of DMD determined 
• 
Medical examination 
• 
Pulse rate, blood pressure, body temperature 
• 
Hematology, biochemistry 
• 
Urinalysis 
• 
12-lead ECG (Heart rate, QTcF interval, findings) 
• 
Cardiac ultrasonography (echocardiography) 
• 
Pulmonary function test [FVC (measured value, predicted value, and % of predicted value) 
only] 
• 
Motor function evaluation (6MWD only) 
• 
Evaluation of adverse events 
• 
Concomitant medication/therapy 
5.2.2 
Baseline Period 
• 
Hospitalization, medical examination, investigational product prescription, and explanation 
for/supply of subject medication diary 
• 
Pulse rate, blood pressure, body temperature, and body weight 
• 
Hematology, biochemistry, endocrinology 
• 
Urinalysis 
• 
12-lead ECG (heart rate, QTcF interval, findings) 
• 
Pulmonary function test 
• 
Motor function/muscle volume (skeletal muscle CT, BIA)/muscle strength evaluation 
• 
Lean body mass 
• 
Urine creatine concentration measurement (pooled urine) 
• 
Urine tetranor-PGDM/-PGEM concentrations, urine creatinine concentration, urine volume 
measurement (pooled urine) 
• 
Evaluation of adverse events 
• 
Concomitant medication/therapy 
5.2.3 
Evaluation During the Investigational Product Administration Period 
(Excluding Hospitalization Period) 
• 
Medical examination, additional prescription of the investigational product 
• 
Pulse rate, blood pressure, body temperature, and body weight 
• 
Hematology, biochemistry 
• 
Urinalysis 
42 


• 
12-lead ECG (Heart rate, QTcF interval, findings) 
• 
Pulmonary function test 
• 
Muscle volume evaluation (BIA only) 
• 
Lean body mass 
• 
Evaluation of adverse events 
• 
Concomitant medication/therapy 
• 
Current administration of the investigational product [collection of empty boxes of the 
investigational product (as needed) and subject medication diary as well as drug 
accountability check using subject medication diary] 
5.2.4 
Evaluation During (Hospitalization Period) and at the End of the 
Investigational Product Administration Period 
• 
Hospitalization, medical examination, additional prescription of the investigational product 
• 
Pulse rate, blood pressure, body temperature, and body weight 
• 
Hematology, biochemistry, endocrinology 
• 
Urinalysis 
• 
12-lead ECG (Heart rate, QTcF interval, findings) 
• 
Cardiac ultrasonography (echocardiography) 
• 
Pulmonary function test 
• 
Motor function/muscle volume (skeletal muscle CT, BIA)/muscle strength evaluation 
• 
Lean body mass 
• 
Urine creatine concentration (pooled urine) 
• 
Urine tetranor-PGDM/-PGEM concentration measurement (pooled urine), urine creatinine 
concentration measurement (pooled urine): Day 4 in the initial hospitalization, the day after 
hospitalization in the 2nd hospitalization, and the day after hospitalization in the 3rd 
hospitalization 
• 
Evaluation of adverse events 
• 
Concomitant medication/therapy 
• 
Current administration of the investigational product [collection of empty boxes of the 
investigational product, unused investigational products (at the end of the period), and subject 
medication diary as well as drug accountability check using subject medication diary] 
5.2.5 
Evaluation in the Follow-up Period (Follow-up Test, Discontinuation Test) 
Follow-up test before the end of the study (including discontinuation test) will be performed 21 days 
after the last dose of the investigational product (permissible range: standard ± 7 days). In addition, data on 
any adverse event developed at and after the follow-up test that is determined to be related to the 
investigational product will be reported.  
• 
Medical examination 
• 
Pulse rate, blood pressure, body temperature, and body weight 
• 
Hematology, biochemistry, endocrinology*1 
*1 Endocrinology will be performed only if an abnormal change (adverse event) is observed in the test on the 
discharge day of the 3rd hospitalization. 
43 


• 
Urinalysis 
• 
12-lead ECG (Heart rate, QTcF interval, findings) 
• 
Cardiac ultrasonography (echocardiography) 
• 
Evaluation of adverse events (including confirmation of presence of the follow-up of adverse 
events) 
• 
Concomitant medication/therapy 
• 
Collection of empty boxes of the investigational product, unused investigational products, and 
subject medication diary (only if previously uncollected) 
44 


6. Investigational Product 
The sponsor will provide TAS-205 and control (placebo) until the end of the study period. 
6.1 
Name of the Investigational Product, etc. 
The physical and chemical properties of the active ingredient of TAS-205 are shown in Table 6.1-1 and 
Table 6.1-2. 
 
Table 6.1-1 Overview of TAS-205 [Study Drug] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 6.1-2 Overview of Control (Placebo) 
Dosage form 
Oral placebo tablet identical to TAS-205 in appearance 
 
 
 
 
 
 
 
 
 
 
6.2 
Packaging and Labeling of the Investigational Product 
The investigational product label will include the following information: 
(1) Sponsor name 
(2) Sponsor address 
(3) Storage 
(4) Quantity 
(5) Product number 
45 


 
 
 
 
 
 
6.3 
Management of the Investigational Product 
The investigational product storage manager at the study site will manage all investigational products 
provided to the site in accordance with the ICH and applicable regulatory requirements in Japan. The 
investigational product storage manager at the study site will follow the “Written Procedure for 
Management and Handling of Investigational Products.” All investigational product prescriptions will be 
recorded in the investigational product accountability log. 
The investigational product will be used only in this study. 
6.4 
Instruction to Subjects Regarding the Handling of the Investigational Product 
The investigator will instruct each subject and his legal representative to take the investigational product 
in a specified method during the study period. If the subject or his legal representative does not follow the 
specified method, the investigator or sponsor may discontinue the subject’s participation in the study. The 
subject’s drug accountability will be confirmed by reference to the record in the investigational product 
accountability log and the consistency with the subject medication diary or source documents. 
 
The investigator will instruct each subject and his legal representative regarding the handling of the 
investigational product as follows: 
• 
Store the investigational product at room temperature (1 to 30°C). 
• 
Take necessary number of tablets from the PTP sheet at the time of medication and take them 
without crushing, with several cups of cool or lukewarm water. 
• 
Do not take tablets for next medication from the PTP sheet in advance. 
• 
Take the investigational product within 30 minutes after meals (breakfast and dinner), with 
approximately 8-hour or more interval between breakfast and dinner whenever possible. 
• 
Take the investigational product as scheduled. 
• 
When visiting the study site from afar, bring the investigational product to take after meals of 
the day without fail, if applicable. 
• 
When eating out during the administration period (all meals excluding those at home), bring 
the investigational product to take after meals of the day without fail. 
• 
Do not take missed doses of the investigational product, but indicate and report them in the 
subject medication diary. Return the missed doses of the investigational product to the study 
staff as unused investigational product. 
• 
Return the empty boxes of the investigational product (including empty packages and sheets) 
to the study staff not only at the end of the study (at the follow-up test), but also at applicable 
time points (visits). 
• 
When vomited after taking the investigational product, do not additionally take the amount 
vomited. 
46 


• 
Keep the investigational product in a place safe and out of reach of children other than the 
subject. 
• 
Do not discard, but store all unused investigational product appropriately until recovery. 
Record and report any lost investigational product (especially the lost date and time, number 
of tablets lost, etc.) in the subject medication diary. 
47 


7. Method of Administration 
Subjects will receive the investigational product orally twice daily for 24 consecutive weeks, with the 
first dose after dinner on Day 1 and the last dose after breakfast on the efficacy evaluation day at Week 24, 
until the end day of the study or the subjects meet any of the discontinuation criteria specified in Section 
4.3. 
The administration of the investigational product will be started within 14 days after enrollment (Day 1) 
(if Note 14 in Table 1 is applicable, the administration may be started within up to 16 days after enrollment). 
Any suspended or missed dose during the administration period will not be administered later than 
administration after breakfast on the efficacy evaluation day at Week 24. 
7.1 
Administration Procedures 
7.1.1 
Method of Administration 
The investigational product will be initially prescribed before start of the administration after 
hospitalization in the baseline period (Day -2 to before start of the first dose on Day 1) under management 
of the subject’s legal representative (the study staff may manage the prescribed investigational product for 
each subject during hospitalization). 
Subjects will receive the investigational product under management of their legal representatives or 
study staff (the subject or his legal representative will record drug accountability in the subject medication 
diary at each medication), without crushing, with cool or lukewarm water. Since the number of tablets per 
dose differs by subject, the amount of water to be taken with the tablets will not be specified, but kept 
sufficient. The number of tablets of the investigational product corresponding to the dosage by body weight 
within 14 days before enrollment shown in Table 7.1.1-1 will be administered within 30 minutes after 
breakfast and dinner. The time for administration per dose (time from the 1st to last tablet administration 
per dose specified) will be within 5 minutes whenever possible. 
No dose increase/decrease will be considered (re-calculated) according to body weight 
increase/decrease during the study in any of the 3 groups. 
The investigational product will be additionally prescribed in accordance with Table 3.2-1. 
For hospitalization within the permissible range of standard hospitalization day at Week 24 (Day 167) ± 
7 days (Day 160 to Day 174), the investigational product will not be administered after the efficacy 
evaluations. 
 
 
48 


Table 7.1.1-1 Dosage of the Investigational Product by Body Weight (Within 14 Days Before 
Enrollment)  
Treatment 
group 
Body weight before 
enrollment 
Dosage 
(mg/dose) 
 Dosage*1 
(mg/kg/dose) 
Number of tablets/dose 
TAS-205 
50 mg 
tablet 
Placebo 
tablet 
Total 
Low-dose 
group 
≥ 7.5 kg and < 15 kg 
100 
6.67  
~ 
13.33  
2 
2 
4 
≥ 15 kg and < 30 kg 
200 
6.67  
~ 
13.33  
4 
4 
8 
≥ 30 kg and < 45 kg 
400 
8.89  
~ 
13.33  
8 
8 
16 
≥ 45 kg and < 60 kg  
600 
10.00  ~ 
13.33  
12 
12 
24 
High-dose 
group 
≥ 7.5 kg and < 15 kg 
200 
13.33  ~ 
26.67  
4 
0 
4 
≥ 15 kg and < 30 kg 
400 
13.33  ~ 
26.67  
8 
0 
8 
≥ 30 kg and < 45 kg 
800 
17.78  ~ 
26.67  
16 
0 
16 
≥ 45 kg and < 60 kg  
1200 
20.00  ~ 
26.67  
24 
0 
24 
Placebo 
group 
≥ 7.5 kg and < 15 kg 
- 
- 
~ 
- 
0 
4 
4 
≥ 15 kg and < 30 kg 
- 
- 
~ 
- 
0 
8 
8 
≥ 30 kg and < 45 kg 
- 
- 
~ 
- 
0 
16 
16 
≥ 45 kg and < 60 kg  
- 
- 
~ 
- 
0 
24 
24 
*1 The values are rounded to 2 decimal places. 
7.1.2 
Criteria for Changing the Administration Plan 
If any change in the administration plan is made, necessary items specified in Section 3.2.1 will be 
entered in the IWRS promptly. 
7.1.2.1 
Dose Suspension/Resumption Criteria 
The dose suspension/resumption criteria are shown in Table 7.1.2.1-1. The dose of the investigational 
product will be suspended or resumed according to the criteria below. The rationale for the dose suspension 
criteria is described in Section 14.9. 
(1) Dose suspension/resumption procedures 
- 
The investigator or subinvestigator must suspend the dose if any adverse event specified in 
Table 7.1.2.1-1 occurs. 
- 
After dose suspension, an early subject visit other than the visits specified in this protocol 
will be scheduled to confirm whether the adverse event is resolved or resolving, for the 
earliest possible dose resumption. 
- 
Even if the resumption criteria is met, however, the dose cannot be resumed if prolonged 
dose suspension is determined to be necessary by the investigator or subinvestigator for the 
safety of the subject. 
- 
The dose may be suspended even in the absence of any adverse event specified in Table 
7.1.2.1-1 if the dose suspension is determined to be necessary by the investigator or 
subinvestigator due to any other adverse event. 
- 
Any dose suspension determined by the investigator shall be recorded with the detailed 
medical reason/rationale in the source documents. 
- 
Dose suspension determined by the investigator due to the subject’s complaint of the 
number of tablets to be taken will not be permitted. 
49 


 
Table 7.1.2.1-1 Dose Suspension/Resumption Criteria 
Item 
Dose suspension criteria 
Dose resumption criteria 
Adverse event 
Onset of the following symptoms of 
glucocorticoid deficiency 
(severity: any): 
Hyponatraemia (< 130 mEq/L),  
hypoglycaemia (< 50 mg/dL),  
and orthostatic hypotension 
Hyponatraemia, hypoglycaemia: 
Resolved to the baseline level or site 
reference level 
and 
orthostatic hypotension: resolved 
Onset of severe adverse eventsa 
Resolving to mild or lower in severity 
a Excluding cases in which the relationship with the investigational product is definitely ruled out [e.g., injury associated 
with the motor function disorder due to DMD (underlying disease), including fractures, sprain, bruise, and contusion] 
 
7.1.2.2 
Dose Reduction Criteria 
The dose reduction criteria are shown in Table 7.1.2.2-1. The dose of the investigational product will be 
reduced according to the criteria below. The rationale for the dose reduction criteria is described in Section 
14.10. 
(1) Dose reduction procedures 
- 
The investigator or subinvestigator must reduce the dose after dose suspension or 
resumption if any of the dose reduction criteria specified in Table 7.1.2.2-1 is met. 
- 
Even if none of the dose reduction criteria specified in Table 7.1.2.2-1 
is met, the dose may be reduced after dose suspension or resumption (including the time of 
dose resumption) if determined to be necessary by the investigator or subinvestigator due to 
any adverse event. 
- 
Any dose reduction determined by the investigator shall be recorded with the detailed 
medical reason/rationale in the source documents. 
- 
Dose increase after dose reduction will not be permitted. 
- 
Any dose reduction shall be recorded with the details of the applicable dose in the source 
documents. 
- 
Dose reduction for certain reasons of the subject or his legal representative, including 
complaint about the number of tablets to be taken, will not be permitted. 
- 
Dose reduction only by halving the number of tablets specified will be permitted. 
- 
For subjects administered at a reduced dose, the efficacy and safety will be analyzed as 
randomized at the enrollment. Any expelled dose or partial dose of the specified number of 
tablets due to vomiting or other reasons will be assessed as the dose of the specified number 
of tablets. 
 
 
50 


Table 7.1.2.2-1 Dose Reduction Criteria 
Item 
(Reason for dose suspension 
before dose reduction) 
Dose reduction criteria 
Proportion of dose 
reduction 
Onset of severe adverse drug 
reactions 
Dose suspension (per day) 
continued for 2 weeks or moreb 
Take half the amount of 
 tablets specified 
Onset of severe adverse eventsa 
Dose was suspended after the same 
adverse event specified in the left 
occurred twice 
Onset of the following  
symptoms of glucocorticoid 
deficiency 
(severity: any): 
Hyponatraemia (< 130 mEq/L), 
hypoglycaemia (< 50 mg/dL), 
and orthostatic hypotension 
Dose suspension (per day) 
continued for 2 weeks or moreb 
or 
Dose was suspended after the same 
adverse event specified in the left 
occurred twice 
a: Excluding cases in which the relationship with the investigational product is definitely ruled out [e.g., injury 
associated with the motor function disorder due to DMD (underlying disease), including fractures, sprain, bruise, and 
contusion] 
b Dose will be suspended for a day if both morning and evening doses fail. 2 weeks or more means a total of 28 or 
more consecutive morning and evening doses. 
 
7.1.3 
Time of Dose Resumption 
Subjects who meet any of the dose suspension and dose resumption/reduction criteria specified in Table 
7.1.2.1-1 and Table 7.1.2.2-1 may resume administration with the unchanged or reduced dose during the 
study period. 
 
 
51 


7.2 
Volume of Blood Collected During the Study Period 
The volume of blood collected at each time point during the study period (standard) is shown in Table 
7.2-1. Total volume of blood collected by each subject will be approximately 80 mL. 
 
Table 7.2-1 Volume of Blood Collected During the Study Period 
Item 
Number of blood 
collections 
Volume of blood per 
collection (mL) 
Total volume of blood 
collected (mL) 
Laboratory tests 
10 
Approximately 8 
Approximately 80 
Total 
10 
Approximately 8 
Approximately 80 
 
7.3 
Restrictions 
7.3.1 
Physical Activity 
Subjects will be prohibited from engaging in excessive physical activity, especially excessive exercise 
(including excessive rehabilitation, gymnastics class, and motor function evaluation in clinical research or a 
trial that may affect the efficacy evaluations in the study), during 7 days before the physical function 
evaluations specified for the study period (screening evaluation, baseline evaluation, Week 12 evaluation, 
and Week 24 evaluation). In addition, subjects will avoid continuous excessive exercise beyond daily 
activities whenever possible, stay rested and calm, and sleep sufficient hours during the study period. Study 
staff will instruct the subjects on appropriate levels for these daily physical activities. 
7.3.2 
Fasting 
Subjects will be kept at rest and fasted for 3 to 4 hours (standard) before blood collection for laboratory 
tests whenever possible. 
7.3.3 
Foods and Beverages 
Subjects will be prohibited from taking the following from 7 days before the start of the 
investigational product administration to the end of the follow-up test: 
 
Foods and beverages containing grapefruit or St. John’s Wort (including supplements) 
7.4 
Concomitant Medication/Therapy 
7.4.1 
Prohibited Concomitant Medications/Therapies 
The concomitant medications/therapies specified below will be prohibited during the study period. The 
rationale is described in Section 14.6. 
• 
Immunosuppressive medications (other than corticosteroids for DMD treatment) 
• 
Persistent use of COX-1 and COX-2 inhibitors (excluding acetaminophen or other drugs that 
primarily centrally inhibit COX-3) and NSAIDs (temporary use for as-needed or other 
purpose is permissible) 
• 
Other investigational product/therapy under study (medical device under development, etc.) 
• 
Persistent use of mechanical ventilation (excluding non-persistent use or use while sleeping) 
52 


• 
Use of walking aids other than plantar orthosis (ankle foot orthosis, knee ankle foot orthosis, 
walker, etc.) in the 6MWD test and other motor function evaluations (use of wheelchair in 
daily activities is permissible) 
• 
Rehabilitation proposed as a new program that obviously affects the present study (general or 
daily rehabilitation is permissible) 
• 
Medications continuously used obviously for the improvement of the deterioration of physical 
function 
• 
Sedatives used for skeletal muscle CT 
The following concomitant medications (including temporary use for as-needed or other purpose) or 
therapies will be completely prohibited during 7 days before the motor function test: 
• 
COX-1 and COX-2 inhibitors and NSAIDs 
• 
Motor function test in another clinical research or trial 
7.4.2 
Concomitant Medications/Therapies Requiring Precaution 
The use of the concomitant medications requiring precaution specified below will be avoided whenever 
possible; if used, care should be taken, especially when used with the investigational product. The rationale 
is described in Section 14.7. 
• 
Potent cytochrome P450 (CYP) 3A4 inhibitors including itraconazole, ketoconazole, 
atazanavir, indinavir, nelfinavir, ritonavir, and saquinavir 
• 
P-glycoprotein (P-gp) inhibitors including ketoconazole, erythromycin, and diltiazem 
Concomitant therapies requiring precaution will not be set. 
7.4.3 
Restricted Concomitant Medications/Therapies 
The dosage regimen (dosage and administration) of the following concomitant medications will be 
restricted during the study period: The rationale is described in Section 14.8. 
• 
Oral steroids for DMD treatment: 
In principle, the prescription-based dosage regimen will not be changed after obtaining 
informed consent (This will not be applied if the dose must be reduced or suspended due to an 
adverse event or other reasons, nor will this be applied if change in the dosage regimen for the 
subject with unexpectedly marked increase in body weight associated with growth is 
determined to be necessary by the investigator from an ethical viewpoint. Any change in the 
dosage regimen shall be recorded with the detailed medical rationale/reason in the source 
documents.). 
Restricted concomitant therapies will not be set. 
53 


8. Pharmacokinetic/Pharmacodynamic and Exploratory Evaluations 
The pharmacokinetics of TAS-205 will not be evaluated in this study. The urine samples for 
pharmacodynamic evaluation will be collected and treated in accordance with the separately prepared 
“Procedures for Treatment of Samples for Urine Tetranor-PGDM/-PGEM Concentration Measurement.” 
8.1 
Blood Sampling 
Not applicable. 
8.2 
Urine Sampling 
Time points of pooled urine for measurement of individual concentrations and other parameters for 
pharmacodynamic and exploratory endpoints will be as follows: 
• 
From immediately after waking on the day after initial hospitalization to immediately after waking 
on the efficacy evaluation day at baseline (the day after start of pooled urine); 
• 
From immediately after waking on Day 4 to immediately after waking on Day 5; 
• 
From immediately after waking on the day after the 2nd hospitalization to immediately after waking 
on the efficacy evaluation day (Week 12 evaluation); and 
• 
From immediately after waking on the day after the 3rd hospitalization to immediately after waking 
on the efficacy evaluation day (Week 24 evaluation). 
 
The urine samples will be stored under refrigeration (approximately 4°C) during pooled urine. At each 
time point of pooled urine described above, parts of the urine will be transferred to urine containers 
(approximately 4-mL each) and stored frozen (at or below approximately -70°C) at the study site as 
samples for urine tetranor-PGDM/-PGEM concentration measurement. The frozen samples will then be 
collected by an externally contracted carrier and analyzed at the Pharmacokinetics Research Laboratories of 
Taiho Pharmaceutical Co., Ltd. 
In addition, at each time point of pooled urine described above, the urine volume (mL) will be calculated 
from the separately measured urine weight (g) and urine specific gravity (g/mL), and approximately 4-mL 
each of the urine collected in 2 containers as samples for urine creatinine and creatine concentration 
measurement at the study site. Urine creatinine and creatine concentrations will be measured at the study 
site. 
For details regarding the collection and treatment of samples for urine tetranor-PGDM/-PGEM 
concentration measurement, the separately prepared “Procedures for Treatment of Samples for Urine 
Tetranor-PGDM/-PGEM Concentration Measurement” will be followed. 
8.3 
Pharmacokinetic Analysis of TAS-205 
Not applicable. 
8.4 
Pharmacodynamic Analysis of TAS-205 
The pharmacodynamic analysis is intended to evaluate the inhibitory effect of TAS-205 on PGD2 
production through HPGDS inhibition as the mechanism of the pharmacological effect, based on the 
measured tetranor-PGDM/-PGEM concentrations in the urine samples (pooled urine). Details of the 
analytical method will be specified in the Statistical Analysis Plan. 
54 


8.4.1 
Calculation of Pharmacodynamic and Exploratory Endpoints 
Urinary excretion of tetranor-PGDM, urine tetranor-PGDM/Cre concentration ratio, urinary excretion of 
tetranor-PGEM, and urine tetranor-PGEM/Cre concentration ratio will be calculated as pharmacodynamic 
endpoints, and urinary creatinine excretion, urinary creatine excretion, and creatine in urine (%) will be 
calculated and summarized as exploratory endpoints. Any other calculation of pharmacodynamic and 
exploratory endpoints will be specified in the Statistical Analysis Plan. 
8.4.2 
Pharmacodynamic and Exploratory Evaluations 
The parameters specified below will be evaluated (refer to Section 13.1.3.4, “Analysis of 
Pharmacodynamic and Exploratory Endpoints”) using the pharmacodynamic and exploratory endpoints 
during pooled urine (refer to Section 8.4.1, “Calculation of Pharmacodynamic and Exploratory Endpoints”). 
Any evaluation of the detailed analytical method or other parameters will be specified in the Statistical 
Analysis Plan. 
(1) Effect of TAS-205 on the pharmacodynamic and exploratory endpoints 
(2) Relationship of pharmacodynamic and exploratory endpoints with efficacy endpoints 
8.4.3 
Bioanalytical Method in the Pharmacodynamic Analysis 
Urine tetranor-PGDM/-PGEM concentrations will be measured using a validated liquid 
chromatography/tandem mass spectrometry (LC/MS/MS) assay at the Pharmacokinetics Research 
Laboratories of Taiho Pharmaceutical Co., Ltd. Urine creatinine and creatine concentrations will be 
measured using a validated bioanalytical method at the study site. 
The urine tetranor-PGDM-/-PGEM and creatinine concentrations will be measured in all subjects in the 
placebo, low-dose, and high-dose groups. 
 
55 


9. Pharmacogenomics 
Pharmacogenomic research will not be performed in this study. 
 
 
56 


10. Early Termination or Completion of the Study 
10.1 Criteria for Discontinuation of Participation of the Study Site 
If the proper conduct of the study is or could be undermined because of significant or continuous 
non-compliance with GCP or the protocol by the investigator or subinvestigator, the sponsor or the 
investigator may terminate the study site's participation in the study. In this case, the sponsor or the 
investigator will report promptly to the Investigational Review Board (IRB) in accordance with the relevant 
Standard Operating Procedure (SOP) of the study site. 
10.2 Criteria for Discontinuation of the Study 
The sponsor has the right to discontinue the study, regardless of the timing, for administrative reasons. 
The sponsor will discontinue the whole or part of the study in an appropriate manner if any condition 
requiring discontinuation is found during the study. In this case, the sponsor will inform the head of the 
study site of the decision and the reason promptly in writing. The head of the study site will report the 
decision to the IRB and the investigator promptly in writing. In addition, the investigator or subinvestigator 
will notify subjects promptly, and change their therapy. The sponsor will notify the regulatory authorities of 
discontinuation of the study promptly. 
10.3 Investigations for Individual Subjects at Discontinuation 
If a subject is discontinued from the study as specified in Section 4.3, “Discontinuation Criteria for 
Individual Subjects,” the investigator or subinvestigator will take appropriate measures as needed and 
perform clinical assessments specified for Day 169 (immediately after the end of the administration period) 
or follow-up test (discontinuation during the follow-up period) (clinical assessments for the safety 
endpoints) whenever possible. Any adverse event will be followed up whenever possible, as specified in 
Section 12.1.7, “Follow-up of Adverse Events.” 
 
57 


11. Efficacy Evaluation 
Among the efficacy endpoints, the motor function and muscle strength of subjects will be evaluated by 
the sponsor and the master physical therapist in the study in accordance with the evaluation procedure 
separately prepared. The muscle volume of subjects and other efficacy endpoints will also be evaluated by 
the sponsor and the muscle volume evaluator in the study in accordance with the evaluation procedure 
separately prepared. 
For efficacy evaluation of serum CK concentration, only the values measured during the hospitalization 
period will be used in the evaluation. 
11.1 Training and Prior Certification of Evaluators for Individual Study Sites Before 
Study Initiation 
The evaluators for individual study sites in this study will participate in training on the standardization of 
motor function and other evaluations in advance. In the training, the reliability of the measurement 
techniques of evaluators will be assessed, and prior evaluator certification will then be awarded accordingly. 
The evaluators for individual study sites will preferably be physical therapists; however, if there are limited 
study staff or other reasons, evaluators with experience in caring for patients with DMD (physicians, 
occupational therapists, etc.) will be acceptable. The standardized evaluation methods will be specified in 
separate procedure documents. 
11.2 Order of the Efficacy Evaluations 
The various efficacy evaluations will be performed in each subject in a day in the following order: 
(1) Evaluation of muscle volume by BIA, and of lean body mass (evaluations using a body composition 
monitor; the order of these evaluations will not matter) 
(2) 6MWD test 
(3) Time to rise from the floor test 
(4) Timed Up & Go test 
(5) Timed 10-m walk/run test 
(6) Quantitative muscle strength assessments 
The pulmonary function test, muscle volume evaluation by skeletal muscle CT, and serum CK 
concentration measurement shall be performed by the start of (2) 6MWD test (before start of the motor 
function test). The evaluations will, in principle, be performed in a consistent order to avoid difference in 
the order (for all items) for individual subjects in each evaluation period. 
11.3 Evaluation of Motor Function 
The need for repetition of each evaluation (data recollection) will be determined by the evaluator. Any 
repeated evaluation determined to be necessary for reasons described below will be performed whenever 
possible, taking into consideration the subject’s condition, etc. In this case, the measurement data obtained 
before the repeated evaluation will not be assessed. 
Cases judged to require repeated evaluation: Definite non-compliance with the instruction, marked 
deviation from the track during the test, reversal of direction of the track, discontinuation during the test for 
reasons other than fatigue, etc. 
58 


11.3.1 
6MWD Test 
The distance the subject can walk as fast as possible in 6 minutes will be evaluated. 
The test will be performed using a flat, straight. 25-m track wider than a specified width (a quiet indoor 
hallway, etc.; the distance will be measured accurately with a tape measure, with marks affixed at both ends 
and cones placed). The subject will go back and forth along the 25-m distance until completion of the test is 
announced 6 minutes later (passage time of each 25 m will be recorded). The passage time will be read out 
to the subject while walking, in a specified timing according to the evaluation procedure. The 6-minute 
walk distance will be recorded in metric units (distance less than 1 meter will be rounded down). For any 
subject who falls, information on the time of the fall will be recorded. For details of the preparation, 
implementation procedures, important points, safety considerations, etc., the evaluation procedure will be 
followed. 
For subjects with 6MWD of less than 75 m in the baseline period, before start of administration in this 
study, investigational product administration will be started as scheduled (Day 1), and the 6MWD tests 
after administration (at Weeks 12 and 24) will be performed. 
11.3.2 
Time to Rise from the Floor Test 
The time required for the subject to rise from a supine position on the floor as quickly as possible will 
be evaluated. 
The time from start of rising from a supine position to the judgment of standing up (standing posture 
with arms parallel to the body) will be measured with a stopwatch (unit: second, time measured to 2 
decimal places). There is no time restriction for the test. For details of the preparation, implementation 
procedures, important points, safety considerations, etc., the evaluation procedure will be followed. 
11.3.3 
Timed Up & Go Test 
This test will assess the extent of the subject’s composite mobility, including standing up, walking, 
repositioning the body, and balancing. 
The time required for the subject to stand up from a sitting position on a table (chair), walk to a cone 
placed 3 m ahead as quickly as possible, and then return to the table will be evaluated. 
With the table stabilized against a wall (0-m point will be the front center of the table) and the back of 
the subject leaning against a backrest (wall) at the start, the time from the start call to the subject’s return 
with his back against the backrest after going around the cone will be measured with a stopwatch (unit: 
second, time measured to 2 decimal places). There is no time restriction for the test. For details of the 
preparation, implementation procedures, important points, safety considerations, etc., the evaluation 
procedure will be followed. 
11.3.4 
Timed 10-m walk/run test 
The time required for the subject to run or walk as quickly as possible a 10 m-wide passage with marks 
affixed on the floor will be evaluated. The test will be performed using more than a specified width of flat 
straight line (a quiet indoor hallway, etc.). 10 meters will be measured with a tape measure, and marks 
affixed to both the 0-m (start line) and 10-m (goal line) ends. With the subject in a standing position just 
behind the start line at the start, the time from the start call to the subject’s leg passing the goal line will be 
measured with a stopwatch (unit: second, time measured to 2 decimal places). There is no time restriction 
59 


for the test. For details of the preparation, implementation procedures, important points, safety 
considerations, etc., the evaluation procedure will be followed. 
11.4 Evaluation of Muscle Volume 
11.4.1 
Skeletal Muscle CT 
To estimate the skeletal muscle volume using muscle CT, muscle volume index (MVI), %MVI, and net 
muscle volume_CT (nMV_CT), which indicate the cross-sectional area of the middle of a muscle, muscle 
survival rate (proportion), and CT-based skeletal muscle volume in a given section, respectively, will be 
used. MVI, which is the cross-sectional area of the middle of a muscle (unit: cm2), will be measured in both 
legs. As %MVI, which is intended to estimate the skeletal muscle volume based on the CT values in the 
cross-section of a middle thigh, the muscle survival rate (proportion of actual muscle in the cross-section of 
the original muscle, unit: %) will be measured in only 1 leg (right leg in principle) using an estimator.11) In 
addition, nMV_CT, which is the skeletal muscle volume in a given section of the middle thigh (unit: cm3), 
will be measured in both legs using an estimator.11, 12) All parameters will be measured in the lower leg as 
well as the middle thigh. The obtained CT images (DICOM data) will be submitted to the sponsor by each 
study site. Based on the data submitted to the sponsor, the images will be centrally evaluated by the muscle 
volume evaluator. For details of the measurement method, measured site, and evaluation method, the 
evaluation procedure will be followed. 
11.4.2 
BIA 
The skeletal muscle volume (unit: kg, 2 decimal places) at the left and right sites (in each limb) will be 
measured by BIA (TANITA body composition monitor: Inner Scan® 50V model BC-622). Since the lower 
age limit for skeletal muscle measurement is 6, subjects aged 5 at the baseline evaluation will be handled as 
those aged 6 for the measurement. For all subjects, the age at the baseline evaluation will be used for the 
measurement throughout the study period. For details of the measurement method and evaluation method, 
the evaluation procedure will be followed. 
11.5 Lean Body Mass 
Lean body mass (kg) will be calculated by deducting the body fat that is calculated from the body fat 
percentage measured by BIA (TANITA body composition monitor: Inner Scan® 50 V model BC-622) from 
the body weight. The lean body mass calculation formula shall be as follows: body weight (kg, 1 decimal 
place) - [body weight (kg, 1 decimal place) × body fat percentage (%, 1 decimal place)] = lean body mass 
(kg, the value shall be rounded to 1 decimal place). 
11.6 Evaluation of Muscle Strength 
11.6.1 
Quantitative Muscle Strength Assessments 
Quantitative muscle strength assessments will be performed using a hand-held dynamometer (Nihon 
Medix microFET2TM; manual muscle measurement/evaluation equipment will be specified). Muscle 
strength for hip flexion/extension, knee flexion/extension, ankle extension/flexion will be evaluated 
[measurement unit: newton (N), 1 decimal place]. For details of the preparation, implementation 
procedures, important points, safety considerations, etc., the evaluation procedure will be followed. 
60 


11.7 Other Efficacy Evaluations 
11.7.1 
Serum CK Concentration 
Since CK, a muscle-specific enzyme, is known to leak out of muscle cells of a damaged muscle tissue 
and is released into the blood, plasma CK concentration may reflect the extent of muscle damage. For this 
purpose, serum CK concentration will be measured and evaluated using blood samples collected for 
biochemistry. Only the serum CK concentration measured during the hospitalization period will be used for 
the efficacy evaluation. The rationale is described in Section 14.1. 
11.7.2 
Pulmonary Function Test 
Noninvasive vital capacity measurement will be performed using a spirometer, and the measured values 
of VC (unit: L), FVC (unit: L), FEV1.0 (forced expiratory volume in first second, unit: L), and FEV1.0% 
(percent ratio of FEV1.0 to FVC; FEV1/FVC, unit: %) will be evaluated. 
61 


12. Safety Evaluation 
12.1 Adverse Events 
12.1.1 
Definition of Adverse Event 
An adverse event is defined as any unfavorable medical event that occurs in a subject participating in 
the study, regardless of whether it is considered related to the investigational product. 
A diagnosis will be recorded as an adverse event wherever possible. If no definite diagnosis can be 
established, signs or symptoms will be recorded. 
Symptoms associated with DMD or concurrent illnesses and abnormal laboratory or other test findings 
that have been present since before the study initiation will not be assessed as adverse events. However, 
any new symptoms or worsening of concurrent illnesses will be assessed as adverse events. 
All clinically or medically significant abnormal test values will be reported as adverse events. 
Symptoms derived from a diagnosis already reported as an adverse event by the investigator or 
subinvestigator will not be assessed as adverse events. 
Abnormal laboratory test values assessed as adverse events are: 
• 
those requiring medical treatment 
• 
those requiring prolonged administration, discontinuation, or dose reduction of the 
investigational product 
• 
those deemed medically significant by the investigator or subinvestigator for any other reason 
 
For report on the follow-up of pregnancy of the subject’s partner or definition and report of medication 
errors, misuses, and drug interactions, refer to Section 12.7, “Other Information.” 
Adverse events will be evaluated from the time of informed consent, while those developed or worsened 
after start of investigational product administration will be collected on the CRFs. For any other details of 
recording, the “Instructions for Completing the CRFs and Making Changes or Corrections to the CRFs” 
will be referred to. 
For each efficacy evaluation parameter (serum CK concentration will be applicable only during the 
hospitalization period), any clinically or medically significant change will not be assessed as adverse event. 
12.1.2 
Severity of Adverse Events 
One of the following severities of adverse events will be selected and evaluated [semicolon (;) means 
“or”]: 
Mild:  
Mild; no symptom or mild symptom; only clinical or test finding; requiring no treatment 
Moderate: 
Moderate; requiring minimum/local/non-invasive treatment; limiting age-appropriate activities of daily 
living except for self-care* 
Severe: 
Severe or medically significant, but not immediately life-threatening; requiring hospitalization or 
prolongation of existing hospitalization; disability; limiting self-care activities.** An event leading to 
62 


life-threatening consequences or requiring emergency intervention, or death due to adverse event is also 
assessed as severe. 
* “Activities of daily living except for self-care” refers to meal preparation, shopping for daily goods and 
clothing, use of a telephone, financial management, etc. 
** “Self-care activities” refers to bathing, dressing/undressing, food intake, use of a bathroom, and oral 
drug intake without being bedridden. 
12.1.3 
Causal Relationship to the Investigational Product 
The causal relationship of an adverse event to the investigational product will be assessed as one of 2 
categories as described below, based on various factors (e.g., the subject’s condition, previous medical 
history, concomitant medications, temporal association between investigational product administration and 
the onset of the adverse event). 
 
(1) There is a reasonable possibility: The onset of the adverse event is temporally associated 
with investigational product administration, and meets any of the following conditions: 
- 
The event resolved by dose suspension: The event improved or resolved after 
(temporary or permanent) suspension of investigational product administration. 
- 
The event recurred after dose resumption: The event recurred after resumption of 
investigational product administration. 
- 
The event cannot be explained reasonably based on the subject’s clinical symptoms 
and/or therapies other than the investigational product. 
- 
The event is known to occur, although scarcely, after medication (e.g., angioedema, 
Stevens-Johnson syndrome). 
 
(2) There is no reasonable possibility: There is no evidence of causal relationship of the adverse 
event to the investigational product. 
The adverse event is assessed to have no reasonable possibility under the following 
conditions: 
- 
The adverse event occurred before administration of the investigational product. 
- 
There is no reasonable possibility that the administration of the investigational product 
caused the adverse event. 
- 
The onset of the adverse event is not temporally associated with investigational product 
administration, and may be due to concurrent illness, concomitant medications, clinical 
symptoms, etc., of the subject 
12.1.4 
Definition of Adverse Drug Reaction 
An adverse event (including an abnormal laboratory value) assessed by the investigator, subinvestigator, 
or the sponsor as reasonably related to the investigational product will be regarded as an adverse drug 
reaction in this study. 
12.1.5 
Outcome of Adverse Events 
(1) Resolved: The symptom or finding resolved or returned to the baseline level. 
63 


(2) Resolving: The symptom or finding nearly resolved or returned to the baseline level. 
(3) Not resolved: The symptom or finding is unchanged with no resolve. 
(4) Resolved with sequelae: The symptom resolved, but with evidence of adverse event-related 
dysfunction interfering with daily life. 
(5) Death: The subject died due to the adverse event. 
12.1.6 
Reporting of Adverse Events 
Adverse events will be reported from the day of informed consent by the subject’s legal representative 
or the subject to the end of the evaluation in the follow-up test described in Section 5.2.5. All adverse 
events will be recorded in the source documents. 
Any adverse event determined to be related to the investigational product by the investigator or 
subinvestigator will be collected, regardless of the time of onset. 
12.1.7 
Follow-up of Adverse Events 
If an adverse event occurs, the investigator or subinvestigator will take appropriate measures 
immediately and follow up the event until it is confirmed to have resolved or to be resolving. If follow-up 
of an adverse event cannot be continued for any of the reasons listed below, the reason will be described on 
the CRF. 
• 
The causal relationship between the event and the investigational product cannot be 
determined due to another treatment given to the subject. 
• 
Further follow-up is impossible, due to hospital change, etc. 
• 
The subject and his legal representative refuse follow-up. 
• 
The subject died. 
• 
The adverse event is not resolved or resolving, but the investigator or subinvestigator 
concludes that the event is stable or there will be no further improvement. 
12.2 Serious Adverse Events 
12.2.1 
Definition of Serious Adverse Event 
A serious adverse event is defined, regardless of the dosage of the investigational product, as any 
adverse event that: 
(a) Results in death. 
(b) Is life-threatening. 
Note: “Life-threatening” serious adverse event refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
(c) Requires hospitalization or prolongation of existing hospitalization for the treatment. However, the 
following will not be assessed as hospitalization in the evaluation of seriousness of adverse events: 
- 
Visit to the emergency department less than 24 hr after the event 
- 
Previously scheduled hospitalization 
- 
Hospitalization to receive tests related to the study 
(d) Results in persistent or significant disability/incapacity. 
64 


(e) Results in congenital anomaly/birth defect. (where exposure to the investigational product 
immediately before or during pregnancy adversely affected the fetus) 
(f) Is an important medical event. 
Note: This refers to an important medical event that is not immediately life-threatening or fatal, or 
does not result in hospitalization, but may expose the subject to danger or require intervention or 
treatment to prevent the results described in above (a) to (e). 
This includes, for instance, allergic bronchospasm requiring intensive care at the emergency 
department, home, etc.; blood disorder or spasm that does not result in hospitalization; and drug 
dependence or abuse. 
12.2.2 
Reporting of Serious Adverse Events 
Serious adverse events will be reported to the sponsor within 24 hr from the time the investigator or 
subinvestigator first becomes aware of the event. The causal relationship and seriousness shall be carefully 
determined, and the comprehensive information obtained at the first reporting of the event (e.g., clinical 
course, previous medical history, concomitant medications) reported.  
After the first reporting of the serious adverse event to the sponsor, any significant additional 
information on the event (diagnosis, outcome, evaluation of the causal relationship, certain test results, etc.) 
will be reported whenever it is obtained. 
The investigator will respond to any request for further necessary information by the sponsor, the head 
of the study site, or IRB. 
All serious adverse events that occur during the study period will be reported to the sponsor. 
Any serious adverse event (including death) that occurs outside the study period will be reported to the 
sponsor only if the relationship of the event to the investigational product is indicated by the investigator. 
 
[Emergency contact (sponsor)] 
Clinical Development Division, Taiho Pharmaceutical Co., Ltd. 
 
 
(from 8:40 am to 5:30 pm, except weekends, holidays, and December 29 to January 4) 
After office hours, contact the product leader or clinical team leader. 
For contact information of the product leader and clinical team leader, see the attachment. 
 
12.2.3 
Follow-up of Serious Adverse Events 
If a serious adverse event occurs, the investigator or subinvestigator will take appropriate measures and 
follow up the event until it is confirmed to have resolved or to be resolving. If follow-up of a serious 
adverse event cannot be continued for any of the reasons listed below, the reason will be recorded on the 
Serious Adverse Event Report and CRF. 
• 
The causal relationship between the event and the investigational product cannot be 
determined due to another treatment given to the subject. 
• 
Further follow-up is impossible, due to hospital change, etc. 
• 
The subject and his legal representative refuse follow-up. 
65 


• 
The subject died. 
• 
The serious adverse event is not resolved or resolving, but the investigator or subinvestigator 
concludes that the event is stable or there will be no further improvement. 
12.3 Worsening of Underlying Disease 
Worsening of underlying disease will not be used as an adverse event term. For worsening of underlying 
disease, the associated signs, symptoms, or concurrent illnesses will be reported as adverse events, or as 
serious adverse events if any of the seriousness criteria are met. In any case, the relationship of the signs, 
symptoms, or concurrent illnesses to the worsening of underlying disease will be clarified. 
12.4 Reporting of Death 
Any death, including that due to worsening of underlying disease, during the study period will be 
reported to the sponsor within 24 hr from the time the investigator or subinvestigator first becomes aware 
of the event, following the same procedure as for serious adverse events. 
Since death is an outcome of an adverse event, it will not be used as an adverse event or serious adverse 
event term. 
12.5 Adverse Events of Special Interest 
12.5.1 
Definition of Adverse Events of Special Interest 
Adverse events of special interest will not be defined in this study. 
12.6 Predictability 
Since no serious adverse drug reactions have occurred with TAS-205, all adverse events that occur in 
this study will be handled as “unexpected” events. 
12.7 Other Information 
12.7.1 
Follow-up of Pregnancy 
Any pregnancy or outcome of the pregnancy of a subject’s partner during participation in this study that 
is found by the investigator or subinvestigator will be reported promptly. 
The information on pregnancy will be recorded on a pregnancy evaluation sheet and reported to the 
sponsor via e-mail or fax. 
Any new information and/or correction of the previous information obtained after submission of the 
pregnancy evaluation sheet will be newly recorded on another pregnancy evaluation sheet and reported to 
the sponsor via e-mail or fax. 
The investigator or subinvestigator will follow up the pregnancy of the subject’s partner and report the 
outcome. Outcome of the pregnancy such as stillbirth, congenital disorder/birth defect, or serious maternal 
event, will be reported to the sponsor as a serious adverse event. In addition, the investigator or 
subinvestigator will follow up the child and convey any information indicative of involvement of the 
investigational product to the sponsor even after study completion. 
12.7.2 
Medication Errors 
In this study, a medication error is defined as any unintended error, for instance, in the prescription, 
dispensing, or administration of the investigational product, that occurs under the management of a health 
66 


care provider or a subject. Medication errors may occur in association with administration of a different 
drug, property or administration route of the investigational product, or dosage or number of doses 
specified in the protocol. 
The following procedure shall be followed: 
The investigator or subinvestigator will report any medication error with TAS-205 that occurs, 
regardless of the onset of adverse events (even if the definition of a serious adverse event is not 
met), to the sponsor promptly. 
12.7.3 
Misuse 
In this study, misuse is defined as any intended misuse of the investigational product (including abuse 
and use of more than the right dose) that increase risks. Any intended administration of the investigational 
product to subjects for whom the product is contraindicated will also be included. Any misuse found by the 
investigator or subinvestigator will be reported to the sponsor promptly. 
12.7.4 
Drug Interaction 
In this study, drug interaction is defined as any interaction that occurs between the investigational 
product and concomitant medications affecting the pharmacokinetic profile and/or efficacy/adverse drug 
reactions, meals, or lifestyle habits (e.g., smoking, alcohol intake), etc. Any drug interaction found by the 
investigator or subinvestigator will be reported to the sponsor promptly. 
67 


13. Statistical Analysis 
Statistical analysis will be performed in accordance to the plan described below. Details be specified in 
a separately prepared Statistical Analysis Plan. 
13.1 Analysis Plan 
13.1.1 
Timing of Statistical Analysis 
Statistical analyses will be performed after all subjects have completed the study. 
13.1.2 
Analysis Sets and Criteria for Handling Subject Data 
13.1.2.1 
Analysis Sets 
The analysis sets in this study are defined as below. 
 
Table 13.1.2-1 Definition of Analysis Sets 
Analysis set 
Definition 
Enrolled subjects 
All subjects enrolled in the study 
Subjects administered the 
investigational product 
All enrolled subjects who received at least 1 dose of the investigational 
product 
Full Analysis Set 
 (FAS) 
All subjects administered the investigational product who were evaluated 
for at least 1 efficacy endpoint (regardless of whether primary or 
secondary endpoint) after initiation of investigational product 
administration 
Per Protocol Set 
 (PPS) 
All subjects in the FAS, excluding those who met any of the following 
conditions: 
• Subjects who were found to fail to meet any of the inclusion criteria after 
enrollment 
• Subjects who were found to meet any of the exclusion criteria after 
enrollment 
• Subjects who did not receive sufficient doses of the investigational 
product (administration rate at Week 24 < 70%) 
• Subjects who used prohibited concomitant medications/therapies 
• Subjects who failed to comply with the dosage regimen of restricted 
concomitant medications 
• Subjects who were not evaluated for the primary endpoint 
 
If there is any subject for whom there are problems in determination of inclusion in the analysis sets, the 
handling of such subject will be determined through discussion between the sponsor and the medical expert 
before data lock. 
13.1.2.2 
Criteria for Handling Subject Data 
The criteria for handling subject data in this study are shown below. 
68 


If it is questionable beyond the criteria shown below as to how some subject data are to be handled, the 
sponsor will discuss the case(s) with the medical expert to make a decision before code breaking. 
 
(1) Handling of missing values and abnormal values 
- 
For missing values, no imputation will be applied. Data employed at each time point will be 
used in analysis. For primary and secondary efficacy endpoints, LOCF or MMRM 
imputation will be applied as needed. The incidence of adverse events, etc. will be analyzed 
using the analysis set as the denominator. 
- 
All measurement data will be used in analysis, except for abnormal values that can be 
clearly explained, including laboratory values affected by hemolysis at blood collection. 
Any abnormal value excluded from analysis will be identified, and the rationale for 
exclusion will be provided. 
 
(2) Deviation from investigational product assignment 
- 
Data from subjects who have been administered the investigational product different from 
their randomized investigational product will be handled as data for the actually 
administered investigational product in the analysis of subjects administered the 
investigational product or PPS. 
- 
In the analysis of FAS, the data will be handled as data for the randomized investigational 
product. 
13.1.3 
Statistical Analysis Methods 
The methods of main statistical analyses for the primary and secondary purposes of this study are 
described below. 
13.1.3.1 
Subject Disposition and Characteristics 
(1) Subject disposition 
- 
The number of subjects randomized to each group will be totaled in a manner so as to 
clarify inclusion of subjects in each analysis set, and a list of subjects excluded from each 
analysis set will be provided with the reason for exclusion. 
(2) Subject characteristics 
- 
For each analysis set, excluding enrolled subjects, distribution of main subject and disease 
characteristics will be summarized. 
13.1.3.2 
Analysis of the Primary Endpoint 
The following analyses will be performed for the primary endpoint, defined as the change from baseline 
in 6MWD at Week 24: 
(1) Primary analysis 
- 
To evaluate the efficacy of TAS-205 appropriately, summary statistics will be calculated for 
each treatment group in the PPS. 
(2) Sensitivity analysis for the primary analysis 
- 
The analysis described in (1) will be performed in the FAS. 
69 


(3) Secondary analyses of the primary endpoint 
The following analyses will be performed in the PPS and FAS: 
- 
A 2-sample t-test will be performed between each treatment group and placebo group. This 
analysis will be performed with and without the LOCF imputation. 
- 
The treatment effect will be estimated using the MMRM. The changes from baseline in 
6MWD measured at other time points will also be included in this analysis. 
- 
Using the MMRM, the dose relationship will be analyzed with treatment contrasts of 
(placebo group, low-dose group, high-dose group) = (-2 1 1), (-1 0 1), and (-1 -1 2). The 
changes from baseline in 6MWD measured at other time points will also be included in this 
analysis. 
13.1.3.3 
Analysis of the Secondary Endpoints 
13.1.3.3.1 
Efficacy Analysis 
The following analyses will be performed in the PPS and FAS: 
(1) 6MWD 
- 
Summary statistics will be calculated at each time point for each treatment group. 
- 
A 2-sample t-test will be performed between each treatment group and placebo group at 
Week 12. This analysis will be performed with and without the LOCF imputation. 
- 
The time course by each time point will be plotted for each treatment group. 
(2) The following analyses will be performed for each value measured in each motor function test 
(time to rise from the floor test, Timed 10-m walk/run test, Timed Up & Go test), measurement of 
muscle volume (skeletal muscle CT, BIA), lean body mass, quantitative muscle strength 
assessments (hip flexion/extension, knee flexion/extension, ankle extension/flexion), serum CK 
concentration (only the serum CK concentration during the hospitalization period will be used for 
the efficacy evaluation), and pulmonary function test (VC, FVC, FEV1.0, FEV1.0%): 
- 
Summary statistics will be calculated at each time point for each treatment group. 
- 
Summary statistics for the change from baseline will be calculated, followed by a 2-sample 
t-test between each treatment group and placebo group at each time point. This analysis will 
be performed with and without the LOCF imputation. 
- 
The treatment effect will be estimated using the MMRM. 
- 
Using the MMRM, the dose relationship will be analyzed with treatment contrasts of 
(placebo group, low-dose group, high-dose group) = (-2 1 1), (-1 0 1), and (-1 -1 2).  
- 
The time course by each time point will be plotted for each treatment group. 
13.1.3.3.2 
Safety Analysis 
The analyses described below will be performed in subjects administered the investigational product for 
each treatment group. 
(1) Adverse events 
- 
The incidence of adverse events will be calculated. 
- 
For each adverse event type, the number and proportion of subjects with adverse events 
will be calculated by severity. 
70 


- 
For each adverse event type, all adverse events reported from the start of investigational 
product administration to the end day of the follow-up period will be listed for each 
subject with the adverse event term, severity, onset date, treatment provided, outcome, 
date the outcome confirmed, causal relationship to the investigational product, and 
comments on the event. 
(2) Adverse drug reactions 
- 
For adverse drug reactions, analyses will be performed in the same way as for adverse 
events. 
(3) 
Laboratory values 
- 
For each laboratory parameter, summary statistics at each evaluation time point will be 
shown. 
- 
For each laboratory parameter, the time course of each measured value will be plotted for 
each subject. 
(4) 
12-lead ECG 
For QTc interval, a test parameter of 12-lead ECG, Fridericia’s formula will be used. 
- 
For QTcF interval and heart rate, summary statistics of measured values at each 
evaluation time point will be shown. 
- 
For QTcF interval and heart rate, summary statistics of the change from immediately 
before Day 1 dose in measured values at each evaluation time point after start of the dose 
will be shown. 
- 
For each QTcF interval will be categorized, the frequency at each evaluation time point 
will be tabulated. 
- 
Change in QTcF interval from immediately before Day 1 dose will be categorized, and 
for each category, the frequency at each evaluation time point will be tabulated. 
- 
The proportion of subjects with abnormal change in 12-lead ECG and the two-sided 95% 
confidence interval will be calculated. A list of subjects with abnormal change in 12-lead 
ECG will also be created. 
(5) 
Blood pressure, pulse rate, and body temperature 
- 
For systolic blood pressure, diastolic blood pressure, pulse rate, and body temperature 
(axilla), summary statistics at each evaluation time point will be shown. 
- 
For blood pressure and pulse rate, summary statistics of the change from immediately 
before Day 1 dose at each evaluation time point will be calculated. 
(6) 
Cardiac ultrasonography (echocardiography) 
- 
For left ventricular EF and left ventricular FS, summary statistics at each evaluation time 
point will be shown. 
- 
For left ventricular EF and left ventricular FS, summary statistics of the change from the 
baseline value measured in the screening period at each evaluation time point will be 
calculated. 
 
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13.1.3.4 
Analyses of Pharmacodynamic and Exploratory Endpoints 
The following analyses will be performed for urinary excretion of tetranor-PGDM/-PGEM, urine 
tetranor-PGDM/Cre concentration ratio, urine tetranor-PGEM/Cre concentration ratio, urinary creatinine 
excretion, urinary creatine excretion, and creatine in urine (%) in the PPS and FAS: 
- 
Summary statistics at each time point will be calculated for each treatment group. 
- 
Summary statistics of the change rate from baseline at each time point will be calculated, 
followed by a 2-sample t-test between each treatment group and placebo group at each time 
point. This analysis will be performed with and without the LOCF imputation. 
- 
The treatment effect will be estimated using the MMRM. 
- 
Using the MMRM, the dose relationship will be analyzed with treatment contrasts of 
(placebo group, low-dose group, high-dose group) = (-2 1 1), (-1 0 1), and (-1 -1 2).  
- 
The correlation coefficient (Pearson, Spearman) between the change rate from baseline at 
each time point in each treatment group and the change from baseline in each item specified 
in (1) and (2) of Section 13.1.3.3.1 will be calculated. 
- 
The time course by each time point will be plotted for each treatment group. 
13.1.3.5 
Current Administration 
The following analyses by treatment group will be performed in subjects administered the 
investigational product: 
(1) Current administration 
- 
Summary of the total dose and total duration of administration for each subject will be 
shown. 
(2) Completed administration 
- 
Summary statistics of the administration rate of TAS-205 will be calculated. 
- 
The rate of completed administration of TAS-205 (proportion of subjects who were 
administered TAS-205 as in a specified schedule) will be calculated. 
- 
The presence or absence of and the reasons for study discontinuation will be summarized. 
13.1.4 
Target Sample Size and Rationale for the Sample Size 
Target sample size: a total of 33 subjects (11 subjects for each group) 
Given that DMD is a rare disease that allows only limited recruitment of subjects and that this study is 
primarily intended to evaluate the efficacy of TAS-205 in an exploratory manner, the sample size was 
determined not statistically, but based on feasibility. 
72 


14. Rationale 
14.1 Rationale for the Endpoints 
The 6MWD test, used for the measurement of the primary endpoint, is a self-paced test that has 
achieved a global consensus in the statement of the American Thoracic Society (ATS) in 2002.13) The test 
was developed for evaluation of motor function in patients with metabolic or cardiopulmonary diseases. 
In the field of DMD in Japan, the Practical Guideline for Duchenne Muscular Dystrophy (DMD) 2014 
was published in 2014 jointly by the Muscular Dystrophy Clinical Trial Site Preparation and 
Comprehensive Practical Guideline Research Group, the Japanese Society of Neurology, and the Japanese 
Society of Child Neurology, while no guidelines for clinical evaluation have been created yet. Similarly, no 
firm guidelines for clinical evaluation recommending efficacy endpoints in this field have been established 
in other countries. 
In the above-mentioned practical guideline, the 6MWD test is described to “be a useful item for the 
measurement of motor function through strict condition adjustment and evaluator training, but with many 
issues to be discussed, including the burdens to patients.”14) While issues on the difficulties in evaluating 
motor function in pediatric patients and the various confounders remain unsolved, the 6MWD test may be 
expected to be used as a primary method for the measurement of motor function by eliminating the issues 
as much as possible, through strict specification of the conditions and procedures or provision of evaluator 
training before study initiation, etc. The 6MWD test has been widely used as a primary endpoint in the 
international joint clinical trials of exon-skipping, readthrough, and other similar therapies being developed 
for treatment of DMD. 
Based on these circumstances, the 6MWD test for the evaluation of motor function was selected as the 
efficacy primary endpoint in the present study. 
Since the present study is positioned as a small-scale early Phase II study with the nature of a pilot study 
to evaluate the efficacy of TAS-205 in an exploratory manner, the 6MWD test in the study may be 
performed without the necessity to determine statistical significances. The target sample size, therefore, 
was not determined statistically. On the premise that the efficacy of TAS-205 will be determined in terms of 
the numerical trends in an appropriate manner, the sample size was determined from the viewpoint of 
feasibility. Given the development status of similar therapies to date and the future study plan of TAS-205, 
etc., it may be difficult to determine the efficacy of TAS-205 appropriately based only on the 6MWD and 
other evaluations of motor function in the early Phase II study; therefore, other efficacy endpoints, 
including the evaluations of muscle volume, lean body mass, or muscle strength, were added to these 
evaluations to ensure comprehensive assessment of the efficacy of TAS-205. In addition, the muscle 
volume will be evaluated using skeletal muscle CT in the present study. In consideration of the radiation 
effects, the evaluation will be limited to lower extremities and only 2 time points, before start (baseline 
period) and at the end (end of the administration period) of investigational product administration, in 
consideration of number of measurements. For serum CK concentration, unlike the evaluation during the 
hospitalization period, which involves relatively low patient burden, including physical activities, and 
rested conditions, the outpatient evaluation may be subject to various effects/confounders during daily 
activities; therefore, only the values measured during the hospitalization period will be used for the efficacy 
evaluation. 
73 


14.2 Rationale for the Method of Administration 
Since Study 10053030 demonstrated that TAS-205, after repeated oral administration twice daily after 
meals for 7 consecutive days, decreased the total excretion of tetranor-PGDM and tetranor-PGDM/Cre 
concentration ratio with increasing dose, the repeated oral administration twice daily, once after breakfast 
and once after dinner, was selected for the present study. In addition, based on the development of DMD in 
subjects and the planned evaluation duration (48 weeks) of a confirmatory study positioned as the next 
study, a minimum 24-week administration period, in which the POC of TAS-205 may be evaluated in an 
exploratory manner, was selected in the present study. 
14.3 Rationale for the Inclusion Criteria 
(1) This criterion was set to ensure ethical conduct of the study in accordance with GCP and the 
principles of the Declaration of Helsinki by including only subjects from whom informed consent 
can be obtained in an appropriate manner through their legal guardians (legal representatives). 
(2) This criterion was set to identify patients with DMD or with symptoms characteristic of DMD to 
ensure appropriate evaluation of the study. 
(3) Age 5 was set as the minimum age for inclusion because this is considered the minimum age at 
which specified study procedures can be performed and a definitive diagnosis of DMD can be 
made.15) In addition, only male pediatric patients will be included in this study on the grounds that 
DMD is usually seen in boys, although no nonclinical study of fertility and early embryonic 
development has been conducted. 
(4) The lower and upper limits of body weight were set based on an expected body weight distribution 
of the ambulatory patients with DMD. 
(5) This criterion was set to select patients who can complete individual motor function evaluations of 
the efficacy endpoints. 
(6) This criterion was set to select patients who can stay in the hospital during the hospitalization period 
specified in the study, because approximately 24-hr (1 day) pooled urine is required a total of 4 
times during the study period (baseline period, Day 4, Week 12, and Week 24). 
(7) This criterion was set to ensure proper conduct of the study in consideration of the formulation of 
the investigational product. 
(8) The only currently available drug therapy for DMD is treatment with Predonine® Tablets 5 mg16) (a 
synthetic corticosteroid), for which approval has been only obtained for additional indication in 
September 2013 following its public knowledge-based application in February in the same year, and 
rehabilitation and management of concurrent illnesses, etc., remain the mainstays of treatment. 
Under ethical considerations in view of the scarcity of drug therapy options, the concomitant use of 
steroids will be allowed in patients who are on corticosteroids at the time of informed consent as far 
as no changes are made to their dosage regimen after informed consent. 
14.4 Rationale for the Exclusion Criteria 
(1) to (6), (8), (9) These criteria were set to ensure subject safety and proper conduct of the efficacy and 
safety evaluations in this study. 
74 


(7) 
Since the use of COX-1 or COX-2 inhibitors, or NSAIDs is completely prohibited during 7 days 
before the motor function test during the study period (including the screening period), this 
criterion was set to exclude patients who are on such drug before enrollment. 
(10) 
This criterion was set to exclude patients who may undermine appropriate pharmacodynamic 
evaluation on the grounds that PGD2 is a chemical mediator involved in inflammatory response 
and thus associated with various allergic diseases. 
(11) This criterion was set because, for subjects who received another investigational product that 
produces dystrophin protein, the effects of the another investigational product cannot be ruled out 
regardless of the administration period. In addition, this criterion was set for patients who have 
received investigational products other than that described above, in accordance with “General 
Considerations for Clinical Trials,” in which it is stated that repeated enrollment of the same 
subject in clinical studies without adequate washout to ensure safety and eliminate carry-over 
effects is not desirable. 
(12) It is known that a relatively high proportion of patients with DMD participate in clinical research 
or trials on motor function, etc., independently performed by rehabilitation or other departments. 
Since excluding all these patients from the present study may impair recruitment of patients with 
DMD, a rare disease, this criterion was set to exclude at least patients who undergo a motor 
function test at the same timing as the present study to avoid any effect on the study. 
(13) This criterion was set to exclude patients who are HBs antigen-, HCV antibody-, or HIV antigen- 
or antibody-positive before enrollment to ensure the safety of personnel handling blood samples 
and other subjects in this study involving blood collection. 
(14) Since no upper limit of age for subjects is set for the present study, although this is a study in 
pediatric patients, and no study of fertility or early embryonic development has been conducted 
with TAS-205 in nonclinical studies, this criterion was set to select patients who can give consent 
for the use of appropriate contraception throughout the study period and for 180 days after the 
end of the study through their legal guardians (legal representatives) who are required to provide 
written informed consent for the study.  
(15) This criterion was set because there was a need to select only patients who can understand and 
follow the instructions of the study staff properly during evaluation of motor function, which is 
subject to various confounders. 
(16) This criterion was set to ensure subject safety and proper conduct of the safety evaluations in this 
study, because TAS-205 will be administered for a long term of 24 consecutive weeks, although 
no effects on the QTc or other 12-lead ECG findings have been demonstrated after repeated 
administration twice-daily for 7 days in Study 10053030. 
(17) This criterion was set to exclude patients who may impair subject safety or prevent the study 
from being conducted in compliance with the protocol. 
14.5 Rationale for Randomization Adjustment Factors 
• 
Since DMD, a progressive muscular dystrophy, develops with increasing age, age was set as a 
randomization adjustment factor. The age classification (between 5 and 7 years, 7 years or 
older) was set by reference to the reports on a stratified analysis of 6MWD in the placebo 
75 


group administered a similar drug17) and on a 36-month natural course data in ambulatory 
patients with DMD.18) The presence or absence of concomitant steroid use was also set as a 
randomization adjustment factor because the concomitant use of steroid can considerably 
affect the efficacy evaluation.  
14.6 Rationale for the Prohibited Concomitant Medications/Therapies 
• 
All of the prohibited concomitant medications/therapies were set because they may impair 
appropriate efficacy and safety evaluations of TAS-205 during the study. 
• 
In particular, persistent use of COX inhibitors involved in arachidonic acid cascade or 
NSAIDs was included because it may affect the efficacy evaluation of TAS-205. The use of 
prohibited concomitant medications/therapies, including as-needed use, was completely 
prohibited during 7 days before the motor function test. However, since this study may be 
affected by COX-1 and COX-2 inhibitors, which are known to be primarily involved in 
peripheral anti-inflammatory activity, but not by COX-3 inhibitors, which primarily act 
centrally and hardly inhibit peripheral prostaglandin synthesis, the use of acetaminophen, etc., 
is not prohibited. 
14.7 Rationale for the Concomitant Medications Requiring Precaution 
• 
 
 
 
 
 
14.8 Rationale for the Restricted Concomitant Medications 
• 
In this study, the efficacy of TAS-205 in patients will be evaluated. In addition, urine 
tetranor-PGDM/PGEM concentrations will be measured for pharmacodynamic evaluation. 
Restricted concomitant medications were defined to ensure that these study endpoints can be 
evaluated appropriately. 
14.9 Rational for the Dose Suspension Criteria 
• 
 
 
 
 
 
 
 
 
 
 
 
76 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
In case of severe adverse events, excluding those definitely unrelated to the investigational 
product, the efficacy of TAS-205 will also be evaluated with close attention to safety, with 
thorough dose suspension measures taken to ensure subject safety. 
14.10 Rationale for the Dose Reduction Criteria 
• 
If a severe adverse event occurs as an adverse drug reaction of TAS-205, the same adverse 
drug reaction is expected to recur after dose resumption. Since severe adverse reactions 
requiring at least 2 consecutive weeks of washout per period may indicate that the dosage for 
the subject is not appropriate to continue administration or ensure subject safety, the dose 
reduction measure is included. 
• 
In addition, since severe adverse events not reasonably related to the investigational product 
may be possibly related to the investigational product (the causal relationship will be 
reassessed depending on the situation) if they recur after dose suspension or resumption, and 
thus may indicate that the dosage for the subject is not appropriate to continue administration 
or ensure subject safety, the dose reduction measure is included. 
• 
Similarly, since any symptom of glucocorticoid deficiency requiring at least 2 consecutive 
weeks of washout or resulting in recurrence of the same syndrome may indicate that the 
77 


dosage for the subject is not appropriate to continue administration or ensure subject safety, 
the dose reduction measure is included. 
14.11 Rationale for the Contraception Period 
• 
Since no study of fertility and early embryonic development has been conducted with 
TAS-205 in nonclinical studies, the contraception period of 180 days after the end of 
investigational product administration was set as a period sufficiently exceeding the expected 
duration of spermatogenesis (growth from spermatogonia to sperm takes approximately 10 
weeks) and sperm retention up to ejaculation. 
14.12 Rationale for the Restrictions on Foods and Beverages 
• 
 
 
 
 
78 


15. Case Report Forms 
A CRF will be completed for all subjects enrolled in this study (enrolled subjects). 
The investigator or subinvestigator will complete the CRFs as specified in the “Instructions for 
Completing the CRFs and Making Changes or Corrections to the CRFs.” 
Data on the CRFs must be consistent with the source documents. Any inconsistency must be explained 
by the investigator in writing and submitted to the sponsor; the investigator will retain a copy. 
15.1 Recording of CRFs 
The investigator or subinvestigator will complete the CRFs as specified in Section 15.3, “Instructions 
for Completing Case Report Forms.” After completion, the CRFs will be signed/sealed or signed and dated. 
If the subinvestigator or trial collaborator completes the CRFs, the investigator will review the CRFs for 
completeness before data lock, and sign/seal or sign and date the CRFs before submission to the sponsor. 
The investigator will retain a copy of the submitted CRFs at the study site. 
 Adverse events that develop or worsen after start of investigational product administration will be 
collected on the CRFs. 
15.2 Changes to or Correction of the Case Report Forms 
The investigator, subinvestigator, and trial collaborator will make any change or correction to a CRF as 
specified in Section 15.3, “Instructions for Completing Case Report Forms.” 
The investigator will add a “Record of Changes and Corrections to the CRFs” to the CRF, and submit the 
CRF to the sponsor. In addition, the investigator will retain a copy. 
15.3 Instructions for Completing Case Report Forms 
(1) The sponsor will create the “Instructions for Completing the CRFs and Making Changes or Corrections 
to the CRFs” and deliver it to the investigator and subinvestigator (and trial collaborator). The 
investigator or subinvestigator will complete the CRFs and make any change, correction, or addition to 
the CRFs in accordance with the instructions. In addition, the trial collaborator may help with 
completion the CRFs in accordance with the instructions in cases of simple mechanical operation 
requiring no medical judgment. 
(2) A ballpoint pen, etc. will be used so that the entries cannot be easily erased. 
(3) To protect the privacy of subjects, each subject in the study will be identified by a unique subject ID 
code. 
(4) Any correction to the CRF will include striking out the corrected text with a double-line so that the 
original information can be read, and will be sealed or signed with the date of correction. For significant 
change or correction, the reason should additionally be included. If any change, correction, or addition 
to the CRF is required after submission to the sponsor, the change, correction, or addition will be made 
directly to the CRF, and the date of change, correction, or addition, and reason for the change, 
correction, or addition (if necessary) will be described. The investigator will confirm the change, 
correction, or addition, and sign or sign/seal and date the record. 
 
[Significant change or correction] 
1) Change or correction to the description of informed consent and assent 
79 


2) Change or correction to the assessment of abnormal change in 12-lead ECG, cardiac ultrasonography 
(echocardiography), blood pressure, pulse rate, or body temperature 
3) Change or correction to an adverse event term and the description of causal relationship to the 
investigational product 
 
(5) Signatures and seals must be consistent with those in a list submitted to the sponsor beforehand. 
(6) Any blank field must be struck out or completed with “Not performed,” “No,” etc., as appropriate to 
clarify that the blank field is not a failure to fill it in. 
(7) After the CRFs are completed, the investigator will cross-check the CRFs against the medical record 
(medical chart), etc., and sign or sign/seal and date the CRFs. 
 
80 


16. Compliance with, Deviations from, and Amendments to the Protocol 
16.1 Compliance with the Protocol 
The investigator will sign or sign/seal and date the protocol or equivalent together with the sponsor to 
declare that the investigator agrees with the sponsor on the protocol and sample CRF, and that the 
investigator agrees to comply with the protocol. 
In the event that the protocol or sample CRF is revised or corrected by order of the head of the study 
site based on the recommendation of the IRB, the investigator will do as described above. 
16.2 Deviations from the Protocol 
Significant deviations from the protocol will be defined as below. However, item (1) will be applicable 
only if the safety of a subject is definitely endangered. 
(1) Prohibited concomitant medications/therapies were administered. 
(2) The subject did not withdraw from the study although he met the discontinuation criteria. 
(3) The dose for the subject was not suspended or reduced although the subject met the dose 
suspension or reduction criteria. 
The protocol must not be changed without prior written agreement between the investigator and the 
sponsor or prior written approval from the IRB based on a review. 
The investigator must submit a report of every change to the study that may significantly affect the 
implementation of the study or increase the risk to subjects to the sponsor and the head of the study site, 
and to the IRB through the head of the study site, without delay.  
The investigator may deviate from the protocol or change the protocol without prior written agreement 
with the sponsor or the prior approval from the IRB if the medical situation inevitably requires the action, 
for instance, to avoid an emergency risk to a subject. In such a case, the investigator must promptly report 
the details of the deviation or change and the reason to the sponsor and the head of the study site, and 
submit the report to the IRB through the head of the study site to obtain written approval. 
The investigator must record all protocol deviations, irrespective of the reason. 
16.3 Amendments to the Protocol 
If any amendment to the protocol or sample CRF is deemed necessary, the sponsor must submit the 
revised protocol or sample CRF to the investigator. The investigator must review the revised protocol or 
sample CRF thoroughly. 
The sponsor must obtain agreement from the investigator to revise the protocol or sample CRF.  
The sponsor must submit the revised protocol or sample CRF to the head of the study site and obtain 
approval from the IRB through the head of the study site promptly. 
However, amendment due to only a change in administrative affairs (e.g., change of the sponsor’s 
organization or structure, change of name of the study site or department, change of address or phone 
number of the study site or the sponsor, change of job title of the investigator, or change of layout of the 
CRF) will require no new agreement. 
81 


17. Direct Access to Source Documents 
The investigator and the head of the study site must provide direct access to all the study-related records 
such as source documents during study-related monitoring, audits, and inspections by the IRB and 
regulatory authorities. 
17.1 Source Documents 
Source documents refer to original documents, data, and records (e.g., hospitalization records, medical 
records, test records, memoranda, checklists for subject evaluation, medication records, recorded data of 
automatic measuring instruments, CT image data, subject files, records retained at the Pharmacy 
Department, Inspection Department, and medical engineering departments involved in this study, 
IWRS-related materials, etc.). 
Specific details of source documents for this study will be recorded in the list of source documents, etc. 
(or any documents to replace it) after preview with the investigator, and a copy of the list will be provided 
to the investigator. 
Items listed below are “materials to be entered directly into the CRFs and regarded as source data.” 
• 
Diagnosis 
• 
Presence or absence of previous medical history or concurrent illness that is considered to 
have a significant effect on the study in the opinion of the investigator or subinvestigator 
• 
History of steroid use (age of initiation of use) 
• 
Assessment of the presence or absence of abnormal change in blood pressure, pulse rate, body 
temperature, 12-lead ECG, or cardiac ultrasonography (echocardiography) 
• 
Reasons for use of any concomitant medications or therapies (including steroids), their route 
of administration, and names or therapies and routes of administration of any drugs prescribed 
at another hospital 
• 
Presence or absence of adverse events, names of the adverse events, severity (intensity), 
serious/non-serious, action concerning the investigational product, outcome, reason for 
completion of follow-up, and causal relationship to the investigational product 
• 
Presence or absence of withdrawal/dropout and reason 
• 
Comments 
17.2 Direct Access 
The sponsor's monitor will cross-check the CRFs against the source documents to ensure the items 
listed below. For any inconsistency with a source document, a document that explains the reason must be 
obtained from the investigator. 
• 
Data required by the protocol are accurately described on the CRFs or Serious Adverse Event 
Report and are consistent with the source documents. 
• 
All changes in the regimen or treatment are described on the CRFs. 
• 
Adverse events are described on the CRFs in accordance with the protocol. 
• 
For subjects enrolled, all withdrawals and dropouts are described with the reasons on the 
CRFs. 
82 


18. Study Quality Control and Quality Assurance 
The duties related to the quality control and quality assurance of the study will be implemented as 
described below, in accordance with the sponsor's SOPs. 
18.1 Study Quality Control 
The sponsor will control the quality of the study in accordance with the respective SOPs for clinical 
trials and the monitoring plan of this study. The main responsibilities are as follows: 
• 
To explain the method for selecting subjects, methods for investigating and evaluating 
efficacy/safety, etc., to the investigator, subinvestigator, or trial collaborator through protocol 
explanatory meetings, etc. 
• 
To make periodic monitoring visits to the study site to ensure that the study is being conducted in 
compliance with the protocol and GCP 
• 
To inspect the source documents to ensure that the entries on the CRFs are accurate; and to create 
the “Instructions for Completing the CRFs and Making Changes or Corrections to the CRFs” and 
make a request to the investigator or subinvestigator for a change or correction if necessary 
• 
To check the entries on the CRF 
• 
To ensure that relevant essential documents are appropriately retained at the study site 
• 
To document and report the study management, data collection, data management, statistical 
analyses, analyses of adverse events, etc., in accordance with the sponsor's SOPs, and check the 
completeness 
18.2 Audits by the Sponsor and Inspection by the Regulatory Authorities 
The investigator will accept audits by the sponsor and inspection by the regulatory authorities to ensure 
thorough compliance with the protocol, GCP, and applicable regulatory requirements. 
The investigator will agree to the direct access of the auditors and inspectors to the study records. The 
auditors and inspectors must not disclose personal information or personal medical information on any 
individual evaluated. 
The investigator will make efforts to cooperate in implementation of audits and inspections as far as 
possible, including approval of access to all necessary facilities as well as data and materials related to the 
study. The investigator will promptly inform the sponsor of information obtained from the regulatory 
authorities or the IRB regarding any scheduling of inspection. The investigator will report any results of the 
inspection to the sponsor promptly. The investigator will take appropriate measures requested by the 
sponsor and perform corrective actions for all issues indicated in the audits and inspections. 
83 


19. Data Handling and Record Retention 
19.1 Data Handling 
All information provided by the sponsor to the investigator, including the protocol, CRFs, investigator's 
brochure, etc., created during the study, and any results obtained in the process of this study, is confidential. 
The study personnel will agree not to refer to such information by any means without prior written approval 
of the sponsor. 
The personal data of the subjects, the investigator, or subinvestigator that may be reflected in the 
sponsor’s database will be handled in compliance with all applicable laws and regulations. 
If the sponsor processes or retains the personal data of the subjects, the investigator, or subinvestigator, 
the sponsor will take all appropriate measures to protect these data from access by any unauthorized third 
party. 
19.2 Record Retention 
19.2.1 
Investigator/Study Site 
The investigator/study site is responsible for retaining all study-related documents in accordance with 
the applicable regulatory requirements and the ICH E6 Guideline (Part 4.9.4, 4.9.5). 
The investigator/study site will agree to inform the sponsor of any intention to delete or destroy any 
study-related record in writing. Before informing the sponsor, the investigator/study site must confirm that 
the record meets the applicable regulatory requirements for record retention. The sponsor will approve the 
destruction of the record in writing to the investigator/study site. 
If the sponsor requests longer management of the record, although all requirements for record retention 
are met, the investigator/study site will make additional adjustment. 
19.2.2 
Sponsor 
The sponsor must retain essential documents to be retained by itself in compliance with the regulatory 
requirements applied in countries in which the investigational product is approved or application for 
approval is planned. 
If the development of the investigational product is discontinued, the sponsor must retain essential 
documents to be retained by itself in accordance with the applicable regulatory requirements. 
84 


20. Compensation for Injury 
The sponsor will obtain insurance in accordance with the applicable regulatory requirements, and 
submit an outline of the compensation scheme to the study site. 
In preparation for compensation requests for any injury that may occur during the study, for which the 
sponsor is found not to be legally responsible, excluding those that occur due to malpractice or negligence, 
the sponsor will specify a policy and payment procedure for any study-related injury in the outline of the 
compensation. 
Compensation for subjects will be made in accordance with the outline of the compensation. 
21. Publication and Secondary Use of Data 
21.1 Publication 
The sponsor has the right to make use of the results of this study and submit them to the governments or 
regulatory authorities. 
The results of this study may be presented in academic conferences or published in scientific journals 
only after review by the sponsor in accordance with the applicable guidelines for publications or financial 
agreement. 
The timing of publication and persons involved in the publication will be determined through discussion 
between the coordinating investigator and the sponsor. 
21.2 Secondary Use of Data 
The sponsor has the right for secondary use of the study data. Secondary use of data means the use of 
data collected in this study for purposes other than the study (including provision to third parties). 
The primary examples of secondary use of data are as follows: 
• 
Use in another clinical study 
• 
Integrated analysis with the relevant clinical studies 
• 
Independent analysis by or information sharing among regulatory authorities 
• 
Use for epidemiological research 
22. Ethics 
22.1 Ethical Matters 
The protocol, the ICH Guideline, the ethical principles that have their origin in the Declaration of 
Helsinki, and all applicable regulatory requirements must be followed and any information be updated to 
ensure that all measures are taken for protection of subjects. 
22.2 Approval of the Institutional Review Board (IRB) 
As required in the ICH E6 Guideline (Part 3), the study must be approved by the appropriately 
established IRB. The conduct of the study must be approved by the head of the study site after review and 
approval by the IRB. 
During the study, the qualifications of the investigator must be reviewed on an ongoing basis. The 
review will be updated in accordance with the IRB requirements, while at least once a year of review is 
required by regulation. At the completion of the study, the completion and results of the study will be 
reported to the IRB. 
85 


22.3 Procedure for Obtaining Informed Consent 
Informed consent must be obtained in compliance with the Declaration of Helsinki, the ICH E6 
Guideline, and applicable regulatory requirements. 
The investigator will create an informed consent/assent form based on a draft informed consent/assent 
form provided by the sponsor. If an amendment to the informed consent/assent form is required, the 
investigator will discuss with the sponsor and create revisions, and obtain approval from the IRB. 
The investigator or subinvestigator will provide sufficient explanation about all matters related to the 
study to the legal representative of each patient. The investigator or subinvestigator will provide sufficient 
explanation to all the legal representatives using simple sentences. Sufficient explanation will also be 
provided to each patient in a way that suits his level of understanding, using simple sentences depending on 
the situation. 
Prior to participation in the study, the legal representative of each patient, the patient, and the person 
who provided explanation about the informed consent will sign and date the informed consent form. A copy 
of the informed consent/assent form signed and dated by the legal representative of each patient or the 
patient will be provided to the legal representative or the patient before any study-related procedure 
described in the informed consent form is implemented. The informed consent/assent form approved by the 
IRB will be used. 
The legal representative of each patient will be deemed to have consented to participate in the study by 
signing and dating the informed consent form before implementation of the study procedures specified in 
the protocol. However, voluntary will of the patient will be fully respected, considered, and given priority. 
If a patient becomes able to give consent during the study, his willingness to continue to participate in the 
study will be newly confirmed and his written consent obtained. 
22.4 Administration of the Investigational Product After the Study Period 
Continued administration of the investigational product after the end (discontinuation) of the 
administration period in this study will not be permitted. 
23. Clinical Study Organization 
Details of the clinical study organization are described in the Attachment. 
24. References 
1. 
Urade Y, Fujimoto N, Hayaishi O. Purification and characterization of rat brain prostaglandin D 
synthetase. J Biol Chem. 1985; 260: 12410-12415. 
2. 
Gerena RL, Eguchi N, Urade Y, Killian GJ. Stage and region-specific localization of lipocalin-type 
prostaglandin D synthase in the adult murine testis and epididymis. J Androl. 2000; 21: 848-854. 
3. 
Kanaoka Y, Urade Y. Hematopoietic prostaglandin D synthase. Prostaglandins Leukot Essent Fatty 
Acids. 2003; 69: 163-167. 
4. 
Okinaga T, Mohri I, Fujimura H, Imai K, Ono J, Urade Y, et al. Induction of hematopoietic 
prostaglandin D synthase in hyalinated necrotic muscle fibers: its implication in grouped necrosis. 
Acta Neuropathol 2002; 104: 377-384. 
5. 
Shimohata T, Umeda M, Tanaka K, Nishizawa M. Reevaluation of validity of percent creatinuria for 
diagnosing steroid myopathy. Brain and Nerve. 2006; 58: 39-42. 
86 


6. 
Takase M, Sakata H, Shikada M, Tatara K, Fukushima T, Miyakawa T. Development of the 
spirometric reference value in Japanese children (final report) (in Japanese). Japanese Journal of 
Pediatric Pulmonology. 2008; 19: 164-176. 
7. 
Urade Y. Structure and function of prostaglandin D synthase. Protein, nucleic acid and enzyme. 2008; 
53: 217-226. 
8. 
Mohri I, Aritake K, Taniguchi H, Sato Y, Kamauchi S, Nagata N, et al. Inhibition of prostaglandin D 
synthase suppresses muscular necrosis. Am J Pathol 2009; 174: 1735-1744. 
9. 
Song WL, Wang M, Ricciotti E, Fries S, Yu Y, Grosser T, et al. Tetranor PGDM, an abundant urinary 
metabolite reflects biosynthesis of prostaglandin D2 in mice and humans. J Biol Chem 2008; 283: 
1179-1188. 
10. Nakagawa T, Takeuchi A, Kakiuchi R, Lee T, Yagi M, Awano H, et al. A prostaglandin D2 metabolite 
is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years 
old. Clin Chim Acta 2013; 423: 10-14. 
11. Kuru S, Sakai M, Tanaka N, Konagaya M, Nakayama T, Kawai M. Natural course of muscular 
involvement assessed by a new computed tomography method in Duchenne muscular dystrophy. 
Neurol Clin Neurosci 2013; 1: 63-68. 
12. Nakayama T, Kuru S, Okura M, Motoyoshi Y, Kawai M. Estimation of net muscle volume in patients 
with muscular dystrophy using muscle CT for prospective muscle volume analysis: an observational 
study. BMJ Open 2013; 3: e003603. doi:10.1136/bmjopen-2013-003603. 
13. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166: 
111-117. 
14. Edited by the “Practical Guideline for Duchenne Muscular Dystrophy” Creation Committee. Practical 
guideline for Duchenne muscular dystrophy (DMD) 2014. Nankodo Co., Ltd., Tokyo, 2014. p. 31-36. 
15. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, et al. Diagnosis and management 
of Duchenne muscular dystrophy, part 1:diagnosis, and pharmacological and psychosocial 
management. Lancet Neurol. 2010; 9: 77-93. 
16. Package insert for Predonine® Tablets 5 mg, revised in June 2015 (21st revised edition, revision of the 
Indications and Dosage and Administration sections based on partial changes to the existing marketing 
authorization). 
17. Bushby K, Finkel R, Wong B, Barohn R, Campbell C, Comi GP et al. Ataluren treatment of patients 
with nonsense mutation dystrophinopathy. Muscle Nerve 2014; 50: 477-487. 
18. Pane M, Mazzone ES, Sivo S, Sormani MP, Messina S, D Amico A, et al. Long term natural history 
data in ambulant boys with Duchenne muscular dystrophy: 36-month changes. PLoS ONE 2014; 
9(10): e108205. doi:10.1371/journal.pone.0108205 
 
 
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SAP_001.pdf: 
TAIHO Pharmaceutical Co., Ltd. 
Date 
8/14/2018 
TAS-205 Protocol: 10053040 
Page 
1 
/ 18 
 
Statistical Analysis Plan 
Version 4.0 
Investigational product TAS-205 
Study title 
Early Phase II Randomized Study of TAS-205 in Patients with Duchenne Muscular 
Dystrophy 
Protocol No. 
10053040 
Date of creation or 
revision 
8/14/2018 
Author 
 
 
Creation and revision history 
Date 
Author 
Reason of creation or revision 
May 15, 2017 
 Creation of first version 
July 18, 2017 
 Creation of Version 2.0 
October 18, 2017 
 Creation of Version 3.0 
August 14, 2018 
 Creation of Version 4.0 
 
Date and signature 
Taiho Pharmaceutical Co., Ltd. 
Statistical team leader 
Date (dd-Mmm-yyyy) 
 
Mediscience Planning Inc. 
Statistical analysis 
manager 
Date (dd-Mmm-yyyy) 
 
Author 
Date (dd-Mmm-yyyy) 
 
 


TAIHO Pharmaceutical Co., Ltd. 
Date 
8/14/2018 
TAS-205 Protocol: 10053040 
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Table of Contents 
1. 
SYNOPSIS ...................................................................................................................................... 4 
2. 
TARGET SAMPLE SIZE AND RATIONALE FOR THE SAMPLE SIZE ........................................... 4 
3. 
STATISTICAL ANALYSIS METHODS AND STATISTICAL AND ANALYTICAL ISSUES .............. 4 
3.1 
STUDY OBJECTIVES ......................................................................................................................... 4 
3.2 
TIMING OF STATISTICAL ANALYSIS .................................................................................................. 4 
3.3 
DOCUMENTS OR DATA NECESSARY FOR STATISTICAL ANALYSIS OTHER THAN CASE REPORT FORMS 4 
3.4 
STATISTICAL AND ANALYTICAL ISSUES ............................................................................................ 5 
3.4.1 
Adjustments for Covariates ......................................................................................................... 5 
3.4.2 
Handling of missing values and abnormal values ...................................................................... 5 
3.4.3 
Interim Analyses and Data Monitoring ....................................................................................... 6 
3.4.4 
Multicenter Studies ..................................................................................................................... 6 
3.4.5 
Multiple Comparisons and Multiplicity ....................................................................................... 6 
3.4.6 
Use of an “Efficacy Subset” of Patients .................................................................................... 6 
3.4.7 
Active-Control Studies Intended to Show Equivalence ................................................................. 6 
3.4.8 
Examination of subgroups .......................................................................................................... 6 
4. 
DEFINITION OF ANALYSIS SETS AND CRITERIA FOR HANDLING IN ANALYSIS .................... 6 
4.1 
DEFINITION OF ANALYSIS SETS ....................................................................................................... 6 
4.2 
CRITERIA FOR HANDLING IN ANALYSIS............................................................................................ 7 
5. 
PRIMARY ANALYSIS .................................................................................................................... 7 
6. 
SECONDARY ANALYSIS ............................................................................................................... 7 
6.1 
ANALYSIS OF THE PRIMARY ENDPOINT ............................................................................................ 7 
6.2 
ANALYSIS OF SECONDARY ENDPOINTS ............................................................................................. 8 
6.2.1 
Efficacy Analysis ........................................................................................................................ 8 
6.2.2 
Safety Analysis ......................................................................................................................... 10 
6.3 
ANALYSES OF PHARMACODYNAMIC AND EXPLORATORY ENDPOINTS ............................................... 11 
6.4 
SUBJECT DISPOSITION AND CHARACTERISTICS ................................................................................ 12 
6.5 
DOSING INFORMATION ................................................................................................................... 12 
6.6 
EXPLORATORY ANALYSIS .............................................................................................................. 13 
7. 
LIST OF ITEMS ANALYZED ........................................................................................................ 14 
8. 
GENERAL MATTERS IN DATA ANALYSIS ................................................................................. 15 
8.1 
STATISTICAL ANALYTICAL SOFTWARE ............................................................................................ 15 
8.2 
GENERAL MATTERS RELATED TO FORMAT OF FIGURES, TABLES AND TABULATED LISTS ................ 15 
8.3 
COMMON RULES FOR DATA PROCESSING ....................................................................................... 15 
9. 
REFERENCES .............................................................................................................................. 17 
10. APPENDIX ................................................................................................................................... 18 


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ABBREVIATIONS AND DEFINITION OF TERMS 
 
As a rule, the definitions in the protocol will be followed for abbreviations and terms. However, the 
abbreviation used only in this document is defined below. 
 
Abbreviation (Term) 
Full expression (Definition) 
ICH Guideline 
“Structure and Content of Clinical Study Reports”1) 
 
 


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1. Synopsis 
This document shows the details of the statistical analysis plan regarding “Early Phase II Randomized Study 
of TAS-205 in Patients with Duchenne Muscular Dystrophy (Protocol Number 10053040).” 
 
2. Target Sample Size and Rationale for the Sample Size 
Target sample size: a total of 33 subjects (11 subjects for each group) 
Given that DMD is a rare disease that allows only limited recruitment of subjects and that this study is 
primarily intended to evaluate the efficacy of TAS-205 in an exploratory manner, the sample size was 
determined not statistically, but based on feasibility. 
 
3. Statistical Analysis Methods and Statistical and Analytical Issues 
3.1 
Study Objectives 
The primary objective of this study is to evaluate the efficacy of TAS-205 administered orally twice daily for 
24 consecutive weeks compared with placebo in patients with DMD in an exploratory manner. 
The secondary objective is to evaluate the safety and dose relationship of TAS-205 administered orally twice 
daily for 24 consecutive weeks compared with placebo in patients with DMD. 
The exploratory objectives are to evaluate the effect of TAS-205 on the urinary excretion of tetranor-PGDM 
and tetranor-PGEM in pooled urine samples after twice-daily oral administration for 24 consecutive weeks, as 
well as the relationship between the urinary excretions and efficacy of TAS-205 in patients with DMD, and also 
to evaluate the change in the urinary excretion of creatinine and creatine in pooled urine samples after 
twice-daily oral administration of TAS-205 for 24 consecutive weeks in patients with DMD in an exploratory 
manner. 
 
 
3.2 
Timing of Statistical Analysis 
Statistical analyses will be performed after all subjects have completed this study. 
 
3.3 
Documents or Data Necessary for Statistical Analysis Other than Case Report Forms 
The documents and data necessary for statistical analysis other than the information recorded in case report 
forms are as follows. 
 
 


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Table 3.1  Documents or Data Necessary for Statistical Analysis Other than Case Report Forms 
Item 
Document or data 
Remarks 
Information 
regarding 
attribution and 
deviation of 
patients 
Flag showing attribution of each 
patient in each analysis set and 
reasons for exclusion from analysis 
sets 
To identify the following information 
regarding handling of patients from the records 
of discussion between the sponsor and the 
medical expert. 
(Flag showing attribution of patients, reasons 
for exclusion from analysis set, reasons why 
the investigational product is not administered, 
deviation flag, and details of deviation) 
Patients who have not received the 
investigational product, and the 
reasons why the patients concerned 
have not received the investigational 
product 
Copy of deviation report, and list of 
patients with deviation (including 
deviation flag and reasons for 
deviation) 
Key code 
Key code for each patient 
To identify key code for each patient in key 
code breaking. 
Date of 
enrollment and 
randomization 
adjustment factors 
IWRS data 
Because it is entered only in IWRS data. 
Conversion to 
MedDRA terms 
 
Table showing correspondence of 
adverse event terms recorded by the 
investigator with MedDRA terms 
Because the adverse events recorded by the 
investigator in case report forms need to be 
converted to MedDRA terms for the purpose 
of summarization of adverse events. 
Table showing correspondence of the 
terms of previous medical history 
and complication with MedDRA 
terms 
To list previous medical history and 
complication. 
Normal reference 
range of study site 
Normal reference range of laboratory 
test values 
Because information regarding the normal 
reference range of laboratory test values is 
necessary. 
Drug name 
Table showing correspondence of the 
terms of concomitant drugs recorded 
by the investigator with WHO-DD 
terms 
To designate alignment sequence and grouped 
analysis. 
Evaluation of 
muscle volume 
Skeletal muscle CT 
Because it is not recorded in the case report 
forms. 
Pharmacodynamic 
and exploratory 
endpoints 
Urinary tetranor-PGDM 
concentration, urinary 
tetranor-PGEM concentration, 
urinary creatinine concentration, and 
urinary creatine concentration 
Because it is not recorded in the case report 
forms. 
 
3.4 
Statistical and Analytical Issues 
The points to consider for statistical issues in ICH-E3 Guideline are as follows. 
3.4.1 
ADJUSTMENTS FOR COVARIATES 
Adjustments for covariates are conducted using the MMRM. Details about specific covariates are 
described individually. 
 
3.4.2 
HANDLING OF MISSING VALUES AND ABNORMAL VALUES 
For missing values, no imputation will be applied. Data employed at each time point will be used in 
analysis. For primary and secondary efficacy endpoints, LOCF or MMRM imputation will be applied as 
needed. The incidence of adverse events, etc. will be analyzed using the analysis set as the denominator. 


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All measurement data will be used in analysis, except for abnormal values that can be clearly explained, 
including laboratory values affected by hemolysis at blood collection. Any abnormal value excluded from 
analysis will be identified, and the rationale for exclusion will be provided. 
 
3.4.3 
INTERIM ANALYSES AND DATA MONITORING 
Interim analyses will not be conducted in this study. 
 
3.4.4 
MULTICENTER STUDIES 
Although this study is a multicenter joint study, no related special analysis has been planned. 
Additional analyses will be planned after this study if necessary from the exploratory stand point. 
 
3.4.5 
MULTIPLE COMPARISONS AND MULTIPLICITY 
Adjustments for multiplicity will not be conducted in this study. 
 
3.4.6 
USE OF AN “EFFICACY SUBSET” OF PATIENTS 
In this study, the analysis for efficacy evaluation will be conducted in the per protocol set (PPS). The 
analysis will also be conducted in the full analysis set (FAS) as supplementary analysis. 
 
3.4.7 
ACTIVE-CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE 
Not applicable in this study. 
 
3.4.8 
EXAMINATION OF SUBGROUPS 
In this study, the analysis of subgroups is planned. Details about specific analytical methods are 
described individually. 
 
4. Definition of Analysis Sets and Criteria for Handling in Analysis 
4.1 
Definition of Analysis Sets 
The analysis sets in this study are defined as below.  
Table 4.1  Definition of Analysis Sets 
Analysis set 
Definition 
All enrolled patients 
All subjects enrolled in this study 
Treated patients 
All enrolled patients who received at least 1 dose of the investigational 
product 
Full Analysis Set 
(FAS) 
All treated patients who were evaluated for at least 1 efficacy endpoint 
(regardless of whether primary or secondary endpoint) after initiation of 
investigational product administration 
Per Protocol Set 
(PPS) 
All subjects in the FAS, excluding those who met any of the following 
conditions: 
 Subjects who were found to fail to meet any of the inclusion criteria after 
enrollment 
 Subjects who were found to meet any of the exclusion criteria after 
enrollment 
 Subjects who did not receive sufficient doses of the investigational product 
(dosing rate at Week 24 < 70%) 
 Subjects who used prohibited concomitant medications/therapies 
 Subjects who failed to comply with the dosage regimen of restricted 
concomitant medications 
 Subjects who were not evaluated for the primary endpoint 
 


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If there is any subject for whom there are problems in determination of attribution in the analysis sets, the 
handling of such subject will be determined through discussion between the sponsor and the medical expert 
before database lock. 
 
4.2 
Criteria for Handling in Analysis 
− 
If it is questionable as to how some subject data are to be handled, the sponsor will discuss the case(s) 
with the medical expert to make a decision before key code breaking. 
− 
Data from subjects who have been administered the investigational product different from their 
randomized investigational product will be handled as data for the actually administered 
investigational product in the analysis of treated patients or PPS. 
− 
In the analysis of FAS, the data will be handled as data for the randomized investigational product. 
− 
Evaluation made in the period other than the period of clinical assessments stipulated in the protocol 
will be excluded as a rule (Table 4.2). If the evaluation is included in the analysis, the fact should be 
stated clearly. If examination is conducted twice or more during the period, the examination closest to 
the stipulated date will be adopted. 
 
Table 4.2 Permissible Range for Clinical Assessments 
Stipulated days 
Permissible range 
Baseline period 
Within 2 weeks after enrollment 
Day4 
±1 day 
Day6 
Day 6 only 
Day15 
+5 days* 
Day29 
±5 days 
Day57, Day127 
±7 days 
Day85, Day169 
±7 days 
Follow-up period (21 days after the end of 
investigational product administration) 
±7 days 
* If all the days in the permissible range are holidays/national holidays and clinical assessments cannot 
be performed, the first working day after the holidays/national holidays is permitted. 
 
5. Primary Analysis 
The following analyses will be performed for the primary endpoint, defined as the change from 
baseline in 6-minute walk distance (6MWD) at Week 24: 
(1) To evaluate the efficacy of TAS-205 appropriately, summary statistics will be calculated for each 
treatment group in the PPS. 
(2) As sensitivity analysis, the analysis described in (1) will be performed in the FAS. 
 
6. Secondary Analysis 
Major items of secondary analysis in this study are shown below. Other items of standard analysis are shown 
in the list of the items of analysis. 
6.1 
Analysis of the Primary Endpoint 
The following analyses will be performed in the PPS and FAS: 
The following analyses will be performed for the primary endpoint, defined as the change from 
baseline in 6MWD at Week 24: Analysis will also be conducted in the group combining the low-dose 
group and the high-dose group excluding the analysis of MMRM. 


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− A 2-sample t-test will be performed between each treatment group and placebo group. This 
analysis will be performed with and without the LOCF imputation. Analyses will also be 
conducted with the following baseline definitions. 
(1) Analysis excluding the subjects for whom the value of (6MWD on Day 1 - 6MWD at 
screening)/6MWD at screening is 0.2 or higher or -0.2 or lower 
(2) Analysis using the mean value of 6MWD on Day 1 and 6MWD at screening as the 
baseline value 
− With respect to the above analysis, subgroup analysis will be conducted for the following 
items. 
Subgroup analysis:  Presence or absence of the history of steroid use, age category (≥5 years and 
<7 years, and ≥7 years), and baseline 6MWD (<350 m, and ≥350 m) 
− The treatment effect will be estimated using the MMRM. The changes from baseline in 6MWD 
measured at other time points will also be included in this analysis. Covariates will be the 
assigned group, baseline value, time point, and the interaction term of the assigned group and 
time point. 
− Using the MMRM, the dose relationship will be analyzed with treatment contrasts of (placebo 
group, low-dose group, high-dose group) = (-2 1 1), (-1 0 1), and (-1 -1 2). The changes from 
baseline in 6MWD measured at other time points will also be included in this analysis. 
Covariates will be the assigned group, baseline value, time point, and the interaction term of 
the assigned group and time point. 
− For the above 2 analyses, analyses will be conducted in the PPS by adding age and the presence 
or absence of the history of steroid use to explanatory variables. In addition, subgroup analysis will 
be conducted for the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
 
6.2 
Analysis of Secondary Endpoints 
6.2.1 
EFFICACY ANALYSIS 
The following analyses will be performed in the PPS and FAS: Analysis will also be conducted in the 
group combining the low-dose group and the high-dose group excluding the analysis of MMRM and 
charts. 
 
(1) 6MWD 
Analyses will also be conducted with the following baseline definitions when analyses are conducted 
using the baseline summary and changes of 6MWD excluding the analysis of MMRM. 
(1) Analysis excluding the subjects for whom the value of (6MWD on Day 1 - 6MWD at 
screening)/6MWD at screening is 0.2 or higher or -0.2 or lower 
(2) Analysis using the mean value of 6MWD on Day 1 and 6MWD at screening as the baseline 
value 
− Summary statistics will be calculated at each time point for each treatment group. The data at 
Week 24 will be analyzed with and without the LOCF imputation. 
− Summary statistics for the change from baseline to Week 12 will be calculated, followed by a 
2-sample t-test between each treatment group and placebo group. 
− With respect to the above 2 analyses, subgroup analysis will be conducted for the following 
items. 


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Subgroup analysis:  Presence or absence of the history of steroid use, age category (≥5 years and 
<7 years, and ≥7 years), and baseline 6MWD (<350 m, and ≥350 m) 
− The time course by each time point will be plotted for each treatment group. Similarly, changes 
from baseline in the PPS will be plotted. 
− For 6MWD at baseline in each group and the group combining all groups in the PPS, the 
correlation coefficient (Pearson) of the %MVI (%) in both legs of muscle volume measurement 
(skeletal muscle CT) at each time point will be calculated. See Table 10.1 Method to 
Derive %MVI (%) for derivation of %MVI (%) of the muscle volume measurement (skeletal 
muscle CT). 
− For the changes in 6MWD from baseline to each time point in each group and the group 
combining all groups in the PPS, the correlation coefficient (Pearson) of the %MVI (%) in both 
legs of muscle volume measurement (skeletal muscle CT) will be calculated. 
 
(2) The following analyses will be performed for each value measured in each motor function test (time to 
rise from the floor test, Timed 10-m walk/run test, Timed Up & Go test), measurement of muscle 
volume (skeletal muscle CT, BIA), lean body mass, quantitative muscle strength assessments (hip 
flexion/extension, knee flexion/extension, ankle extension/flexion), serum CK concentration (only the 
serum CK concentration during the hospitalization period will be used for the efficacy evaluation), and 
pulmonary function test (VC, FVC, FEV1.0, FEV1.0%): In the analysis of the muscle volume 
measurement (skeletal muscle CT) in the PPS, the subjects of the reference values will be excluded. 
See Table 10.1 Method to Derive %MVI (%) for derivation of %MVI (%) of the muscle volume 
measurement (skeletal muscle CT). In quantitative muscle strength assessments, the maximum 
values in the measurement without compensation will be used. 
- Summary statistics will be calculated at each time point for each treatment group. 
- Summary statistics for the change from baseline will be calculated, followed by a 2-sample 
t-test between each treatment group and placebo group at each time point. The data at Week 24 
will be analyzed with and without the LOCF imputation. 
- With respect to the above 2 analyses, subgroup analysis will be conducted for the following 
items. 
Subgroup analysis:  Presence or absence of the history of steroid use, age category (≥5 years and 
<7 years, and ≥7 years), and baseline 6MWD (<350 m, and ≥350 m) 
- The treatment effect will be estimated at each time point using the MMRM. The changes from 
baseline in the values measured at other time points will also be included in this analysis. 
Covariates will be the assigned group, baseline value, time point, and the interaction term of 
the assigned group and time point. 
- Using the MMRM, the dose relationship will be analyzed at each time point with treatment 
contrasts of (placebo group, low-dose group, high-dose group) = (-2 1 1), (-1 0 1), and (-1 -1 2). 
Covariates will be the assigned group, baseline value, time point, and the interaction term of 
the assigned group and time point. 
- For the above 2 analyses, %MVI (%) of muscular amount measurement (skeletal muscle CT) will 
be analyzed in the PPS by adding age and the presence or absence of the history of steroid use to 
explanatory variables. In addition, subgroup analysis will be conducted for the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
- The time course by each time point will be plotted for each treatment group. Similarly, changes 
in the muscle volume measurement (skeletal muscle CT) from baseline in the PPS will be plotted. 


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6.2.2 
SAFETY ANALYSIS 
The analyses described below will be performed in treated patients for each treatment group. In 
tabulation of adverse events (adverse drug reactions), System Organ Class (SOC) and Preferred terms (PT) 
of MedDRA will be used. An exact method based on F distribution will be used for estimation of the 
confidence interval of incidences.2) 
The adverse events which have occurred or become exacerbated after administration of the investigational 
product will be tabulated. 
(1) Adverse events 
− The incidence of adverse events will be calculated. 
− The incidence for each of the following conditions will be calculated. 
Adverse events, severe adverse events, serious adverse events, adverse events leading to suspension 
of administration, adverse events leading to dose reduction, adverse events leading to 
discontinuation of this study, and adverse events leading to death  
− The incidence of adverse events for each adverse event type according to PT of MedDRA will 
be calculated. When a same event has occurred several times in a same patient, the event will be 
regarded as 1 event in tabulation. 
− For each adverse event type, the number and proportion of subjects with adverse events will be 
calculated by severity. When a same event has occurred several times in a same patient, the event 
will be regarded as 1 event in tabulation. Tabulation of severity will be conducted by extracting 1 
event in the priority order of severe, moderate, and then mild. 
− For each adverse event type, all adverse events reported from the start of investigational product 
administration to the end day of the follow-up period will be listed for each subject with the adverse 
event term, severity, onset date, treatment provided, outcome, date of theoutcome confirmed, causal 
relationship to the investigational product, and comments on the event. 
(2) Adverse drug reactions 
− For adverse drug reactions, analyses will be performed in the same way as for adverse events. 
(3) Laboratory values 
Concerning Mg, the data collected by using the unit of mEq/L will be converted to the unit of mg/dL 
by the following formula before analysis. 
Mg concentration after conversion (mg/dL) = 1.2 × Mg concentration before conversion (mEq/L) 
− For each laboratory parameter, summary statistics at each evaluation time point will be calculated. 
− For each laboratory parameter, the time course of each measured value will be plotted for each 
subject. 
(4) 12-lead ECG 
For QTc interval, a test parameter of 12-lead ECG, Fridericia’s formula will be used. 
− For QTcF interval and heart rate, summary statistics of measured values at each evaluation time 
point will be calculated. 
− For QTcF interval and heart rate, summary statistics of the change from immediately before Day 1 
dose in measured values at each evaluation time point after start of the dose will be calculated. 
− The QTcF interval at each evaluation time point will be categorized into “≤450 msec, > 450 msec 
and ≤480 msec, > 480 msec and ≤500 msec, and > 500 msec” before frequency tabulation. 
− The change in QTcF interval from the value immediately before Day 1 dose to each time point of 
evaluation will be categorized into “≤30 msec, > 30 msec and ≤60 msec, and > 60 msec” before 
frequency tabulation. 


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− The proportion of subjects with abnormal change in 12-lead ECG (patients for whom the result is 
judged to be “Abnormal with clinical significance”) and the 2-sided 95% confidence interval will 
be calculated. A list of subjects with abnormal change in 12-lead ECG will also be created. 
(5) Body weight, blood pressure, pulse rate, and body temperature 
− For body weight, systolic blood pressure, diastolic blood pressure, pulse rate, and body temperature 
(axilla), summary statistics at each evaluation time point will be calculated. 
− For body weight, blood pressure and pulse rate, summary statistics of the change from immediately 
before Day 1 dose at each evaluation time point will be calculated. 
(6) Cardiac ultrasonography (echocardiography) 
− For left ventricular EF and left ventricular FS, summary statistics at each evaluation time point will 
be calculated. 
− For left ventricular EF and left ventricular FS, summary statistics of the change from the baseline 
value measured in the screening period at each evaluation time point will be calculated. 
− The incidence of the cases with abnormalities on echocardiography (patients for whom Clinical 
Significance was judged to be “Yes”) and 2-sided 95% confidence interval will be calculated. 
 
6.3 
Analyses of Pharmacodynamic and Exploratory Endpoints 
The following analyses will be performed for urinary excretion of tetranor-PGDM/-PGEM, urine 
tetranor-PGDM/Cre concentration ratio, urine tetranor-PGEM/Cre concentration ratio, urinary creatinine 
excretion, urinary creatine excretion, and creatine in urine (%) in the PPS and FAS: Analysis will also be 
conducted in the group combining the low-dose group and the high-dose group excluding the analysis of 
MMRM and charts. 
For the method to derive each endpoint, refer to Table 10.2. Method to Derive Pharmacodynamic 
Endpoints and Exploratory Endpoints. 
− Summary statistics at each time point will be calculated for each treatment group. 
− Summary statistics of the change rate from baseline at each time point will be calculated, 
followed by a 2-sample t-test between each treatment group and placebo group at each time 
point. If the data at Week 24 are missing, conduct analyses with and without the LOCF 
imputation. 
− With respect to the above 2 analyses, subgroup analysis of the following items will be 
conducted for urinary tetranor-PGDM/creatinine concentration ratio in the PPS. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
− The treatment effect will be estimated using the MMRM. The changes from baseline in the 
values measured at other time points will also be included in this analysis. Covariates will be 
the assigned group, baseline value, time point, and the interaction term of the assigned group 
and time point. 
− Using the MMRM, the dose relationship will be analyzed with treatment contrasts of (placebo 
group, low-dose group, high-dose group) = (-2 1 1), (-1 0 1), and (-1 -1 2). Covariates will be 
the assigned group, baseline value, time point, and the interaction term of the assigned group 
and time point. 
− With respect to the above 2 analyses, subgroup analysis of the following items will be 
conducted for urinary tetranor-PGDM/creatinine concentration ratio in the PPS. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
− The correlation coefficients (Pearson and Spearman) with the change from baseline in each 
item specified in (1) and (2) of Section 6.2.1 will be calculated for the change rate from 


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baseline at each time point in each treatment group and the group combining all groups. In 
addition, scatter plots of pharmacodynamic endpoints will be generated for each group by 
plotting the change rates of urinary tetranor-PGDM excretion, urinary tetranor-PGEM 
excretion, 
urinary 
tetranor-PGDM/creatinine 
concentration 
ratio, 
and 
urinary 
tetranor-PGEM/creatinine concentration ratio from baseline to Week 24 along the horizontal 
axis, and the changes at Week 24 along the vertical axis. Moreover, scatter plots of exploratory 
endpoints will be generated by plotting the change rates of urinary creatinine excretion, urinary 
creatine excretion, and % creatine urine from baseline to Week 24 along the horizontal axis, 
and the changes in 6MWD and muscle volume (skeletal muscle CT) from baseline to Week 24 
along the vertical axis. 
− The time course by each time point will be plotted for each treatment group. Similarly, charts 
showing the time course of the change rates from baseline for urinary tetranor-PGDM excretion, 
urinary tetranor-PGEM excretion, urinary tetranor-PGDM/creatinine concentration ratio, and 
urinary tetranor-PGEM/creatinine concentration ratio in the PPS will be generated. 
 
6.4 
Subject Disposition and Characteristics 
(1) Subject disposition 
− 
The number of subjects randomized to each group will be tabulated in a manner so as to clarify 
attribution of subjects in each analysis set, and a summary and a list of subjects excluded from each 
analysis set will be provided with the reason for exclusion. 
− The presence or absence of important protocol deviations will be tabulated among the all 
enrolled patients. The types of deviations will be displayed together with the number of 
subjects. 
− The presence or absence of and the reasons for study discontinuation will be summarized 
among the all enrolled patients. 
(2) Subject characteristics 
− For each analysis set, excluding all enrolled patients, distribution of the following subject and 
disease characteristics will be summarized. 
1) Demographic variables: Gender, race, age, age category (≥5 years and <7 years, and ≥7 years), 
height, body weight, presence or absence of previous medical history, and presence or absence of 
complication. 
2) Subject characteristics variables: Previous medical history, complication, presence or absence of 
diagnosis of DMD, diagnosis of DMD, presence or absence of the history of steroid use, history 
of steroid use, presence or absence of history of surgery, history of surgery, rehabilitation status, 
presence or absence of fitting of splint/insole, presence or absence of the use of wheel chair, 
6MWD test, time to rise from the floor test, timed 10-m walk/run test, Timed Up & Go test 
 
6.5 
Dosing Information 
The following analyses by treatment group will be performed in treated patients: 
(1) Dosing Information 
− Summary of the total dose and total duration of administration for each subject will be shown. 
Analyses will also be conducted for the PPS. 
(2) Completed administration 
− Summary statistics of the dosing rate of TAS-205 will be calculated. The dosing rate will be 
calculated by the following formula. 


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Dosing Rate = 
Actual number of tablets
(Criteria number of tablets (Administration number of days*1 × Tablets/dose × n Dose/day))*2 
*1 To be induced from Day of last administration - Day of first administration + 1, because 
there is an allowable period for the day of last administration. The number of days will be 
calculated by subtracting 0.5 from the number of days of administration if administration is 
started in the evening on the day of first administration, and also by subtracting 0.5 from the 
number of days of administration if administration is terminated in the morning of the day of 
last administration. 
*2 If the dose is reduced during the study, the denominator for the dosing rate will be the sum 
of the number of days of administration before dose reduction × tablets/dose before dose 
reduction × twice/day and the number of days of administration after dose reduction × 
tablets/dose after dose reduction × twice/day. 
− 
The Dosing Completed Rate of TAS-205 (proportion of subjects who were administered 
TAS-205 as in a specified schedule) will be calculated. The subjects will be the patients for 
whom the dosing rate is lower than 100%. 
− The presence or absence of concomitant medication and concomitant therapy (other than steroids) 
will be tabulated. 
− The presence or absence of the use of steroids will be tabulated. 
 
6.6 
Exploratory Analysis 
The following analyses will be performed in the PPS. The analysis of %MVI of muscle volume 
measurement (skeletal muscle CT) will be performed in the lower leg, thigh, and thigh + lower leg. 
(1) 6MWD 
− For the group combining all groups, the correlation coefficients (Pearson and Spearman) of 
6MWD at Week 24 and %MVI (%) of muscle volume measurement (skeletal muscle CT) will be 
calculated. 
− For each group and the group combining all groups, the correlation coefficients (Pearson and 
Spearman) of the changes in 6MWD at Week 24 and the changes in MVI (%) of the muscle 
volume measurement (skeletal muscle CT) in both legs and P values for the correlation 
coefficients will be calculated. In addition, subgroup analysis will be conducted for the 
following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
- Analysis of covariance will be performed using the following variables as conditions. 
Objective variable: Change in 6MWD at Week 24 
Explanatory variables: Baseline 6MWD, age, presence or absence of the history of steroid use, 
baseline %MVI (%) in both legs, and changes in %MVI (%) in both legs at Week 24 
In addition, subgroup analysis will be conducted for the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
− For each group and the group combining all groups, the correlation coefficients (Pearson and 
Spearman) of the changes in 6MWD at Week 24 and the change rates of urinary 
tetranor-PGDM/creatinine concentration ratio and urinary tetranor-PGDM on Day 168 and P 
values for the correlation coefficients will be calculated. In addition, subgroup analysis will be 
conducted for the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
- Analysis of covariance will be performed using the following variables as conditions. 


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Objective variable: Change in 6MWD at Week 24 
Explanatory variable: Baseline 6MWD, age, presence or absence of the history of steroid use, 
baseline urinary tetranor-PGDM/creatinine concentration ratio, and the change rate of urinary 
tetranor-PGDM/creatinine concentration ratio on Day 168 
In addition, subgroup analysis will be conducted for the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
(2) %MVI (%) of muscle volume measurement (skeletal muscle CT) 
− For each group and the group combining all groups, summary statistics of baseline %MVI (%) 
in both legs will be calculated. 
− For each group, summary statistics of baseline %MVI (%) will be calculated, and 2-sample 
t-test between groups will be performed. In addition, subgroup analysis will be conducted for 
the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
− For the group combining all groups, the correlation coefficients (Pearson and Spearman) of 
each %MVI (%) at baseline will be calculated. 
− For each group and the group combining all groups, the correlation coefficients (Pearson and 
Spearman) of the changes in the %MVI (%) in both legs at Week 24 and the change rates of 
urinary tetranor-PGDM/creatinine concentration ratio and urinary tetranor-PGDM on Day 168, 
and P values for the correlation coefficients will be calculated. In addition, subgroup analysis 
will be conducted for the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
- Analysis of covariance will be performed using the following variables as conditions. 
Objective variables: Changes in %MVI (%) in both legs at Week 24 
Explanatory variables: Baseline %MVI (%) in both legs, age, presence or absence of the history 
of steroid use, baseline urinary tetranor-PGDM/creatinine concentration ratio, and the change 
rate of urinary tetranor-PGDM/creatinine concentration ratio on Day 168 
In addition, subgroup analysis will be conducted for the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
(3) Pharmacodynamic Endpoints 
− For each group and the group combining the low-dose group and the high-dose group, 
summary statistics of the change rates of urinary tetranor-PGDM excretion, urinary 
tetranor-PGEM excretion, urinary tetranor-PGDM/creatinine concentration ratio, and urinary 
tetranor-PGEM/creatinine concentration ratio will be calculated at each time point, and 
1-sample t-test using the change rate = 0% as null hypothesis will be conducted at each time 
point. In addition, subgroup analysis will be conducted for the following items. 
Subgroup analysis: Baseline 6MWD (<350 m, and ≥350 m) 
 
7. List of Items Analyzed 
A list and summary of the items analyzed, including the above-mentioned items of primary analysis and 
secondary analysis, as well as the standard items of analysis considering ICH-E3 Guideline are shown in 
Appendix. 


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8. General Matters in Data Analysis 
8.1 
Statistical Analytical Software 
Generation of the figures, tables and tabulated lists planned in this document will be performed using 
SAS Version 9.4. The format of output of the results will be RTF. 
When any statistical analytical software other than those mentioned above or any self-made software is 
used, it should be clearly stated in the statistical analysis plan. 
 
8.2 
General Matters related to Format of Figures, Tables and Tabulated Lists 
Details about the form of output of individual figures and tables will be stipulated in the report analysis 
plan. 
The paper size will be A4. Portrait will be used as the standard for figures and summary tables, and 
landscape will be used as the standard for tabulated lists and data lists. However, it will be decided 
according to the characteristics of individual figures and tables. 
The name of the investigational product and the protocol number will be shown at the left top of each 
page; the date and time of output and page number will be shown at the right top; the output program name 
will be shown at the left bottom; and the user ID of the person executing the analytical program will be 
shown at the right bottom. 
 
8.3 
Common Rules for Data Processing 
 Rules regarding number of days and period 
1. 
The number of days will be calculated by subtracting the day of start from the day of completion 
and adding 1. 
(Example) 
Number of days of administration: if administration is terminated on the day of the start of 
administration, the administration period will be 1 day. 
Duration to the onset of adverse events: If any adverse event occurs on the day after the day of 
the start of administration, the duration to the first occurrence of adverse event will be 2 
days. 
2. 
When the number of days is converted to the number of years, number of months, and number of 
weeks, 1 year will be counted as 365.25 days, 1 month will be counted as 30.4375 days, and 1 
week will be counted as 7 days. 
 Rules for number of decimal places and rounding 
1. 
Mean values, standard deviations, and median values will be displayed (rounded) to the place (or 
decimal place) next to the lowest place of source data. 
2. 
Percentage will be displayed to 1 decimal place (example, 12.3%). Values are rounded to 1 
decimal place. 
3. 
In calculation of statistic values such as mean values, standard deviations, and median values, 
rounding is not performed during the process of calculation. Only the final values obtained as a 
result of calculation will be rounded. 
4. 
P values will be displayed to 3 decimal places (example, 0.001). The values will be rounded to 3 
decimal places. 


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 Summary statistics 
When summary statistics are displayed, the “number of subjects,” “median values,” “mean 
values,” “standard deviations,” “minimum values,” and “maximum values” will be displayed as a 
set unless otherwise there are any particular reasons. 
 LOCF 
If the data at the last time point of observation are missing, the data which are not missing and 
have been obtained immediately before that time point will be used for interpolation, irrespective 
of whether or not the data are within the acceptable range. 
 Confidence interval of incidences 
The confidence interval of incidences (or incidence rates) will be obtained by an exact method 
based on F distribution. 
The number of subjects in the analysis set is put as N and the number of subjects exhibiting 
adverse events is put as X. Thus, the incidence ( P ) and the upper limit (
U
P ) and lower limit 
(
L
P ) of the exact 2-sided 100(1-α)% confidence interval of the incidence will be estimated 
by the following formulas.2) In the case of 95% confidence interval, α=0.05. 
 
X
X
N
F
P
X
N
X
F
F
P
N
X
P
L
U
⋅
=
+
−
⋅
=
⋅
+
=
−
⋅
=
+
⋅
=
⋅
+
⋅
=
=
2
)1
(
2
,)
,
(
)
(
2
)1
(
2
,)
,
(
)
,
(
/
2
1
2
1
2
/
1
2
2
2
1
2
1
2
/
1
2
2
1
2
/
1
υ
υ
υ
υ
υ
υ
υ
υ
υ
υ
υ
υ
υ
υ
υ
υ
α
α
α
 
 Adverse events 
Adverse events will be coded according to MedDRA/J, and Preferred Terms (PT) will be used 
for tabulation unless otherwise specified. The version of MedDRA to be used will be the newest 
version available as of the time of data fixation as a rule, but it will be decided by the MedDRA 
manager. 
 
 


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 MMRM 
The confidence coefficient for estimation of confidence interval will be 2-sided 95%. 
In the analysis of MMRM, SAS MIXED procedure will be used as shown in the following SAS 
code. 
proc mixed data = INDATA ; 
class 
ATRTN† (ref=’1’[Placebo]) AVISITN† SUBJID† ; 
model 
AVAL† = BASE† ATRTN AVISITN ATRTN*AVISITN / ddfm = KR ; 
lsmeans 
ATRTN*AVISITN / diff cl alpha = 0.05 ; 
repeated 
AVISITN / subject = SUBJID type = UN# ; 
estimate 
"Low Dose TAS-205 Saturation - Week 12"  ATRTN  -2 1 1‡  
 
 
ATRTN*AVISITN  -2 0 1 0 1 0 / cl alpha = 0.05 ; 
estimate 
"Low Dose TAS-205 Saturation - Week 24"  ATRTN  -2 1 1‡  
 
 
ATRTN*AVISITN  0 -2 0 1 0 1 / cl alpha = 0.05 ; 
estimate 
"Placebo vs High Dose TAS-205 - Week 12"  ATRTN  -1 0 1‡  
 
 
ATRTN*AVISITN  -1 0 0 0 1 0 / cl alpha = 0.05 ; 
estimate 
"Placebo vs High Dose TAS-205 - Week 24"  ATRTN  -1 0 1‡  
 
 
ATRTN*AVISITN  0 -1 0 0 0 1 / cl alpha = 0.05 ;  
estimate 
"High Dose TAS-205 Saturation - Week 12 "  ATRTN  -1 -1 2‡  
 
 
ATRTN*AVISITN  -1 0 -1 0 2 0 / cl alpha = 0.05 ; 
estimate 
"High Dose TAS-205 Saturation - Week 24 "  ATRTN  -1 -1 2‡  
 
 
ATRTN*AVISITN  0 -1 0 -1 0 2 / cl alpha = 0.05 ; 
run ; 
† ATRTN: Treatment group (placebo group [reference group], low-dose group, high-dose group) 
AVISITN: Time point (Week 12, Week24) 
SUBJID: Patient ID 
AVAL: Response variable 
BASE: Baseline value 
‡ Contrast coefficient (-2 1 1): Paired comparison of low-dose group saturation 
Contrast coefficient (-1 0 1): Paired comparison of linear trend 
Contrast coefficient (-1 -1 2): Paired comparison of high-dose group saturation 
# If convergence is not achieved with UN, TOEP will be used. If convergence is not achieved yet, the 
following will be used in this order: AR(1)→CS→VC. 
 
9. References 
1. 
“Structure and Content of Clinical Study Reports” (May 1, 1996, PAB/ED Notification No. 335) 
2. 
Sakuma, A., Igaku Tokei (Medical Statistics) Q&A, p75, Kanehara Shuppan, 1987 
 
 
 


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10. Appendix 
Table 10.1  Method to Derive %MVI (%) 
Evaluation of muscle 
volume 
Method of derivation 
%MVI (%) in right leg 
Muscle in middle part (right surface area) / (muscle in middle part (right surface 
area) + fat in middle part (right surface area) - subcutaneous fat in middle part 
(right surface area)) × 100 
%MVI (%) in left leg 
Muscle in middle part (left surface area) / (muscle in middle part (left surface 
area) + fat in middle part (left surface area) - subcutaneous fat in middle part 
(left surface area)) × 100 
%MVI (%) in both 
legs 
Muscle in middle part (bilateral surface area) / (muscle in middle part (bilateral 
surface area) + fat in middle part (bilateral surface area) - subcutaneous fat in 
middle part (bilateral surface area)) × 100 
 
Table 10.2  Method to Derive Pharmacodynamic Endpoints and Exploratory Endpoints 
Pharmacodynamic and exploratory endpoints 
Method of derivation 
Urine tetranor-PGDM/Cre concentration ratio 
(ng/mg creatinine) 
PGDM† / Cre† 
Total urinary tetranor-PGDM excretion (ng) 
PGDM† × urine volume (mL) 
Urinary tetranor-PGEM/creatinine 
concentration ratio 
(ng/mg creatinine) 
PGEM† / Cre† 
Total urinary tetranor-PGEM excretion (ng) 
PGEM† × urine volume (mL) 
Urinary creatinine excretion (g) 
Cre† × urine volume (mL) 
Urinary creatine excretion (g) 
Cr† × urine volume (mL) 
% creatine in urine (%) 
Urinary creatine excretion (g) / [Urinary creatine 
excretion (g) + Urinary creatinine excretion (g)] × 100 
 
†PGDM: Urinary tetranor-PGDM concentration (ng/mL) 
 PGEM: Urinary tetranor-PGEM concentration (ng/mL) 
 Cre: Urinary creatinine concentration (g/mL) 
 Cr: Urinary creatine concentration (g/mL)