Clinical trial NCT02337751
Conditions: Parkinson's Disease
Sponsor: Takeda
Start date: 2015-07-10; Completion date: 2017-03-14
Enrollment: 198 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the long-term safety of TVP-1012 (1 mg/day) in Japanese participants with early Parkinson's disease.

Detailed description:
This is a multicenter, open-label, long-term, extension, phase 3 study to evaluate the safety and efficacy of long-term administration of TVP-1012 at 1 mg for another 26 weeks in participants with early Parkinson's disease who have completed the preceding TVP-1012/CCT-001 (NCT02337725) study.

Among participants of the TVP-1012/CCT-001 study, those consenting to participate in this study prior to complete the preceding study and fulfilling the eligibility criteria will be enrolled in this study. From the day after the Visit 8 of the preceding study, participants will receive 1 mg of TVP-1012 once daily for 26 weeks in an unblinded manner.

Arms: arm 1: TVP-1012 (1 mg/day) once daily, either before or after breakfast.
Interventions: intervention 1: TVP-1012 1mg
Intervention descriptions: intervention 1: TVP-1012 1mg Tablets

Protocol documents:
Prot_000.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable information or 
company confidential information may be removed in their entirety if it is considered that they do not add 
substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). 
Note; This document was translated into English and the language in original document was Japanese.


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PROTOCOL 
<Title> 
A Multicenter, Open-label, Long-term, Extension, Phase 3 Study  
to Evaluate the Safety and Efficacy of TVP-1012 at 1 mg  
in Early Parkinson's Disease Patients Not Treated with Levodopa 
 
<Short Title> 
A Phase 3, Long-term, Extension Study of TVP-1012 (1 mg)  
in Early Parkinson’s Disease Patients 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Japan 
Study Number: 
TVP-1012/OCT-001 
Amendment No 
Amendment 2 
IND Number: 
Not Applicable 
EudraCT Number 
Not Applicable 
Compound: 
TVP-1012 (INN: Rasagiline) 
Date: 
24 March 2016 
 
Amendment History  
Date 
Amendment Number 
Region 
25 November 2014 
First edition 
All sites 
16 December 2014 
Amendment 1 
All sites 
24 March 2016 
Amendment 2 
All sites 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without 
written authorization from Takeda except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered. Furthermore, the information is only meant for review 
and compliance by the recipient, his or her staff, and applicable institutional review committee and 
regulatory agencies to enable conduct of the study. 


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1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
A separate contact information list will be provided to each site. 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation E6 Good Clinical Practice: 
Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations. 
 


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TABLE OF CONTENTS 
2.0 
STUDY SUMMARY ............................................................................................ 8 
3.0 
LIST OF ABBREVIATIONS ............................................................................. 11 
4.0 
INTRODUCTION ............................................................................................... 12 
4.1 
Background .................................................................................................... 12 
4.2 
Rationale for the Proposed Study .................................................................. 15 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 16 
5.1 
Objectives ...................................................................................................... 16 
5.1.1 
Primary Objective(s) ............................................................................. 16 
5.1.2 
Secondary Objectives(s) ........................................................................ 16 
5.2 
Endpoints ....................................................................................................... 16 
5.2.1 
Primary Endpoint .................................................................................. 16 
5.2.2 
Secondary Endpoints ............................................................................. 16 
5.2.3 
Additional Endpoints ............................................................................. 16 
6.0 
STUDY DESIGN AND DESCRIPTION ........................................................... 17 
6.1 
Study Design ................................................................................................. 17 
6.2 
Justification for Study Design, Dose, and Endpoints .................................... 19 
6.2.1 
Justification for Study Subject .............................................................. 19 
6.2.2 
Justification for Study Design ............................................................... 19 
6.2.3 
Justification for Dose Regimen ............................................................. 19 
6.2.4 
Justification for Treatment Period ......................................................... 20 
6.2.5 
Justification for Endpoints..................................................................... 20 
6.3 
Premature Termination or Suspension of Study or Investigational Site ....... 20 
6.3.1 
Criteria for Premature Termination or Suspension of the Study ........... 20 
6.3.2 
Criteria for Premature Termination or Suspension of Investigational 
Sites ....................................................................................................... 21 
6.3.3 
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Site(s) ........................................ 21 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS .......................................................................................................... 22 
7.1 
Inclusion Criteria ........................................................................................... 22 


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7.2 
Exclusion Criteria .......................................................................................... 23 
7.3 
Excluded Medications and Treatments.......................................................... 23 
7.4 
Diet, Fluid, Activity Control ......................................................................... 26 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................. 28 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject ......................... 29 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .......................................... 30 
8.1 
Study Medication ........................................................................................... 30 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ...................... 30 
8.1.2 
Storage ................................................................................................... 30 
8.1.3 
Dose and Regimen................................................................................. 31 
8.1.4 
Overdose ................................................................................................ 31 
8.2 
Investigational Drug Assignment and Dispensing Procedures...................... 31 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs ........................ 32 
9.0 
STUDY PLAN .................................................................................................... 33 
9.1 
Study Procedures ........................................................................................... 33 
9.1.1 
Informed Consent Procedure ................................................................. 33 
9.1.2 
Demographics, Medical History, and Medication History Procedure .. 33 
9.1.3 
Physical Examination Procedure ........................................................... 33 
9.1.4 
Skin Examination .................................................................................. 33 
9.1.5 
Weight ................................................................................................... 34 
9.1.6 
Vital Sign Procedure ............................................................................. 34 
9.1.7 
Documentation of Concomitant Medications........................................ 34 
9.1.8 
Documentation of Concurrent Medical Conditions .............................. 34 
9.1.9 
Procedures for Clinical Laboratory Samples......................................... 34 
9.1.10 
Contraception and Pregnancy Avoidance Procedure ............................ 36 
9.1.11 
Pregnancy .............................................................................................. 36 
9.1.12 
ECG Procedure ...................................................................................... 37 
9.1.13 
MDS-UPDRS ........................................................................................ 37 
9.1.14 
QOL assessment .................................................................................... 39 
9.1.15 
Documentation of Screen Failure .......................................................... 39 
9.1.16 
Documentation of Study Entrance ........................................................ 40 


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9.2 
Monitoring Subject Treatment Compliance .................................................. 40 
9.3 
Schedule of Observations and Procedures .................................................... 40 
9.3.1 
Study Entrance/Week 26 in Treatment Period ...................................... 40 
9.3.2 
Treatment Period (Weeks 29, 32, 36, 40, and 46) ................................. 40 
9.3.3 
Week 52 (Treatment Period) or Early Termination .............................. 42 
9.3.4 
Post Study Care ..................................................................................... 43 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ................................ 44 
10.1 
Definitions ..................................................................................................... 44 
10.1.1 
PTEs ...................................................................................................... 44 
10.1.2 
AEs ........................................................................................................ 44 
10.1.3 
Additional Points to Consider for PTEs and AEs ................................. 44 
10.1.4 
SAEs ...................................................................................................... 47 
10.1.5 
Severity of PTEs and AEs ..................................................................... 48 
10.1.6 
Causality of AEs .................................................................................... 48 
10.1.7 
Relationship to Study Procedures.......................................................... 50 
10.1.8 
Start Date ............................................................................................... 50 
10.1.9 
Stop Date ............................................................................................... 51 
10.1.10 Frequency .............................................................................................. 51 
10.1.11 Action Concerning Study Medication ................................................... 51 
10.1.12 Outcome ................................................................................................ 52 
10.2 
Procedures ..................................................................................................... 53 
10.2.1 
Collection and Reporting of AEs .......................................................... 53 
10.2.2 
Collection and Reporting of SAEs ........................................................ 54 
10.2.3 
Reporting of Abnormal Liver Function Tests ....................................... 55 
10.3 
Follow-up of SAEs ........................................................................................ 55 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities .. 55 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................. 57 
12.0 
DATA HANDLING AND RECORDKEEPING ................................................ 58 
12.1 
CRFs (Electronic and Paper) ......................................................................... 58 
12.2 
Record Retention ........................................................................................... 59 
13.0 
STATISTICAL METHODS ............................................................................... 60 


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13.1 
Statistical and Analytical Plans ..................................................................... 60 
13.1.1 
Analysis Sets ......................................................................................... 60 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ............ 60 
13.1.3 
Efficacy Analysis .................................................................................. 60 
13.1.4 
Safety Analysis ...................................................................................... 61 
13.2 
Interim Analysis and Criteria for Early Termination .................................... 62 
13.3 
Determination of Sample Size ....................................................................... 62 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 64 
14.1 
Study-Site Monitoring Visits ......................................................................... 64 
14.2 
Protocol Deviations ....................................................................................... 64 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections .................... 64 
15.0 
ETHICAL ASPECTS OF THE STUDY ............................................................. 66 
15.1 
IRB Approval ................................................................................................ 66 
15.2 
Subject Information, Informed Consent, and Subject Authorization ............ 67 
15.3 
Subject Confidentiality .................................................................................. 68 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy .................... 68 
15.4.1 
Publication and Disclosure .................................................................... 68 
15.4.2 
Clinical Trial Registration ..................................................................... 69 
15.4.3 
Clinical Trial Results Disclosure ........................................................... 69 
15.5 
Insurance and Compensation for Injury ........................................................ 69 
16.0 
REFERENCES .................................................................................................... 70 
 


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LIST OF IN-TEXT TABLES 
Table 7.a 
Excluded Medications and Treatments.................................................... 24 
Table 8.a 
Study Medication ..................................................................................... 30 
Table 9.a 
Clinical Laboratory Tests ........................................................................ 35 
Table 9.b 
MDS-UPDRS Score Sheet ...................................................................... 38 
Table 10.a 
Takeda Medically Significant AE List .................................................... 48 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ...................................................................... 18 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ................................................................. 71 
Appendix B 
Responsibilities of the Investigator ......................................................... 72 
Appendix C 
Detailed Description of Amendments to Text ......................................... 73 
 


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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
TVP-1012 
Title of Protocol: 
A Multicenter, Open-label, Long-term, Extension, Phase 
3 Study to Evaluate the Safety and Efficacy of 
TVP-1012 at 1 mg in Early Parkinson's Disease Patients 
Not Treated with Levodopa 
(An extension study from TVP-1012/CCT-001) 
IND No.: 
Not applicable 
EudraCT No.: 
Not applicable 
Study Number: TVP-1012/OCT-001 
Phase: 3 
Study Design: 
This is a multicenter, open-label, long-term, extension, phase 3 study to evaluate the safety and efficacy 
of long-term administration of TVP-1012 at 1 mg for another 26 weeks in patients with early Parkinson’s 
disease who have completed the 26-week treatment period in the preceding TVP-1012/CCT-001 study. 
Among participants of the TVP-1012/CCT-001 study, those consenting to participate in this study prior to 
undergoing the tests, observations, and assessments at Week 26 of the treatment period (VISIT 8) in the 
preceding study, and fulfilling the eligibility criteria will be enrolled in this study. From the day after the 
VISIT 8 of the preceding study, subjects will receive TVP-1012 1 mg once daily for 26 weeks in an 
unblinded manner. 
The visit numbers in this study will be continued from the preceding study, and the study visit week will 
be counted from the start of the treatment period in the preceding study. 
Patients will make a total of 7 visits in this study, i.e., at Weeks 26, 29, 32, 36, 40, 46, and 52 of the 
treatment period, to undergo designated tests, observations, and assessments. 
Primary Objective: 
To evaluate the long-term safety of TVP-1012 (1 mg/day) in Japanese patients with early Parkinson’s 
disease 
Secondary Objective: 
To evaluate the long-term efficacy of TVP-1012 (1 mg/day) in Japanese patients with early Parkinson’s 
disease 
Subject Population: Japanese patients with early Parkinson’s disease who have completed the 26-week 
treatment period in the preceding study 
Number of Subjects: 
Approximately 182 continued from the preceding study 
Number of Sites: 
Approximately 55 sites 
(Same study sites as the preceding study) 


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Dose Levels: 
TVP-1012 (1 mg/day) once daily, either before or after 
breakfast (the timing of the dose must be the same as in 
the preceding study) 
Route of Administration: 
Oral 
Duration of Treatment: 
26 weeks in total 
Period of Evaluation: 
26 weeks in total 
Main Criteria for Inclusion: 
 The subject has completed the preceding study. 
 The subject has shown no safety issues during the study treatment in the preceding study, in the 
judgment of the investigator or sub-investigator. 
Main Criteria for Exclusion: 
 Subject has donated 400 mL or more of his or her blood volume within 90 days prior to the initiation 
of the investigational drug in this study. 
 The subject is required to receive any of the excluded medications or treatments. 
 The subject is required surgery or hospitalization for surgery during the study period. 
Main Criteria for Evaluation and Analyses: 
Primary endpoint 
 Adverse events (AEs) 
Secondary endpoints 
 Clinical laboratory test values, vital signs, electrocardiogram (ECG), and weight 
 MDS-UPDRS Part II + Part III total score 
Statistical Considerations: 
The analyses for this study will be performed using pooled data from the preceding study and this study, 
in principle, based on data obtained after administration of TVP-1012. 
[Analysis methods for the primary endpoint] 
The following analysis will be based on the safety analysis set. 
A treatment-emergent adverse event (TEAE) is defined as an adverse event whose date of onset occurs on 
or after the start of treatment period study drug in the preceding study. 
TEAEs whose date of onset occurs on or after the start of TVP-1012 will be coded using the MedDRA 
dictionary. The frequency distribution will be provided using the system organ class and the preferred 
term for each treatment group as follows: 
 All TEAEs 
 Drug-related TEAEs 
 Intensity of TEAEs 
 Intensity of drug-related TEAEs 


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 TEAEs leading to study drug discontinuation 
 Serious TEAEs 
 TEAEs over time 
Sample Size Justification: 
In the preceding study, the planned number of subjects to be randomized was a total of 240 (120 per 
group) and the planned number of subjects evaluable for the primary endpoint (change in the 
MDS-UPDRS Part II + Part III total score from baseline to Week 26 of the treatment period (LOCF)) was 
a total of 220 (110 per group). 
Since this study is a long-term extension study in patients with early Parkinson’s disease who have 
completed the 26-week treatment period in the preceding study, considering the potential dropouts in the 
preceding study, approximately 182 subjects will be enrolled in this study. 
In addition, considering the potential dropouts in this study and in the preceding study, it is estimated that 
155 subjects will be treated with 1 mg of TVP-1012 for 26 weeks and 59 subjects for 52 weeks. 
 


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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
Cmax 
maximum observed serum concentration 
COMT 
catechol-O-methyltranferase 
CRO 
contract research organization 
CYP 
Cytochrome P-450 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
γ-GTP 
γ-glutamyl transpeptidase 
hCG 
human chorionic gonadotropin 
ICH 
International Conference on Harmonisation 
INN 
international nonproprietary name 
INR 
international normalized ratio 
LDH 
lactate dehydrogenase 
MAO 
Monoamine oxidase 
MDS 
Movement Disorders Society 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
PDQ-39 
The 39-item Parkinson’s disease questionnaire 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
preferred term 
PTE 
pretreatment event 
QOL 
quality of life 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
UPDRS 
unified Parkinson’s disease rating scale 
WHO 
World Health Organization 


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4.0 
INTRODUCTION 
4.1 
Background 
Parkinson’s disease is the second most common neurodegenerative disorder of the 
central nervous system after Alzheimer’s disease. The prevalence of Parkinson’s disease 
is estimated to be 100-150/100,000 in the Japanese population, mostly affecting elderly 
people with peak age in the late 50s to 60s [1]. A significant increase in the number of 
patients is expected as the population ages in the future. 
The 4 major symptoms of Parkinson’s disease are resting tremor, muscle rigidity 
(muscle stiffness), bradykinesia, and postural instability. These motor symptoms are 
suspected to occur due to damage or death of substantia nigra dopaminergic neurons in 
the midbrain, followed by a reduction in dopamine volume in the striatum. 
The Japanese therapeutic guideline recommends initially treating motor symptoms of 
Parkinson’s disease with levodopa or a dopamine agonist, in principle, and rich 
evidence with these drugs used as first-line therapy are available [2]. 
In clinical practice overseas, the efficacy of initial treatment with MAO-B inhibitors has 
been demonstrated in Parkinson’s disease and the therapeutic algorithm recommends 
MAO-B inhibitors as the first-line treatment for mild Parkinson’s disease in addition to 
levodopa and dopamine agonists [3][4]. In Japan, selegiline is one of the MAO-B 
inhibitors available but not approved for first-line treatment of Parkinson’s disease. If 
clinical development of MAO-B inhibitors is promoted in Japan, treatment options for 
patients with mild or early Parkinson’s disease may expand. 
TVP-1012 (INN: rasagiline) is a MAO-B inhibitor without an amphetamine structure. 
In comparison with selegiline, TVP-1012 is characterized by (1) a 5 to 10-fold MAO-B 
inhibitory effect, and (2) easy drug management due to not having an amphetamine 
structure and not being designated as ingredient in narcotics. As of September, 2014, 
rasagiline has been approved in 53 countries in Europe, the United States, and East 
Asian countries as a monotherapy for early Parkinson’s disease, and also as concomitant 
therapy with levodopa for Parkinson’s disease. Currently, clinical development for 
TVP-1012 as monotherapy for early Parkinson’s disease and as an add-on therapy to 
levodopa for Parkinson’s disease is ongoing in Japan. 
 
 
 
 


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Efficacy Summary 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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Safety Summary 
 
 
 
 
 
 
 
 
 
 


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4.2 
Rationale for the Proposed Study 
 
 
 
 
 
 
 
 
Based on these results, this study was planned to evaluate the efficacy and safety of 
long-term extension administration with TVP-1012 in Japanese patients with early 
Parkinson’s disease who have completed the preceding study (TVP-1012/CCT-001). 
The comprehensive evaluation of the efficacy and safety of TVP-1012 in early 
Parkinson’s disease will be performed based on the results of this study, Study 
TVP-1012/CCT-001, and overseas clinical studies. 
The clinical development of TVP-1012 as an add-on to levodopa for Parkinson’s 
disease is ongoing in Japan. Currently, a Phase 2/3 study (TVP-1012/CCT-002) and a 
Phase 3 study (TVP-1012/OCT-002) are underway. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective(s) 
 
To evaluate the long-term safety of TVP-1012 (1 mg/day) in Japanese patients with 
early Parkinson’s disease 
5.1.2 
Secondary Objectives(s) 
 
To evaluate the long-term efficacy of TVP-1012 (1 mg/day) in Japanese patients 
with early Parkinson’s disease 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
 
Adverse events (AEs) 
5.2.2 
Secondary Endpoints 
 Clinical laboratory test values, vital signs, electrocardiogram (ECG), and weight 
 Movement Disorder Society-Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) Part II＋Part III total score 
5.2.3 
Additional Endpoints 
 
MDS-UPDRS Part I total score 
 
MDS-UPDRS Part II total score 
 
MDS-UPDRS Part III total score 
 
MDS-UPDRS Part IV total score 
 
MDS-UPDRS tremor score 
 
MDS-UPDRS bradykinesia score 
 
MDS-UPDRS muscle rigidity score 
 
MDS-UPDRS individual score 
 
Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index scores for 
individual domain 
 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
Patients will make a total of 7 visits in this study, i.e., at Weeks 26, 29, 32, 36, 40, 46 
and 52 of the treatment period, to undergo designated tests, observations, and 
assessments. 
This is a multicenter, open-label, long-term, extension, phase 3 study to evaluate the 
safety and efficacy of long-term administration of TVP-1012 at 1 mg for another 26 
weeks in patients with early Parkinson’s disease who have completed the 26-week 
treatment period in the preceding TVP-1012/CCT-001 study. 
Among participants of the TVP-1012/CCT-001 study, those consenting to participate in 
this study prior to undergoing the tests, observations, and assessments at Week 26 of the 
treatment period (VISIT 8) in the preceding study, and fulfilling the eligibility criteria 
will be enrolled in this study. From the day after the VISIT 8 of the preceding study, 
subjects will receive TVP-1012 1 mg once daily for 26 weeks in an unblinded manner. 
The visit numbers in this study will be continued from the preceding study, and the 
study visit week will be counted from the start of the treatment period in the preceding 
study. 
This study will be conducted in the same study sites as those of the preceding study (55 
sites) and the number of subjects to be enrolled in this study is estimated to be 182 
subjects after considering dropouts in the preceding study. 
Schematic of Study Design is included as Figure 6.a. A schedule of study procedures is 
listed in Appendix A. 
 


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V: VISIT 
* Informed consent for this study must be obtained prior to tests, observations, and assessments at Week 
26 of the treatment period in the preceding study. Those who consent to participate in this study and 
fulfilling the eligibility criteria will be enrolled in this study. Subjects will start dosing from the day 
after the VISIT 8. 
Figure 6.a 
Schematic of Study Design 
 


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6.2 
Justification for Study Design, Dose, and Endpoints 
6.2.1 
Justification for Study Subject 
To evaluate the safety and efficacy of long-term administration of TVP-1012 in 
Japanese patients with early Parkinson’s disease, this study will target subjects who 
have completed the preceding study and were assessed as not demonstrating safety 
concerns in the opinion of the investigator or sub-investigator.  
6.2.2 
Justification for Study Design 
This open-label, long-term extension study has a common study design that allows for 
the evaluation of long-term safety. This study was designed as an extension study 
following the preceding study, to collect pertinent data on long-term administration in 
an efficient manner.  
See Section 13.3 for Sample Size Justification. 
6.2.3 
Justification for Dose Regimen 
 
 
 
 
 
 
 
  
In the preceding study, 1 mg of TVP-1012 or placebo was administered for 26 weeks to 
evaluate the efficacy and safety of TVP-1012 1 mg. 
In this study, the dose of 1 mg of TVP-1012 will be maintained for subjects treated with 
1 mg of TVP-1012 in the preceding study, to evaluate administration at 1 mg for 52 
weeks. In addition, subjects treated with placebo in the preceding study will be switched 
to 1 mg of TVP-1012 in this study, to evaluate administration at 1 mg for 26 weeks, for 
the purpose of evaluating a large number of subjects as much as possible.  
 
 
 
 


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6.2.4 
Justification for Treatment Period 
Parkinson’s disease is a progressive disease and long-term administration is anticipated 
when TVP-1012 is prescribed. Therefore, another 26-week extension of treatment was 
planned following the 26-week treatment in the preceding study to evaluate the 
long-term safety of TVP-1012 for 6 months and 12 months.  
6.2.5 
Justification for Endpoints 
In this study, the long-term safety and efficacy of TVP-1012 following the preceding 
study will be evaluated. As the safety and efficacy will be evaluated in pooled data from 
this and preceding studies, the same endpoints used for the preceding study were set.  
Safety evaluation is the primary objective of this study. Of the safety evaluation 
variables in the preceding study, the frequency of adverse events (AEs) will be used as 
the primary endpoint and clinical laboratory test results, vital signs, ECGs, and weight 
will be used for the assessment of secondary endpoints. 
In addition, MDS-UPDRS Part II + Part III total score, which was the primary efficacy 
endpoint in the preceding study, will be used as a secondary endpoint. The efficacy 
endpoints in the preceding study other than MDS-UPDRS Part II + Part III total score 
will be set as additional endpoints. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study. 
 
New information or other evaluation regarding the safety or efficacy of the study 
medication that indicates a change in the known risk/benefit profile for the 
compound, such that the risk/benefit is no longer acceptable for subjects 
participating in the study. 


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 
Significant violation of Good Clinical Practice (GCP) that compromises the ability 
to achieve the primary study objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the 
investigator) is found in significant violation of GCP, protocol, or contractual agreement, 
is unable to ensure adequate performance of the study, or as otherwise permitted by the 
contractual agreement. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority 
elects to terminate or suspend the study or the participation of an investigational site, a 
study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable investigational sites during the 
course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to the administration 
of the investigational drug. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria:  
1. In the opinion of the investigator or sub-investigator, the subject is capable of 
understanding and complying with protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required 
privacy authorization prior to the initiation of any study procedures. 
3. The subject has completed the preceding study (TVP-1012/CCT-001 study). 
4. The subject has shown no safety issues during the study treatment in the 
preceding study, in the judgment of the investigator or sub-investigator. 
5. A female subject of childbearing potential* who is sexually active with a 
nonsterilized* male partner agrees to use routinely adequate contraception* from 
signing of informed consent to 1 month after the last dose of the investigational 
drug. 
*Definition of female subjects of chiledbearing potential is defined in 
Section 9.1.10. 
Contraception and Pregnancy Avoidance Procedure and reporting 
responsibilities are defined in Section 9.1.11. 
 
[Justification of Inclusion Criteria] 
1, 2： 
These criteria were set to include subjects who understand the objective of 
the study and will cooperate in the study conduct. 
3： 
This criterion was set as this study is designed to conduct with subjects who 
have completed the 26-week treatment period in the preceding study. 
4： 
This criterion was set in consideration of subject safety. 
5： 
This criterion was set in consideration of safety risk associated with 
pregnancy. 
 


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7.2 
Exclusion Criteria 
Any subject who meets the following criteria will not qualify for entry into the study: 
1. The subject is an immediate family member, study site employee, or is in a 
dependant relationship with a study site employee who is involved in conduct of 
this study (e.g., spouse, parent, child, sibling) or may consent under duress. 
2. Subject has donated 400 mL or more of his or her blood volume within 90 days 
prior to the initiation of the investigational drug in this study. 
3. The subject is required to receive excluded medications or treatments. 
4. If female, the subject is intending to become pregnant during, or within 1 month 
after the last dose of the investigational drug; or intending to donate ova during 
such time period. 
5. The subject requires surgery or hospitalization for surgery during the study 
period. 
6. The subject who, in the opinion of the investigator or sub-investigator, is 
unsuitable for any other reason. 
 
[Justification of Exclusion Criteria] 
1, 5： These criteria were set as basic matters to conduct clinical studies. 
2： 
This criterion was set as basic matters to conduct clinical studies in 
consideration of subject safety. 
3： 
This criterion was set in consideration of efficacy evaluation and subject safety. 
4： 
This criterion was set to avoid the safety risk associated with pregnancy to 
pregnant woman and fetus. 
6： 
This criterion was set to exclude subjects with unknown factors which might 
influence the evaluation of efficacy. 
 
7.3 
Excluded Medications and Treatments 
The list of excluded medications and treatments is shown in Table 7.a. Subjects must be 
instructed not to take any medications, including over-the-counter products, without 
first consulting with the investigator or sub-investigator. 


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Table 7.a 
Excluded Medications and Treatments 
Medication/Treatment 
Duration 
Exception 
Excluded Medication 
(1) selegiline 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(2) pethidine, tramadol 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(3) reserpine, methyldopa 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(4) Other investigational drug From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(5) levodopa containing drug 
(6) Dopamine agonist 
(7) amantadine 
(8) Anticholinergic agent 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(9) COMT inhibitor 
(10) droxidopa 
(11) zonisamide 
(12) istradefylline 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(13) Psychoneurotic agent 
(phenothiazine, 
butyrophenone, benzamide, 
Atypical antipsychotic drug) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
Quetiapine may be 
concomitantly administrered 
without change in dose 
regimen throughout the 
study if the drug has been 
continuously administered in 
the preceding study. 
(14) Antinauseant with 
dopamine agonistic property  
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
domperidone may be 
concomitantly administered 
without change in dose 
regimen throughout the 
study if the drug has been 
continuously administered in 
the preceding study. 
(15) CYP1A2 inhibitor 
(including ciprofloxacin, 
enoxacin, fluvoxamine, 
zafirlukast) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 


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Medication/Treatment 
Duration 
Exception 
(16) dextromethorphan 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(17) Antidepressant  
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(18) St. John’s Wort 
(including supplements) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(19) Narcotic analgesic agent 
(excluding ≤ 1% of codeine, 
dihydrocodeine) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
Excluded Treatment 
(20) Neurosurgical 
intervention 
 (Pallidotomy, 
Thalamotomy, deep brain 
stimulation) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(21) Transcranial magnetic 
stimulation 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
 
Medications/treatments for AEs during the study period may be administered, provided 
that these treatments do not deviate from the above range. If a drug listed above is 
chosen as routine medication after study completion, this medication should be 
administered following a reasonable interval as needed, based on the precautions for use 
for each drug. 


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[Justification of Excluded Medications and Treatments] 
(1), (2), (18), (19) 
These criteria were set to ensure the safety of subjects, in consideration of  
adverse drug reactions due to concomitant use. 
(3), (13), (14) 
These criteria were set since there is a possibility of worsening Parkinsonism, 
which may affect the efficacy evaluation of TVP-1012; however, some drugs 
may be used concomitantly, if these drugs do not affect the efficacy 
evaluation of TVP-1012. 
(4)-(12), (20), (21) 
 These criteria were set because they could influence the evaluation of 
efficacy. 
(15) 
This criterion was set due to the effect on the pharmacokinetics of TVP-1012, 
considering the metabolic pathway mainly via CYP1A2. 
(16) 
This criterion was set to ensure the safety of subjects, in consideration of 
possibly elevating serotonin level due to concomitant use. 
(17) 
This criterion was set to ensure the safety of subjects and to minimize the 
effect on the efficacy evaluation due to mutually potentiated pharmacological 
action with concomitant use. 
 
7.4 
Diet, Fluid, Activity Control 
The investigator, sub-investigator, or study coordinator will give subjects the following 
instructions: 
1. 
Subjects should be punctual for visit appointments and undergo the physical 
examinations and prescribed tests. Subjects should also contact the investigator, 
sub-investigator or study coordinator promptly if they cannot visit the site as 
planned. 
2. 
Subjects should contact the investigator, sub-investigator, or study coordinator by 
telephone, etc., to ask for instructions immediately after symptoms worsen 
between planned visits. 
3. 
Subjects should follow instructions regarding treatment adherence provided by the 
investigator or sub-investigator. Subjects should visit the site after taking the 
study drug on planned visit days.* If the subject does not comply with treatment 
procedures, the subject must report this to the investigator, sub-investigator, or 


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study coordinator at the next visit. Unused study drug(s) and drug sheet(s) (blister 
sheet) should be returned at the next visit. 
* For the day the serum chemistry is scheduled, the study medication must be taken without 
having breakfast. In this case, deviation from the original dose timing (not before or after 
breakfast) will be permitted. 
4. Subjects are not allowed to take any medications other than drugs prescribed by the 
investigator or sub-investigator, including over-the-counter products, without first 
consulting with the investigator (except for emergency use). 
5. 
If a subject visits another medical institution from signing of the informed consent 
to 1 month after the last administration of the investigational drug, the investigator 
should notify the primary care physician that the subject was participating in a 
clinical study. 
6. 
If a subject visits another medical institution from signing of the informed consent 
to 1 month after the last administration of the investigational drug, the investigator 
or sub-investigator should be informed of the circumstances and therapy. 
7. 
On the days on which clinical serum chemistry tests are scheduled, blood must be 
collected in fasted state (≥ 8 hours), whenever possible. 
8. 
A female subject of childbearing potential who is sexually active with a 
nonsterilized male partner must agree to use routinely adequate contraception 
from signing of informed consent to 1 month after the last dose of the 
investigational drug. 
9. 
Excessive eating, drinking, exercise and drastic change of the meal are not 
allowed during the study period. 
10. Blood donation is not allowed from the start of the investigational drug 
administration until at least 1 month after the last administration of the 
investigational drug. Subject must immediately report the blood donation during 
this period, if any, to the investigator. 
11. Subjects should avoid driving vehicles, operating machinery, and working in high 
areas, etc., in consideration of possible treatment-emergent dizziness, or reduced 
attention, concentration, or reflex function. 


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7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study 
should be recorded in the case report form ([e]CRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.15. 
1. Pretreatment Event or AE 
The subject has experienced a pretreatment event (PTE) or AE that requires early 
termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
 Liver Function Test (LFT) Abnormalities 
 Study medication should be discontinued immediately with appropriate clinical 
follow-up until a subject’s laboratory profile has returned to normal or the value 
immediately after the informed consent (for PTEs), or the value before the initiation 
of the investigational drug* (for AEs). (See Section 9.1.9) if the following 
circumstances occur at any time during study medication treatment: 
* The value before the initiation of the study medication is defined as the value prior to the start of 
the run-in period in the preceding study for AEs occurred before first study medication 
administration in the treatment period in the preceding study, and as the value at baseline in the 
preceding study for AEs occurred after first study medication administration in the treatment 
period in the preceding study. 
 ALT or AST > 8 × ULN, or 
 ALT or AST > 5 × ULN and persists for more than 2 weeks, or 
 ALT or AST > 3 × ULN in conjunction with elevated total bilirubin >2 × ULN 
or international normalized ratio (INR) > 1.5, or 
 ALT or AST > 3 × ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
2. Significant protocol deviation 
The discovery after the first dose of study medication that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up 
The subject did not return to the clinic and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented. 
4. Voluntary withdrawal 
The subject wishes to withdraw from the study. The reason for withdrawal, if 
provided, should be recorded in the (e)CRF. 


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Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be 
recorded (i.e., withdrawal due to an AE or lack of efficacy). 
5. Study termination 
The sponsor, IRB, or regulatory agency terminates the study. 
6. Pregnancy 
The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn 
immediately. The procedure is described in Section 9.1.11. 
7. Lack of efficacy 
The investigator or sub-investigator has determined that the subject is not benefiting 
from investigational treatment; and, continued participation would pose an 
unacceptable risk to the subject. 
8. Other 
Note: The specific reasons should be recorded in the “specify” field of the (e)CRF. 
 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator or sub-investigator may terminate a subject’s study participation at any 
time during the study when the subject meets the study termination criteria described in 
Section 7.5. In addition, a subject may discontinue his or her participation without 
giving a reason at any time during the study. Should a subject’s participation be 
discontinued, the primary criterion for termination must be recorded by the investigator 
or sub-investigator. In addition, efforts should be made to perform all procedures 
scheduled for the Early Termination Visit. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, 
including important sections describing the management of clinical trial material. 
8.1 
Study Medication 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study medication refers to all or any of the drugs defined 
below. 
(1) Dosage Form and Manufacturing 
Drug substance code number: TVP-1012 
Nonproprietary name: rasagiline (INN) 
Chemical name: N-propargyl-1-(R)-aminoindan mesylate 
Table 8.a 
Study Medication 
Type of the drug 
Dosage form 
TVP-1012 1 mg tablet 
A white to yellowish white round shape tablet containing 
rasagiline, engraved with “
 on one surface. 
 
All the study medication were manufactured in 
  
(2) Packaging and Labeling 
Ten tablets of the TVP-1012 1 mg are encapsulated in an aluminum blister sheet and 19 
sheets of the TVP-1012 1 mg tablet are packed in a carton. 
The label affixed to the carton containing the investigational drug should include a 
description that the content is an investigational drug, name of the drug “TVP-1012 
1.0 mg tablet”, study number “TVP-1012/OCT-001”, the name and address of the 
sponsor, manufacturing number, number of the drugs, and storage. 
8.1.2 
Storage 
The investigational drug must be stored at 1°C to 30°C. 
All clinical trial material must be kept in an appropriate, limited-access, secure place 
until it is used or returned to the sponsor or designee for destruction. Investigational 
drug must be stored under the conditions specified on the label, and remain in the 


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original container until dispensed. A daily temperature log of the drug storage area must 
be maintained every working day. 
8.1.3 
Dose and Regimen 
The administration of the study medication will start on the day after VISIT 8 and the 
subjects will be orally administered 1 tablet of TVP-1012 1.0 mg once daily before or 
after breakfast ( at the same timing with the preceding study). 
The investigator or its designee will supply sufficient amount of the study medication 
required during the period between study visits. Subjects will be instructed to take study 
medication in the morning of study visits* and to bring unused study medications and 
blister sheets to the site at each study visit. Also, compliance of the study medication 
from the last study visit will be checked by the investigator or sub-investigator (see 
Section 9.2). 
* For the day the serum chemistry is scheduled, the study medication must be taken without having 
breakfast. In this case, deviation from the timing of dose (not before or after breakfast) will be 
permitted. 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a study subject, at a dose above that which is assigned to 
that individual subject according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an 
Overdose page of the (e)CRF, in order to capture this important safety information 
consistently in the database. AEs associated with an overdose will be documented on 
AE CRF(s) according to Section 10.0, PRETREATMENT EVENTS AND ADVERSE 
EVENTS. 
Serious adverse events (SAEs) of overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Investigational Drug Assignment and Dispensing Procedures 
The same investigational drug is used for all subjects at each study site where the study 
is conducted. The investigator or sub-investigator will assign the investigational drug 
allocated to each study site to the subjects according to the study procedure. 


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8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
Upon receipt of the procedures for handling, storage, and management of the 
investigational drug prepared by the sponsor, the investigational drug manager will 
appropriately manage all the drugs supplied by the sponsor. The investigator will also 
receive the same procedures from the sponsor. The procedures will define the processes 
necessary to ensure that receipt, handling, storage, management, and prescription of the 
sponsor-supplied drugs, as well as collection of the unused drugs from subjects and 
return to the sponsor or disposal of unused drugs should be performed appropriately and 
reliably. 
The investigational drug manager will return unused drugs to the sponsor immediately 
after the completion of the clinical study at the study site. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or sub-investigator 
whenever possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to tests, observations and evaluations at Week 
26 (VISIT 8) in the preceding study. 
The same identification code provided in the preceding study will be assigned and will 
be used throughout the study period. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
The same demographic information, medical history and medication history obtained in 
the preceding study will be used in this study. 
9.1.3 
Physical Examination Procedure 
A physical examination will consist of the following body systems:  
(1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) 
gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal 
system; (9) nervous system; (10) lymph nodes; (11) other.  
All subsequent physical examinations should assess clinically significant changes from 
the values obtained at baseline (VISIT 2). 
9.1.4 
Skin Examination 
A subject should be confirmed as not having melanoma in accordance with separately 
prepared study procedures. If melanoma is suspected, this subject must visit a 
dermatologist. 
 


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9.1.5 
Weight 
Weight will be collected in kilograms to 1 decimal place. 
9.1.6 
Vital Sign Procedure 
Vital signs will include body temperature (infra-axillary measurement), sitting 
systolic/diastolic (mmHg) blood pressure after resting more than 5 minutes, and pulse 
(bpm). 
9.1.7 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These 
may be prescribed by a physician or obtained by the subject over the counter. 
Concomitant medication is not provided by Takeda and all medication including vitamin 
supplements, over-the-counter medications, oral herbal preparations, and St. John’s 
Wort must be recorded in the (e)CRF. If any antiparkinsonian drug is taken, its dosage 
and unit per day must be obtained. 
9.1.8 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that 
are present at signing of informed consent in the preceding study. Concurrent medical 
conditions for this study are those investigated in the preceding study. 
9.1.9 
Procedures for Clinical Laboratory Samples 
Table 9.a lists the samples to be collected for each laboratory test. All samples will be 
collected after fasted for more than 8 hours, whenever possible, in accordance with 
acceptable laboratory procedures. The maximum volume of blood at any single visit is 
approximately 6 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Red blood cells 
Hemoglobin 
Hematocrit 
White blood cells with 
differential  
(neutrophil, eosinophil, 
monocyte, lymphocyte, 
and basophil) 
Platelets 
AST 
ALT 
γ-GTP 
ALP 
LDH 
Albumin 
Total protein 
Total bilirubin 
Total cholesterol 
Triglycerides 
Creatinine 
Blood urea nitrogen (BUN) 
Urine acid 
Creatine kinase 
Sodium 
Potassium 
Chlorine 
Calcium 
Phosphorus 
Protein (qualitative) 
Glucose (qualitative) 
Blood (qualitative) 
Ketone body (qualitative) 
Pregnancy Test (for female subjects of childbearing potential only) 
Urine hCG (qualitative) 
 
The central laboratory will perform laboratory tests for hematology, serum chemistries, 
and urinalysis. However, the urine hCG (qualitative) will be performed at each study 
site for women with childbearing potential. 
If subjects experience ALT or AST > 3 × ULN, follow-up laboratory tests (at a 
minimum, serum ALP, ALT, AST, total bilirubin, γ-GTP, and INR) should be performed 
within a maximum of 7 days and preferably within 48-72 hours after the abnormality 
was noted. (see Section 7.5 and 10.2.3) 
If the ALT or AST remains elevated > 3 × ULN on these 2 consecutive occasions, the 
investigator or sub-investigator must contact the sponsor for consideration of additional 
testing, close monitoring, possible discontinuation of study medication, discussion of 
the relevant subject details and possible alternative etiologies. 
The laboratory test results will be evaluated and maintained by the investigator or 
sub-investigator. And also, the investigator will maintain a copy of the reference ranges 
for the laboratory used. 


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9.1.10 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and for 1 
month after last dose of study medication, female subjects of childbearing potential 
who are sexually active or before menopause with a nonsterilized male partner must 
use adequate contraception. In addition they must be advised not to donate ova during 
this period. Subjects will be provided with information on acceptable methods of 
contraception as part of the subject informed consent process and will be asked to 
sign a consent form stating that they understand the requirements for avoidance of 
pregnancy, donation of ova during the course of the study. During the course of the 
study, regular urine hCG pregnancy tests will be performed only for women of 
childbearing potential and subjects will receive continued guidance with respect to 
the avoidance of pregnancy as part of the study procedures (Appendix A). 
Subjects also must have a negative urine hCG pregnancy test at each evaluation 
point. 
9.1.11 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued.  
If the pregnancy occurs during administration of active study medication, after the end 
of run-in period of the preceding study and within 1 month of the last dose of active 
study medication, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the Safety Information Emergency Call Center (contact listed 
specified in the appendix). 
Should the pregnancy occur during or after administration of blinded drug, the 
investigator or sub-investigator must inform the subject of their right to receive 
treatment information. If the subject chooses to receive unblinded treatment information, 
the individual blind should be broken by the investigator or sub-investigator. 
If the female subject agrees to the primary care physician (gynecologist) being informed, 
the investigator or sub-investigator should notify the primary care physician that the 
subject was participating in a clinical study at the time she became pregnant and provide 
details of treatment the subject received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome, using the pregnancy 
form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted. 


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9.1.12 ECG Procedure 
Standard 12-lead ECGs will be recorded under resting. The investigator or 
sub-investigator (or a qualified observer at the investigational site) will interpret the 
ECG using one of the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal and clinically significant. The following parameters 
will be recorded on the (e)CRF from the subject’s ECG trace: heart rate, RR interval, 
PR interval, QT interval, QRS interval, and QTcB interval. QTcF will be calculated by 
the sponsor. 
9.1.13 MDS-UPDRS 
The investigator or sub-investigator will assess the symptoms of Parkinson’s disease 
according to MDS-UPDRS (Part I: non-motor experiences of daily living, Part II: motor 
experiences of daily living, Part III: motor examination, Part IV: motor complications). 
The investigator or sub-investigator (hereinafter referred to as “evaluator”) responsible 
for evaluating MDS-UPDRS scores will undergo training on MDS evaluations prior to 
study conduct and should be accredited with a training certificate. Only evaluators with 
a training certificate are allowed to evaluate the MDS-UPDRS for the study. 
The evaluator will not evaluate subjects until he/she receives a training certificate for 
MDS evaluations. If the assigned evaluator is replaced (or added) during the study, a 
new evaluator should complete the aforementioned training and receive a training 
certificate for MDS evaluations before starting evaluations in the study. If a new 
evaluator has already received a training certificate for MDS evaluations, re-training 
will not be mandatory. 
In principle, the same subject will be evaluated by the same evaluator as in the 
preceding study throughout the study period. The evaluator will record evaluation 
results for each item in Table 9.b in the CRF. 


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Table 9.b 
MDS-UPDRS Score Sheet 
Part I 
3.1 
Speech 
(0, 1, 2, 3, 4, UR) 
 
Primary source of 
information 
□ Patient 
□ Caregiver 
□ Patient and  
   Caregiver 
3.2 
Facial expression 
(0, 1, 2, 3, 4, UR) 
3.3a 
Rigidity-Neck(b) 
(0, 1, 2, 3, 4, UR) 
3.3b 
Rigidity-RUE(b) 
(0, 1, 2, 3, 4, UR) 
1.1 
Cognitive 
impairment 
(0, 1, 2, 3, 4, UR) 
3.3c 
Rigidity-LUE(b) 
(0, 1, 2, 3, 4, UR) 
1.2 
Hallucinations and 
psychosis 
(0, 1, 2, 3, 4, UR) 
3.3d 
Rigidity-RLE(b) 
(0, 1, 2, 3, 4, UR) 
1.3 
Depressed mood 
(0, 1, 2, 3, 4, UR) 
3.3e 
Rigidity-LLE(b) 
(0, 1, 2, 3, 4, UR) 
1.4 
Anxious mood 
(0, 1, 2, 3, 4, UR) 
3.4a 
Finger tapping-Right hand (c) 
(0, 1, 2, 3, 4, UR) 
1.5 
Apathy 
(0, 1, 2, 3, 4, UR) 
3.4b 
Finger tapping-Left hand (c) 
(0, 1, 2, 3, 4, UR) 
1.6 
Features of DDS 
(0, 1, 2, 3, 4, UR) 
3.5a 
Hand movements-Right hand 
(c) 
(0, 1, 2, 3, 4, UR) 
3.5b 
Hand movements-Left hand (c) 
(0, 1, 2, 3, 4, UR) 
Questionnaire 
3.6a 
Pronation-supination 
movements-Right hand (c) 
(0, 1, 2, 3, 4, UR) 
 
Who is filling out 
this questionnaire: 
□ Patient 
□ Caregiver 
□ Patient and  
   Caregiver 
3.6b 
Pronation-supination 
movements-Left hand(c) 
(0, 1, 2, 3, 4, UR) 
3.7a 
Toe tapping-Right foot(c) 
(0, 1, 2, 3, 4, UR) 
3.7b 
Toe tapping-Left foot (c) 
(0, 1, 2, 3, 4, UR) 
1.7 
Sleep problems 
(0, 1, 2, 3, 4) 
3.8a 
Leg agility-Right leg (c) 
(0, 1, 2, 3, 4, UR) 
1.8 
Daytime sleepiness 
(0, 1, 2, 3, 4) 
3.8b 
Leg agility-Left leg(c) 
(0, 1, 2, 3, 4, UR) 
1.9 
Pain and other 
sensations 
(0, 1, 2, 3, 4) 
3.9 
Arising from chair 
(0, 1, 2, 3, 4, UR) 
3.10 
Gait 
(0, 1, 2, 3, 4, UR) 
1.10 
Urinary problems 
(0, 1, 2, 3, 4) 
3.11 
Freezing of gait 
(0, 1, 2, 3, 4, UR) 
1.11 
Constipation 
problems 
(0, 1, 2, 3, 4) 
3.12 
Postural stability 
(0, 1, 2, 3, 4, UR) 
1.12 
Light headedness 
on standing 
(0, 1, 2, 3, 4) 
3.13 
Posture 
(0, 1, 2, 3, 4, UR) 
1.13 
Fatigue 
(0, 1, 2, 3, 4) 
3.14 
Global spontaneity of 
movement(c) 
(0, 1, 2, 3, 4, UR) 
Part II 
2.1 
Speech 
(0, 1, 2, 3, 4) 
3.15a 
Postural tremor-Right hand(a) 
(0, 1, 2, 3, 4, UR) 
2.2 
Saliva and drooling 
(0, 1, 2, 3, 4) 
3.15b 
Postural tremor-Left hand(a) 
(0, 1, 2, 3, 4, UR) 
2.3 
Chewing and 
swallowing 
(0, 1, 2, 3, 4) 
3.16a 
Kinetic tremor-Right hand(a) 
(0, 1, 2, 3, 4, UR) 
2.4 
Eating tasks 
(0, 1, 2, 3, 4) 
3.16b 
Kinetic tremor-Left hand(a) 
(0, 1, 2, 3, 4, UR) 
2.5 
Dressing 
(0, 1, 2, 3, 4) 
3.17a 
Rest tremor amplitude-RUE(a) 
(0, 1, 2, 3, 4, UR) 
2.6 
Hygiene 
(0, 1, 2, 3, 4) 
3.17b 
Rest tremor amplitude-LUE(a) 
(0, 1, 2, 3, 4, UR) 
2.7 
Handwriting 
(0, 1, 2, 3, 4) 
3.17c 
Rest tremor amplitude-RLE(a) 
(0, 1, 2, 3, 4, UR) 
2.8 
Doing hobbies and 
other activities 
(0, 1, 2, 3, 4) 
3.17d 
Rest tremor amplitude-LLE(a) 
(0, 1, 2, 3, 4, UR) 
2.9 
Turning in bed 
(0, 1, 2, 3, 4) 
3.17e 
Rest tremor 
amplitude-Lip/jaw)(a) 
(0, 1, 2, 3, 4, UR) 
2.10 
Tremor(a) 
(0, 1, 2, 3, 4) 
2.11 
Getting out of bed, 
a car, or a deep 
chair 
(0, 1, 2, 3, 4) 
3.18 
Constancy of rest tremor(a) 
(0, 1, 2, 3, 4, UR) 
 
Were dyskinesias present during 
examination? 
□No 
□Yes 
2.12 
Walking and 
balance 
(0, 1, 2, 3, 4) 
 
If Yes, did these movements 
interfere with ratings? 
□No 
□Yes 
2.13 
Freezing 
(0, 1, 2, 3, 4) 
Part III 
 
Hoehn and Yahr Stage 
(0, 1, 2, 3, 4, 5) 
3a 
Is the patient on 
medication? 
□No 
□Yes  
Part IV 
4.1 
Time spent with dyskinesias 
(0, 1, 2, 3, 4) 


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3b 
Patient's clinical 
state 
□ON 
□OFF 
4.2 
Functional impact of 
dyskinesias 
(0, 1, 2, 3, 4) 
3c 
Is the patient on 
Levodopa? 
□No 
□Yes 
4.3 
Time spent in the OFF state 
(0, 1, 2, 3, 4) 
4.4 
Functional impact of 
fluctuations 
(0, 1, 2, 3, 4) 
3c1 
If yes, minutes 
since last dose: 
 
      
minutes 
4.5 
Complexity of motor 
fluctuations 
(0, 1, 2, 3, 4) 
4.6 
Painful OFF-state dystonia 
(0, 1, 2, 3, 4) 
0: Normal, 1: Slight, 2: Mild, 3: Moderate, 4: Severe, UR: Unable to Rate 
Bolded items represent MDS-UPDRS scores by category. Scores for each bolded item will be added according to 
Parts and the total score of individual Parts (I to IV) will be calculated. Scores for (a), (b), and (c) will be added 
separately and (a) tremor score, (b) muscle rigidity score, and (c) akinesia/bradykinesia score will be calculated. 
 
9.1.14 QOL assessment 
PDQ-39 is a self-administered questionnaire for QOL. Prior to the assessment, subjects 
will be provided instructions on how to record PDQ-39 and assess QOL during 1 month 
prior to the day of the assessment. Answers to all questions will be documented in the 
CRF. 
9.1.15 Documentation of Screen Failure 
The investigator should complete the (e)CRF for the subject who signed the informed 
consent and withdrawn from the study before randomization. 
For subjects discontinued the study before the initiation of the investigational drug in 
this study, the date of signing informed consent, date of birth, sex, eligibility, reason for 
withdrawal, AE assessment (if any, it must be collected as an AE occurred in the 
preceding study), concomitant medications, and the date of the last physical 
examination/evaluations must be recorded in the (e)CRF. 
The primary reason for screen failure is recorded in the (e)CRF using the following 
categories: 
• PTE/AEs 
• Did not meet inclusion criteria or did meet exclusion criteria <specify reason>. 
• Significant protocol deviation.  
• Lost to follow-up. 
• Voluntary withdrawal <specify reason>. 
• Study termination. 
• Other <specify reason>. 
Subject numbers assigned to subjects who fail screening should not be reused. 


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9.1.16 Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria 
are eligible for entrance into the study. If the subject is found to be not eligible for the 
study, the investigator or sub-investigator should record the primary reason for failure 
on the applicable (e)CRF. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be instructed to bring unused investigational drugs and blister sheets to the 
site at each study visit. Also, compliance of the study medication from the last study 
visit will be checked by the investigator or sub-investigator. 
All subjects should be instructed about the dosing requirement during study contacts. If 
a subject is persistently noncompliant with the sponsor-supplied drugs (50% of the 
allocated medication for the period since the last visit), it may be appropriate to 
withdraw the subject from the study. The authorized study personnel conducting the 
re-education must document the process in the subject source records. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix 
A. Assessments should be completed at the designated visit/time point(s). 
9.3.1 
Study Entrance/Week 26 in Treatment Period 
The subject informed consent must be obtained before initiation of 
tests/observations/evaluations scheduled at Week 26 (VISIT 8). 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria 
as described in Section 7.0, and subjects whose eligibility is confirmed will be enrolled 
in this study. See Section 9.1.15 for procedures for documenting screening failures. 
Procedures to be completed at Week 26 (VISIT 8; Day 175 - 189) include: 
• Dispense study medication 
9.3.2 
Treatment Period (Weeks 29, 32, 36, 40, and 46) 
9.3.2.1 Week 29 (Treatment Period) 
Week 29 (VISIT 9; Day 196-210) include: 
• Physical Examination Procedure 
• Vital Sign Procedure 


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• Documentation of Concomitant Medications 
• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.2.2 Week 32 (Treatment Period) 
Procedures to be completed at Week 32 (VISIT 10; Day 217-231) include: 
• Physical Examination Procedure 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 
• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 
• MDS-UPDRS 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.2.3 Week 36 (Treatment Period) 
Procedures to be completed at Week 36 (VISIT 11; Day 245-259) include: 
• Physical Examination Procedure 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 
• MDS-UPDRS 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.2.4 Week 40 (Treatment Period) 
Week 40 (VISIT 12; Day 273-287) include: 
• Physical Examination Procedure 
• Weight 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 


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• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 
• ECG Procedure 
• MDS-UPDRS 
• QOL 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.2.5 Week 46 (Treatment Period) 
Procedures to be completed at Week 46 (VISIT 13; Day 315-329) include: 
• Physical Examination Procedure 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 
• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 
• MDS-UPDRS 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.3 
Week 52 (Treatment Period) or Early Termination 
The following procedures will be performed in the last visit scheduled at Week 52 in the 
treatment period (VISIT 14; Day 357 - 371). For subjects who started the 
investigational drug adninistration in this study and are withdrawn from the study 
before the last visit at Week 52, the procedures scheduled at Week 52 should be 
performed within 7 days from the termination of study medication (the last 
administration day is defined as day 0), whenever possible. 
• Physical Examination Procedure 
• Skin examination 
• Weight 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 
• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 


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• ECG Procedure 
• MDS-UPDRS 
• QOL 
• AE assessment 
• Compliance of study medication 
For all subjects receiving study medication, the investigator must complete the End of 
Study (e)CRF page. 
9.3.4 
Post Study Care 
The study medication will not be available upon completion of the subject’s 
participation in the study. 
 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in the preceding study but prior to 
administration of study medication of the run-in period of the preceding study; it does 
not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions underlying disease should not be 
considered PTEs or AEs.) 
• 
Necessitate therapeutic intervention. 
• 
Require an invasive diagnostic procedure. 
• 
Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
• 
Be considered unfavorable by the investigator for any reason.  
Diagnoses vs signs and symptoms: 
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 


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Laboratory values and ECG findings: 
Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs 
if they are judged to be clinically significant (i.e., if some action or intervention is 
required or if the investigator or sub-investigator judges the change to be beyond the 
range of normal physiologic fluctuation). A laboratory re-test and/or continued 
monitoring of an abnormal value are not considered an intervention. In addition, 
repeated or additional noninvasive testing for verification, evaluation or monitoring of 
an abnormality is not considered an intervention. 
If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis 
only should be reported appropriately as a PTE or as an AE. 
Pre-existing conditions (disease or symptom present before signing of the informed 
consent in the preceding study): 
Pre-existing conditions (present at the time of signing of informed consent in the 
preceding study) are considered concurrent medical conditions and should NOT be 
recorded as PTEs or AEs. Baseline evaluations (e.g., laboratory tests, ECG, X-rays etc.) 
immediately after signing of informed consent in the preceding study should NOT be 
recorded as PTEs unless related to study procedures. However, if a subject experiences 
an abnormality (e.g., internal bleeding due to blood collection) related to the procedures 
for the baseline tests/observations in the preceding study, the abnormality should be 
recorded as a PTE on the (e)CRF. If the subject experiences a worsening or 
complication of such a concurrent condition, the worsening or complication should be 
recorded appropriately as a PTE (worsening or complication occurs before start of study 
medication) or an AE (worsening or complication occurs after start of study medication). 
The investigator or sub-investigator should ensure that the event term recorded captures 
the change in the condition (e.g., “worsening of hypertension”). 
If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence 
of an episode should only be captured as a PTE/AE if the episodes become more 
frequent, serious or severe in nature, that is, the investigator or sub-investigator should 
ensure that the AE term recorded captures the change in the condition from Baseline 
(e.g. “worsening of…”). If a subject has a degenerative concurrent condition (e.g., 
cataracts, rheumatoid arthritis), worsening of the condition should only be captured as a 
PTE/AE if occurring to a greater extent to that which would be expected. Again, the 


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investigator or sub-investigator should ensure that the AE term recorded captures the 
change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
If the subject experiences a worsening or complication of a PTE after starting 
administration of the study medication, the worsening or complication should be 
recorded appropriately as an AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (e.g., worsening of…”). 
If the subject experiences a worsening or complication of an AE after any change in 
study medication (including change from a study medication for the CCT-001 study to 
that for the OCT-001), the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent in the preceding study are not considered PTEs or AEs. However, if a 
preplanned procedure is performed early (e.g., as an emergency) due to a worsening of 
the pre-existing condition, the worsening of the condition should be captured 
appropriately as a PTE or an AE. Complications resulting from any planned surgery 
should be reported as AEs. 
Elective surgeries or procedures: 
Elective procedures performed where there is no change in the subject’s medical 
condition (e.g., cosmetic surgery) should not be recorded as PTEs or AEs, but should be 
documented in the subject’s source documents. Complications resulting from an elective 
surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be 
recorded as an AE. The investigator or sub-investigator must make the distinction 
between exacerbation of pre-existing illness and lack of therapeutic efficacy. 


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Overdose: 
Cases of overdose with any medication without manifested side effects are NOT 
considered PTEs or AEs, but instead will be documented on an Overdose page of the 
(e)CRF. Any manifested side effects will be considered PTEs or AEs and will be 
recorded on the AE page of the (e)CRF. 
10.1.4 SAEs 
A SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING*. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing 
hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately 
life threatening or fatal or does not result in hospitalization. 
 Includes any event or synonym described in the Takeda Medically Significant 
AE List (Table 10.a). 
*The term “life threatening” 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. 


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Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
(ARDS) 
Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizures (including convulsion and 
epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/mucocutaneous 
syndrome (Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial pneumonia) 
Neuroleptic malignant syndrome / malignant 
hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
Confirmed or suspected transmission of infectious 
agent by a medicinal product 
Confirmed or suspected endotoxin shock 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Sections 10.2.2 and 
10.3). 
10.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s 
usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual 
activities. 
 
10.1.6 Causality of AEs 
The relationship of each AE to the investigational drug will be assessed using the 
following categories: 
 


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Term 
Definition 
Clarification 
Unrelated 
This category applies to 
those adverse events which, 
after careful consideration, 
are clearly and 
incontrovertible due to 
extraneous causes (disease, 
environment, etc.) 
This category applied to those adverse events which, after 
careful consideration, are clearly and incontrovertible due to 
extraneous causes (disease, environment, etc.) 
Unlikely 
In general, this category 
can be considered 
applicable to those adverse 
events which, after careful 
medical consideration at 
the time they are evaluated, 
are judged to be unrelated 
to the test drug. 
An adverse experience may be considered unlikely related if 
or when (must have 2): 
・ It does not follow a reasonable temporal sequence from 
administration of the drug. 
・ It could readily have been produced by the subject’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject. 
・ It does not follow a known pattern of response to the test 
drug. 
・ It does not reappear or worsen when the drug is 
re-administered. 
Possibly 
This category applies to 
those adverse events for 
which, after carful medical 
consideration at the time 
they are evaluated, a 
connection with the test 
drug administration appears 
unlikely but cannot be 
ruled out with certainty. 
An adverse experience may be considered possibly related if 
or when (at least 2 of the following): 
・ It follows a reasonable temporal sequence from 
administration of the drug. 
・ It could not readily have been produced by the subject’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject. 
・ It follows a known pattern of response to the test drug. 
Probably 
This category applies to 
those adverse events which, 
after careful medical 
consideration at the time 
they are evaluated, are felt 
with a high degree of 
certainty to be related to 
the test drug. 
An adverse experience may be considered probably related if 
or when (at least 3 of the followings): 
・ It follows a reasonable temporal sequence from 
administration of the drug. 
・ It could not be reasonable explained by the known 
characteristics of the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy 
administered to the subject. 
・ It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an adverse 
event does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists (e.g., bone 
marrow depression, fixed drug eruptions, tardive 
dyskinesia). 
・ It follows a known pattern of response to the test drug. 
 
 
 
 
 
 


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10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the 
relationship should be assessed as Not Related. 
10.1.8 Start Date 
The date of onset of a PTE or an AE will be determined according to the following 
criteria. 
PTE or AE 
Date of onset 
Signs, symptoms, and diseases 
(diagnoses) 
The date on which the subject, the investigator or sub-investigator 
first noted the signs/symptoms of an AE. 
Asymptomatic diseases 
The date on which a definitive diagnosis is obtained through tests. 
The date on which a diagnosis is confirmed should be recorded, 
even when the test result indicates an old sign(s) of the disease, or 
an approximate time of onset. 
Worsening of concurrent 
diseases or PTEs 
Worsening of AEs ovserved in 
the preceding study 
The date on which the subject, the investigator or sub-investigator 
first noted the first worsening of disease/symptom. 
For PTEs: cases in which 
normal values at the time of 
screening (i.e., the first test after 
signing of the informed 
consent) in the preceding study 
are abnormal at the subsequent 
test; 
For AEs: cases in which 
abnormal test values are found 
at the test after the start of 
administration of the 
investigational drug 
The date on which a clinically abnormal laboratory parameter is 
observed. 


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For PTEs: cases in which 
abnormal test values are found 
at the first test after signing of 
the informed consent and they 
are found to have worsened at 
the subsequent test; 
For AEs: cases in which 
abnormal test values are found 
at the test after the start of 
administration of the 
investigational drug and they 
worsen at the subsequent test 
The date on which a clinically obvious increase/decrease in a 
laboratory parameter is confirmed based on the time profile of the 
parameter. 
 
10.1.9 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event 
resolved but with sequelae or the subject died. In the event that the stop date of AE/PTE 
is not comfirmed, AE/PTE will be determined to be continuing. 
10.1.10 Frequency 
Episodic AEs/PTE (e.g., constipation, diarrhoea, vomiting) or those which occur 
repeatedly over a period of consecutive days are intermittent. All other events are 
continuous. 
10.1.11 Action Concerning Study Medication 
Actions associated with the investigational drug will be classified or defined as follows: 
Drug withdrawn 
A study medication is stopped due to the particular AE (including 
discontinuation/withdrawal based on the subject’s own judgment). 
Dose not changed 
The particular AE did not require stopping a study medication.  
Cases in which administration of the investigational drug is discontinued or the 
dose is reduced or increased because of an AE other than the particular AE. 
Cases in which administration of the investigational drug is discontinued or its 
dose is reduced for a reason other than the AE, e.g., inadvertent behavior by the 
subject. 
Unknown 
Only to be used if it has not been possible to determine what action has been 
taken because of loss of follow-up. 
Not Applicable 
A study medication was stopped for a reason other than the particular AE, or 
dosing with study medication was already stopped before the onset of the AE. 


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10.1.12 Outcome 
The outcome of a PTE or an AE will be determined according to the following criteria: 
Category 
Criteria 
Recovered/Resolved 
・The sign and symptom disappeared or resolved. 
・Subject returned to first assessment status (the value before the administration 
of the investigational drug*) in the preceding study for AEs, or the value at 
the first test after signing of the informed consent in the preceding study for 
PTEs. 
Recovering/Resolving 
・The intensity is lowered by one or more stages. 
・The diagnosis or signs/symptoms has almost disappeared. 
・The abnormal laboratory value improved, but has not returned to the normal 
range or to the value before the administration of the investigational drug* in 
the preceding study (for AEs) or the value at the first test after signing of the 
informed consent in the preceding study (for PTEs). 
・The subject died from a cause other than the particular AE/PTE with the 
condition remaining “recovering/resolving” (no need to record the date of 
death). 
Not recovered 
/not resolved 
・There is no change in the diagnosis, signs or symptoms. 
・The intensity of the diagnosis, signs/ symptoms or laboratory value on the last 
day of the observed study period has got worse than when it started. 
・Is an irreversible congenital anomaly. 
・The subject died from another cause with the particular AE/PTE state 
remaining “Not recovered/not resolved” (no need to record the date of 
death). 
Resolved with 
sequelae 
・The subject recovered from an acute AE/PTE but was left with impairment 
which interrupts the subject’s usual activities. 
Fatal 
・PTE/AE directly related to death 
“Direct relationship with the PTE/AE” means that the PTE/AE caused the 
death or apparently contributed to the death. 
・Cases in which the outcome of the PTE/AE observed in the same subject is 
determined or assumed as not having directly caused the death are not 
documented as “fatal.” 
・If the outcome of the PTE/AE is “fatal,” the date of death should be 
documented. 
Unknown 
・The course of the AE/serious PTE cannot be followed up due to hospital 
change or residence change at the end of the subject’s participation in the 
study. 
 
* “The value before the administration of the investigational drug” means the value at the start of the 
study medications in the run-in period in the preceding study for the PTE/AE occurred before the 
initiation of administration for the treatment period in the preceding study, and the value at baseline for 
the AEs occurred after initiation of the investigational drug for the treatment period in the preceding 
study. 


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10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent 
to participate in the preceding study and continue until the subject is first administered 
study medication in the run-in period in the preceding study. For subjects who 
discontinue prior to study medication administration in the run-in period in the 
preceding study, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered 
study medication in this study. Routine collection of AEs will continue until tests 
scheduled at Week 52 in the treatment period (or at early termination). 
AEs occurred between at the end of the last laboratory tests in the preceding study 
(TVP-1012/CCT-001) and before initiation of administration in this study will be 
collected as AEs occurred in the preceding study and any AEs observed in the preceding 
study will be monitored continuously throughout this study. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator or sub-investigator will assess whether any 
subjective AEs have occurred. A neutral question, such as “How have you been feeling 
since your last visit?” may be asked. Subjects may report AEs occurring at any other 
time during the study.  
Subjects experiencing a serious PTE must be monitored until the symptoms subside and 
any clinically relevant changes in laboratory values have returned to the value at the 
first laboratory test after signing of informed consent of the preceding study or there is a 
satisfactory explanation for the change (persistent, irreversible PTE). Non-serious PTEs, 
related or unrelated to the study procedure, need not to be followed-up for the purposes 
of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically 
relevant changes in laboratory values have returned to baseline (to the value at the start 
of the run-in period for AEs occurred before the initiation of the study medications in 
the treatment period in the preceding study, or the value at baseline for AEs occurred 
after administration of the study medication in the treatment period in the preceding 


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study) or until there is a satisfactory explanation for the changes observed (persistent, 
irreversible PTE). All PTEs and AEs will be documented in the PTE/AE page of the 
(e)CRF, whether or not the investigator or sub-investigator concludes that the event is 
related to the drug treatment. The following information will be documented for each 
event: 
 
Event term 
 
Start and stop date 
 
Frequency 
 
Severity 
 
Investigator’s opinion of the causal relationship between the event and 
administration of study medications (Unrelated, Unlikely, Possibly, Probably) 
 
Action concerning study medication 
 
Outcome of event 
 
Investigator’s opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure 
 
Seriousness  
AEs and serious PTEs will be followed up until they have resolved or the investigator or 
sub-investigator judges that the follow-up is no longer necessary. 
10.2.2 Collection and Reporting of SAEs 
When a SAE occurs through the AE collection period it should be reported according to 
the following procedure. PTEs that meet the criteria for SAEs described in Section 
10.1.4 will be reported in a same manner to that for SAEs. 
A SAE should be reported to Safety Information Emergency Call Center (described in 
the separate contact information list) within 1 business day of first onset or subject’s 
notification of the event. The investigator should submit the completed SAE form 
within 10 calendar days to Safety Information Emergency Call Center. Also the original 
document of a Takeda SAE form must be submitted to the sponsor. 
The information to be reported within 1 business day should be completed as fully as 
possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as 
serious 


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• Subject identification number 
• Investigator’s or sub-investigator’s name 
• Name of the study medications 
• Causality assessment (relationship with the study medication or study 
procedure) 
Any SAE spontaneously reported to the investigator or sub-investigator following the 
AE collection period should be reported to the sponsor. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST > 3 × ULN and total bilirubin > 2 × ULN for 
which an alternative etiology has not been identified, the event should be recorded as a 
SAE and reported as per Section 10.2.2. The investigator or sub-investigator must 
contact the Medical Monitor for discussion of the relevant subject details and possible 
alternative etiologies, such as acute viral hepatitis A or B, other acute liver disease, or a 
history or concurrent medical condition. Follow-up laboratory tests as described in 
Section 9.1.9 must also be performed. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later 
date, the investigator or sub-investigator should complete a follow-up SAE form or 
provide other written documentation immediately to the sponsor or Safety Information 
Emergency Call Center. Copies of any relevant data from the hospital notes (e.g., ECGs, 
laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested by the sponsor or IRB. 
All SAEs should be followed up until resolution or permanent outcome of the event. 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
investigators, IRBs, and the head of the study site, as applicable. Relative to the first 
awareness of the event by/or further provision to the sponsor or sponsor’s designee 
(CRO), SUSARs will be submitted to the regulatory authorities as expedited reports 
within 7 days for fatal and life-threatening events and 15 days for other serious events, 
unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current 


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benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration 
or in the overall conduct of the trial. The investigational site also will forward a copy of 
all expedited reports to his or her IRB. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint 
committee will be used in this study. 
 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data 
Management Plan. AEs, PTEs, medical history, and concurrent conditions will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization (WHO) Drug Dictionary. 
12.1 
CRFs (Electronic and Paper) 
Completed (e)CRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to (e)CRFs. The 
sponsor will make arrangements to train the investigator, sub-investigator, and study 
coordinator in the use of the (e)CRF. These forms are used to transmit the information 
collected in the performance of this study to the sponsor and regulatory authorities. 
(e)CRFs must be completed directly recording data in English. 
Corrections to (e)CRFs are recorded in an audit trail that captures the old information, 
the new information, identification of the person making the correction, the date the 
correction was made, and the reason for change. 
The principal investigator must review the (e)CRFs for completeness and accuracy and 
must sign and date the appropriate (e)CRFs as indicated. Furthermore, the investigator 
must retain full responsibility for the accuracy and authenticity of all data entered on the 
(e)CRFs. 
The following data will not be recorded directly into the (e)CRFs. 
1) Laboratory Test Results Measured at Central Laboratory 
After the database lock of clinical study database, any change of, modification of or 
addition to the data on the (e)CRFs should be made by the investigator sub-investigator 
with use of change and modification records of CRFs (Data Clarification Form) 
provided by the sponsor. The principal investigator must review the Data Clarification 
Form for completeness and accuracy, and must sign, or sign and seal, and date the form. 
(e)CRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by study monitors. The sponsor or its designee will be permitted to 
review the subject’s medical and hospital records pertinent to the study to ensure 
accuracy of the (e)CRFs. The completed (e)CRFs are the sole property of the sponsor 
and should not be made available in any form to third parties, except for authorized 
representatives of appropriate governmental health or regulatory authorities, without 
written permission of the sponsor. 


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12.2 
Record Retention 
The investigator or the head of the site agrees to keep the records stipulated in Section 
12.1 and those documents that include (but are not limited to) the study-specific 
documents, the identification log of all participating subjects, medical records, source 
worksheets, all original signed and dated informed consent forms, copies of all paper 
CRFs, electronic copy of (e)CRFs, including the audit trail, and detailed records of drug 
disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. In addition, the investigator and the head of the site are required to retain 
essential relevant documents until the day as 1) or 2) below, whichever comes later. 
However, if the sponsor requests a longer time period for retention, the head of the site 
should discuss how long and how to retain those documents with the sponsor.  
1) The day on which marketing approval of the investigational drug is obtained (or 
the day 3 years after the date of notification in the case that the investigation is 
discontinued.) 
2) The day 3 years after the date of early termination or completion of the clinical 
study.  
In addition, the investigator and the head of the institution should retain the essential 
relevant documents until the receipt of a sponsor-issued notification to state the 
retention is no longer required. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
The analyses for this study will be performed using pooled data from the preceding 
study and this study, in principle, based on data obtained after administration of 
TVP-1012. 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock of 
this study. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to database lock of this study. This 
review will assess the accuracy and completeness of the study database, subject 
evaluability, and appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
In this study, two kinds of analysis sets are defined: full analysis set (FAS) and safety 
analysis set. The safety analysis set, the analysis set used for safety analysis, will be 
defined as “all subjects who were received at least one dose of TVP-1012.” The 
definition of each analysis set will be described in the Handling Rules for Analysis 
Data. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the 
rules for handling data, consulting a medical expert as needed. If necessary, the 
Handling Rules for Analysis Data will be supplemented with new handling rules that 
were not discussed at the planning stage. The Handling Rules for Analysis Data must be 
finalized prior to database lock. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized overall and by 
treatment group of the preceding study using the safety analysis set. 
13.1.3 Efficacy Analysis 
(1) [Secondary endpoint and its analytical method] 
[Secondary endpoint] 
• 
MDS-UPDRS Part II＋Part III total score 
[Analysis method] 


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The following analysis will be performed for FAS. 
Descriptive statistics (number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles) and two-sided 95% confidence intervals of means will be 
provided for the MDS-UPDRS Part II + Part III total score at each visit and the change 
from baseline in the MDS-UPDRS Part II + Part III total score at each visit of the 
treatment period by treatment group in the preceding study. 
(2) Additional efficacy endpoints 
Refer to Section 5.2.3. 
(3) Method of data conversion and handling of missing data 
Details will be described in the Handling Rules for Analysis Data and the Statistical 
Analysis Plan. 
(4) Significance level and confidence coefficient 
• 
Confidence coefficient: 95% (two-sided) 
13.1.4 Safety Analysis 
(1) Primary endpoint and its analytical method 
[Primary endpoint] 
• 
Adverse events 
[Analytical methods] 
The following analyses will be based on the safety analysis set. 
A treatment-emergent adverse event (TEAE) is defined as an adverse event whose date 
of onset occurs on or after the start of treatment period study drug in the preceding 
study. 
TEAEs whose date of onset occurs on or after the start of TVP-1012 will be coded 
using the MedDRA dictionary. The frequency distribution will be provided using the 
system organ class and the preferred term for each treatment group of the preceding 
study as follows: 
 All TEAEs 
 Drug-related TEAEs 
 Intensity of TEAEs 


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 Intensity of drug-related TEAEs 
 TEAEs leading to study drug discontinuation 
 Serious TEAEs 
 TEAEs over time 
(2) Secondary endpoints and their analytical methods 
[Secondary endpoints] 
 Laboratory test results, vital signs, 12-lead ECGs and weight 
[Analytical methods] 
The following analyses will be based on the safety analysis set. 
For continuous variables, the observed values and the changes from baseline will be 
summarized by treatment group of the preceding study for each visit using descriptive 
statistics. 
Case plots will also be presented for the observed values by treatment group of the 
preceding study. 
For categorical variables, shift tables showing the number of subjects in each category 
at baseline and each post-baseline visit will be provided for each treatment group of the 
preceding study. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
Number of subjects to be enrolled in this study: approximately 182 
[Justification of Sample size] 
In the preceding study, the planned number of subjects to be randomized was a total of 
240 (120 per group) and the planned number of subjects evaluable for the primary 
endpoint (change in the MDS-UPDRS Part II + Part III total score from baseline to 
Week 26 of the treatment period (LOCF)) was a total of 220 (110 per group). 
Since this study is a long-term extension study in patients with early Parkinson’s disease 
who have completed the 26-week treatment period in the preceding study, considering 
the potential dropouts in the preceding study, approximately 182 subjects will be 
enrolled in this study. 


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In addition, considering the potential dropouts in this study and in the preceding study, 
it is estimated that 155 subjects will be treated with 1 mg of TVP-1012 for 26 weeks 
and 59 subjects for 52 weeks. 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure 
that all aspects of the protocol are followed. Source documents will be reviewed for 
verification of data recorded on the (e)CRFs. Source documents are defined as original 
documents, data, and records. The investigator and the head of the institution guarantee 
access to source documents by the sponsor or its designee and by the IRB 
All aspects of the study and its documentation will be subject to review by the sponsor 
or designee, including but not limited to the Investigator’s Binder, study medication, 
subject medical records, informed consent documentation, and review of (e)CRFs and 
associated source documents. It is important that the investigator or sub-investigator and 
other study personnel are available during the monitoring visits and that sufficient time 
is devoted to the process. 
14.2 
Protocol Deviations 
The investigator or sub-investigator can deviate and change from the protocol for any 
medically unavoidable reason, for example, to eliminate an immediate hazard to study 
subjects, without a prior written agreement with the sponsor or a prior approval from 
IRB. In the event of a deviation or change, the principal investigator should notify the 
sponsor and the head of the site of the deviation or change as well as its reason in a 
written form, and then retain a copy of the written form. When necessary, the principal 
investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the 
head of the site as soon as possible and an approval from IRB should be obtained. 
The investigator or sub-investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or 
designees. In this circumstance, the sponsor-designated auditor will contact the site in 
advance to arrange an auditing visit. The auditor may ask to visit the facilities where 
laboratory samples are collected, where the medication is stored and prepared, and any 
other facility used during the study. In addition, there is the possibility that this study 
may be inspected by regulatory agencies, including those of foreign governments (e.g., 
the FDA, the United Kingdom Medicines and Healthcare products Regulatory Agency 
[MHRA]). If the study site is contacted for an inspection by a regulatory body, the 


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sponsor should be notified immediately. The investigator and the head of the institution 
guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each 
investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the “Responsibilities of 
the Investigator” that are listed in Appendix B. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable local requirements of each 
participating region. The sponsor or designee will require documentation noting all 
names and titles of members who make up the respective IRB. If any member of the 
IRB has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the 
respective IRB for the protocol’s review and approval. This protocol, the Investigator’s 
Brochure, a copy of the informed consent form, and, if applicable, subject recruitment 
materials and/or advertisements and other documents required by all applicable laws 
and regulations, must be submitted to a central or local IRB for approval. The IRB’s 
written approval of the protocol and subject informed consent must be obtained and 
submitted to the sponsor or designee before commencement of the study (i.e., before 
shipment of the sponsor-supplied drug or before initiation of the run-in period). The 
IRB approval must refer to the study by exact protocol title, number, and version date; 
identify versions of other documents (e.g., informed consent form) reviewed; and state 
the approval date. The sponsor will notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation. Until the site receives notification no 
protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may 
include notification to the IRB regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety 
reporting requirements, reports and updates regarding the ongoing review of the study at 
intervals specified by the respective IRB, and submission of the investigator’s final 
status report to IRB. All IRB approvals and relevant documentation for these items must 
be provided to the sponsor or its designee. 


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Subject incentives should not exert undue influence for participation. Payments to 
subjects must be approved by the IRB and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described 
in the Declaration of Helsinki and the ICH Guidelines for GCP and will be in 
accordance with all applicable laws and regulations. The informed consent form and the 
subject information sheet describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information (to the third party 
including overseas) for purposes of conducting the study. The informed consent form 
and the subject information sheet further explains the nature of the study, its objectives, 
and potential risks and benefits. The informed consent form will detail the requirements 
of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the 
informed consent form and the subject information sheet. The informed consent form 
and the subject information sheet must be approved by both the IRB and the sponsor 
prior to use. 
The informed consent form and the subject information sheet must be written in a 
language fully comprehensible to the prospective subject. It is the responsibility of the 
investigator or sub-investigator to explain the detailed elements of the informed consent 
form and the subject information sheet to the subject. Information should be given in 
both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the study 
and (2) decide whether or not to participate in the study. If the subject determines he or 
she will participate in the study, then the informed consent form must be signed and 
dated by the subject at the time of consent and prior to the subject entering into the 
study. The subject should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator or sub-investigator must also sign and 
date the informed consent form at the time of consent and prior to subject entering into 
the study. 
Once signed, the original informed consent form will be stored in the investigator’s site 
file. The investigator or sub-investigator must document the date the subject signs the 


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informed consent in the subject’s medical record. Copies of the signed informed consent 
form shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects in 
the same manner as the original informed consent. The date the revised consent was 
obtained should be recorded in the subject’s medical record, and the subject should 
receive a copy of the revised informed consent form. 
 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, a subject’s source data 
will only be linked to the sponsor’s clinical study database or documentation via a 
unique identification number. As permitted by all applicable laws and regulations, 
limited subject attributes, such as sex, age, or date of birth may be used to verify the 
subject and accuracy of the subject’s unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, 
the sponsor requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (e.g., FDA, MHRA, Pharmaceuticals and 
Medical Devices Agency [PMDA]), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, 
admission and discharge summaries for hospital admissions occurring during a subject’s 
study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent process 
(see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (i.e., subject name, address, and 
other identifier fields not collected on the subject’s [e]CRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data 
derived by the investigator from the study. During the study, only the sponsor may make 
study information available to other study investigators or to regulatory agencies, except 
as required by law or regulation. Except as otherwise allowable in the clinical study site 


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agreement, any public disclosure (including publicly accessible websites) related to the 
protocol or study results is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 
The investigator or sub-investigator needs to obtain a prior written approval from the 
sponsor to publish any information from the study externally such as to a professional 
association.  
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely 
manner and to comply with applicable law, regulation and guidance, Takeda will, at a 
minimum register all clinical trials conducted in patients that it sponsors anywhere in 
the world on publicly accessible websites, JAPIC-CTI, before trial initiation. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of this clinical trial, regardless of outcome on publicly 
accessible websites, JAPIC-CTI, as required by applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable 
to the site where the subject is participating. If a local underwriter is required, then the 
sponsor or sponsor’s designee will obtain clinical study insurance against the risk of 
injury to clinical study subjects.  
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator or sub-investigator has 
questions regarding this policy, he or she should contact the sponsor or sponsor’s 
designee. 


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24 March 2016
 
CONFIDENTIAL 
16.0 
REFERENCES 
[1] 
Parkinson’s disease and related diseases (3) Parkinson’s Disease (subsidized by 
government), Japan Intractable Diseases Information Center: Japan Intractable 
Diseases Research Foundation/Japan Intractable Diseases Information Center, 
http://www.nanbyou.or.jp/entry/169 (2014/10/30 accessed) 
[2] 
Preparation Committee for Guidelines on Parkinson’s Disease, Japanese Society 
of Neurology, “Practical Guidelines for Parkinson’s Disease 2011” Igaku Shoin, 
2011. 
[3] 
Schapira AH. Treatment options in the modern management of Parkinson disease. 
Arch Neurol. 2007; 64(8): 1083-1088 
[4] 
Schapira AH. Olanow CW. Drug selection and timing of initiation of treatment in 
early Parkinson’s disease. Ann Neurol. 2008; 64(Suppl 2): S47-55 
[5] 
 
 
[6] 
 
 
 
[7] 
 
 
 
 
 
 


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Appendix A Schedule of Study Procedures 
Study Week (a) 
Treatment period 
W26 
W29 
W32 
W36 
W40 
W46 
W52/ 
Early 
Termination (b) 
VISIT Number (c) 
8 
9 
10 
11 
12 
13 
14 
Study Day(d) (Day) 
182 
203 
224 
252 
280 
322 
364 
Visit Windows (d) (Days) 
175 to 
189 
196 to 
210 
217 to 
231 
245 to 
259 
273 to 
287 
315 to 
329 
357 to  
371 
Informed consent 
X (e) 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Physical examination 
X (f) 
X 
X 
X 
X 
X 
X 
Skin examination 
X (f) 
 
 
 
 
 
X 
Weight  
X (f) 
 
 
 
X 
 
X 
Vital signs 
X (f) 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X (f) 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests (g) 
X (f) 
X 
X 
 
X 
X 
X 
ECG 
X (f) 
 
 
 
X 
 
X 
MDS-UPDRS 
X (f) 
 
X 
X 
X 
X 
X 
QOL assessment 
X (f) 
 
 
 
X 
 
X 
Drug compliance 
X (f) 
X 
X 
X 
X 
X 
X 
Dispense investigational drug 
X 
X 
X 
X 
X 
X 
 
AE assessment(h) 
X (f) 
X 
X 
X 
X 
X 
X 
(a) The study visit weeks in this study will be counted from the start of the treatment period in the 
preceding study. 
(b) For subjects withdrawn from the study after the initiation of the investigational drug in this study and 
before Week 52 of the treatment period, the tests, observations, and assessments scheduled for Week 
52 of the treatment period should be performed within 7 days following discontinuation of treatment, 
whenever possible (the day of the last dose regarded as 0 day). 
(c) Visit numbers in this study will be continued from the preceding study. 
(d) Day 1 is defined as the day of first study medication administration for the treatment period in the 
preceding study. 
(e) Informed consent for this study must be obtained prior to tests, observations, and assessments at Week 
26 of the treatment period in the preceding study. 
(f) Results of the tests, observations, and assessments at Week 26 of the treatment period in the preceding 
study will be used also for this study. 
(g) To be measured after fasting for at least 8 hours whenever possible. Women of childbearing potential 
will undergo pregnancy test as well. 
(h) AE collection in this study will begin at the initiation of the investigational drug in this study, and 
continued until Week 52 of the treatment period or early termination. AEs occurring between the final 
assessment in the preceding study and the initiation of the investigational drug in this study will be 
captured by the preceding study. AEs that occurred during the preceding study and persisted into this 
study will be followed up in this study as well. 
 
 


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Appendix B Responsibilities of the Investigator 
1. Conduct the appropriate study in accordance with the protocol and GCP 
considering the rights, safety and wellbeing of human subjects. 
2. When a part of the important activities related to the study are delegated to the 
sub-investigator or the study collaborator, prepare the lists of activities to be 
delegated and responsible personnel, submit the lists to the director of the site in 
advance to get them accepted. 
3. Prepare a written informed consent form and other written information, and update 
as appropriate. 
4. Confirm the contents of the clinical study agreement. 
5. Provide necessary information on the protocol, medications and responsibilities of 
individual personnel to the sub-investigator and study collaborator, and provide 
guidance and supervision. 
6. Screen subjects who meet the requirements of the protocol, provide the explanation 
of the study in writing and obtain the written consent. 
7. Assume responsibility for all the medical judgment related to the study. 
8. Ensure in collaboration with the director of the site that sufficient information on all 
clinically significant adverse events related to the study are provided to subjects 
throughout and beyond the period when subjects participate in the study. 
9. If a subject consults other medical institution or other department, notify the 
physician of the medical institution or department of the subject’s participation in 
the study, as well as the end and termination of the study in writing, and document 
such records. 
10. In case of urgent report of a SAE, immediately notify the director of the site and the 
sponsor in writing. 
11. Determine the need of emergency key code blinding of a subject in case of 
emergency. 
12. Prepare correct and complete (e)CRFs, and submit them to the sponsor with 
electronic signature. 
13. Check and confirm the contents of (e)CRFs prepared by the sub-investigator or 
transcribed from the source data by the study collaborator, and submit them to the 
sponsor with electronic signature. 
14. Discuss any proposal from the sponsor including update of the protocol. 
15. Notify the director of the site of the end of the study in writing. 


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Appendix C Detailed Description of Amendments to Text 
Amendments made from the Amendment1 of this study protocol are listed below. 
 
Page 60, 13.1.3 Efficacy Analysis 
Existing Text 
Descriptive statistics (number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles) and two-sided 95% confidence intervals of means will be 
provided for the MDS-UPDRS Part II + Part III total score at each visit and the change 
from baseline in the MDS-UPDRS Part II + Part III total score at each visit of the 
treatment period by treatment group in the preceding study. 
Revised Text 
Descriptive statistics (number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles) and two-sided 95% confidence intervals of means will be 
provided for the MDS-UPDRS Part II + Part III total score at each visit and the change 
from baseline in the MDS-UPDRS Part II + Part III total score at each visit of the 
treatment period by treatment group in the preceding study. 
 
Rationale for Amendment 
Described maintenance 
 


TVP-1012 
TVP-1012/OCT-001 
Page 1 of 74
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16 December 2014
 
CONFIDENTIAL 
PROTOCOL 
<Title> 
A Multicenter, Open-label, Long-term, Extension, Phase 3 Study  
to Evaluate the Safety and Efficacy of TVP-1012 at 1 mg  
in Early Parkinson's Disease Patients Not Treated with Levodopa 
 
<Short Title> 
A Phase 3, Long-term, Extension Study of TVP-1012 (1 mg)  
in Early Parkinson’s Disease Patients 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Japan 
Study Number: 
TVP-1012/OCT-001 
Amendment No 
Amendment 1 
IND Number: 
Not Applicable 
EudraCT Number 
Not Applicable 
Compound: 
TVP-1012 (INN: Rasagiline) 
Date: 
16 December 2014 
 
Amendment History  
Date 
Amendment Number 
Region 
25 November 2014 
First edition 
All sites 
16 December 2014 
Amendment 1 
All sites 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without 
written authorization from Takeda except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered. Furthermore, the information is only meant for review 
and compliance by the recipient, his or her staff, and applicable institutional review committee and 
regulatory agencies to enable conduct of the study. 


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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
A separate contact information list will be provided to each site. 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation E6 Good Clinical Practice: 
Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations. 
 


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16 December 2014
 
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TABLE OF CONTENTS 
2.0 
STUDY SUMMARY ............................................................................................ 8 
3.0 
LIST OF ABBREVIATIONS ............................................................................. 11 
4.0 
INTRODUCTION ............................................................................................... 12 
4.1 
Background .................................................................................................... 12 
4.2 
Rationale for the Proposed Study .................................................................. 15 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 16 
5.1 
Objectives ...................................................................................................... 16 
5.1.1 
Primary Objective(s) ............................................................................. 16 
5.1.2 
Secondary Objectives(s) ........................................................................ 16 
5.2 
Endpoints ....................................................................................................... 16 
5.2.1 
Primary Endpoint .................................................................................. 16 
5.2.2 
Secondary Endpoints ............................................................................. 16 
5.2.3 
Additional Endpoints ............................................................................. 16 
6.0 
STUDY DESIGN AND DESCRIPTION ........................................................... 17 
6.1 
Study Design ................................................................................................. 17 
6.2 
Justification for Study Design, Dose, and Endpoints .................................... 19 
6.2.1 
Justification for Study Subject .............................................................. 19 
6.2.2 
Justification for Study Design ............................................................... 19 
6.2.3 
Justification for Dose Regimen ............................................................. 19 
6.2.4 
Justification for Treatment Period ......................................................... 20 
6.2.5 
Justification for Endpoints..................................................................... 20 
6.3 
Premature Termination or Suspension of Study or Investigational Site ....... 20 
6.3.1 
Criteria for Premature Termination or Suspension of the Study ........... 20 
6.3.2 
Criteria for Premature Termination or Suspension of Investigational 
Sites ....................................................................................................... 21 
6.3.3 
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Site(s) ........................................ 21 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS .......................................................................................................... 22 
7.1 
Inclusion Criteria ........................................................................................... 22 


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7.2 
Exclusion Criteria .......................................................................................... 23 
7.3 
Excluded Medications and Treatments.......................................................... 23 
7.4 
Diet, Fluid, Activity Control ......................................................................... 26 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................. 28 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject ......................... 29 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .......................................... 30 
8.1 
Study Medication ........................................................................................... 30 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ...................... 30 
8.1.2 
Storage ................................................................................................... 30 
8.1.3 
Dose and Regimen................................................................................. 31 
8.1.4 
Overdose ................................................................................................ 31 
8.2 
Investigational Drug Assignment and Dispensing Procedures...................... 31 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs ........................ 32 
9.0 
STUDY PLAN .................................................................................................... 33 
9.1 
Study Procedures ........................................................................................... 33 
9.1.1 
Informed Consent Procedure ................................................................. 33 
9.1.2 
Demographics, Medical History, and Medication History Procedure .. 33 
9.1.3 
Physical Examination Procedure ........................................................... 33 
9.1.4 
Skin Examination .................................................................................. 33 
9.1.5 
Weight ................................................................................................... 34 
9.1.6 
Vital Sign Procedure ............................................................................. 34 
9.1.7 
Documentation of Concomitant Medications........................................ 34 
9.1.8 
Documentation of Concurrent Medical Conditions .............................. 34 
9.1.9 
Procedures for Clinical Laboratory Samples......................................... 34 
9.1.10 
Contraception and Pregnancy Avoidance Procedure ............................ 36 
9.1.11 
Pregnancy .............................................................................................. 36 
9.1.12 
ECG Procedure ...................................................................................... 37 
9.1.13 
MDS-UPDRS ........................................................................................ 37 
9.1.14 
QOL assessment .................................................................................... 39 
9.1.15 
Documentation of Screen Failure .......................................................... 39 
9.1.16 
Documentation of Study Entrance ........................................................ 40 


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9.2 
Monitoring Subject Treatment Compliance .................................................. 40 
9.3 
Schedule of Observations and Procedures .................................................... 40 
9.3.1 
Study Entrance/Week 26 in Treatment Period ...................................... 40 
9.3.2 
Treatment Period (Weeks 29, 32, 36, 40, and 46) ................................. 40 
9.3.3 
Week 52 (Treatment Period) or Early Termination .............................. 42 
9.3.4 
Post Study Care ..................................................................................... 43 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ................................ 44 
10.1 
Definitions ..................................................................................................... 44 
10.1.1 
PTEs ...................................................................................................... 44 
10.1.2 
AEs ........................................................................................................ 44 
10.1.3 
Additional Points to Consider for PTEs and AEs ................................. 44 
10.1.4 
SAEs ...................................................................................................... 47 
10.1.5 
Severity of PTEs and AEs ..................................................................... 48 
10.1.6 
Causality of AEs .................................................................................... 48 
10.1.7 
Relationship to Study Procedures.......................................................... 50 
10.1.8 
Start Date ............................................................................................... 50 
10.1.9 
Stop Date ............................................................................................... 51 
10.1.10 Frequency .............................................................................................. 51 
10.1.11 Action Concerning Study Medication ................................................... 51 
10.1.12 Outcome ................................................................................................ 52 
10.2 
Procedures ..................................................................................................... 53 
10.2.1 
Collection and Reporting of AEs .......................................................... 53 
10.2.2 
Collection and Reporting of SAEs ........................................................ 54 
10.2.3 
Reporting of Abnormal Liver Function Tests ....................................... 55 
10.3 
Follow-up of SAEs ........................................................................................ 55 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities .. 55 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................. 57 
12.0 
DATA HANDLING AND RECORDKEEPING ................................................ 58 
12.1 
CRFs (Electronic and Paper) ......................................................................... 58 
12.2 
Record Retention ........................................................................................... 59 
13.0 
STATISTICAL METHODS ............................................................................... 60 


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13.1 
Statistical and Analytical Plans ..................................................................... 60 
13.1.1 
Analysis Sets ......................................................................................... 60 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ............ 60 
13.1.3 
Efficacy Analysis .................................................................................. 60 
13.1.4 
Safety Analysis ...................................................................................... 61 
13.2 
Interim Analysis and Criteria for Early Termination .................................... 62 
13.3 
Determination of Sample Size ....................................................................... 62 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 64 
14.1 
Study-Site Monitoring Visits ......................................................................... 64 
14.2 
Protocol Deviations ....................................................................................... 64 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections .................... 64 
15.0 
ETHICAL ASPECTS OF THE STUDY ............................................................. 66 
15.1 
IRB Approval ................................................................................................ 66 
15.2 
Subject Information, Informed Consent, and Subject Authorization ............ 67 
15.3 
Subject Confidentiality .................................................................................. 68 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy .................... 68 
15.4.1 
Publication and Disclosure .................................................................... 68 
15.4.2 
Clinical Trial Registration ..................................................................... 69 
15.4.3 
Clinical Trial Results Disclosure ........................................................... 69 
15.5 
Insurance and Compensation for Injury ........................................................ 69 
16.0 
REFERENCES .................................................................................................... 70 
 


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LIST OF IN-TEXT TABLES 
Table 7.a 
Excluded Medications and Treatments.................................................... 24 
Table 8.a 
Study Medication ..................................................................................... 30 
Table 9.a 
Clinical Laboratory Tests ........................................................................ 35 
Table 9.b 
MDS-UPDRS Score Sheet ...................................................................... 38 
Table 10.a 
Takeda Medically Significant AE List .................................................... 48 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ..................................................................... 18 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ................................................................. 71 
Appendix B 
Responsibilities of the Investigator ......................................................... 72 
Appendix C 
Detailed Description of Amendments to Text ......................................... 73 
 


TVP-1012 
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Page 8 of 74
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16 December 2014
 
CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
TVP-1012 
Title of Protocol: 
A Multicenter, Open-label, Long-term, Extension, Phase 
3 Study to Evaluate the Safety and Efficacy of 
TVP-1012 at 1 mg in Early Parkinson's Disease Patients 
Not Treated with Levodopa 
(An extension study from TVP-1012/CCT-001) 
IND No.: 
Not applicable 
EudraCT No.: 
Not applicable 
Study Number: TVP-1012/OCT-001 
Phase: 3 
Study Design: 
This is a multicenter, open-label, long-term, extension, phase 3 study to evaluate the safety and efficacy 
of long-term administration of TVP-1012 at 1 mg for another 26 weeks in patients with early Parkinson’s 
disease who have completed the 26-week treatment period in the preceding TVP-1012/CCT-001 study. 
Among participants of the TVP-1012/CCT-001 study, those consenting to participate in this study prior to 
undergoing the tests, observations, and assessments at Week 26 of the treatment period (VISIT 8) in the 
preceding study, and fulfilling the eligibility criteria will be enrolled in this study. From the day after the 
VISIT 8 of the preceding study, subjects will receive TVP-1012 1 mg once daily for 26 weeks in an 
unblinded manner. 
The visit numbers in this study will be continued from the preceding study, and the study visit week will 
be counted from the start of the treatment period in the preceding study. 
Patients will make a total of 7 visits in this study, i.e., at Weeks 26, 29, 32, 36, 40, 46, and 52 of the 
treatment period, to undergo designated tests, observations, and assessments. 
Primary Objective: 
To evaluate the long-term safety of TVP-1012 (1 mg/day) in Japanese patients with early Parkinson’s 
disease 
Secondary Objective: 
To evaluate the long-term efficacy of TVP-1012 (1 mg/day) in Japanese patients with early Parkinson’s 
disease 
Subject Population: Japanese patients with early Parkinson’s disease who have completed the 26-week 
treatment period in the preceding study 
Number of Subjects: 
Approximately 182 continued from the preceding study 
Number of Sites: 
Approximately 55 sites 
(Same study sites as the preceding study) 


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CONFIDENTIAL 
Dose Levels: 
TVP-1012 (1 mg/day) once daily, either before or after 
breakfast (the timing of the dose must be the same as in 
the preceding study) 
Route of Administration: 
Oral 
Duration of Treatment: 
26 weeks in total 
Period of Evaluation: 
26 weeks in total 
Main Criteria for Inclusion: 
 The subject has completed the preceding study. 
 The subject has shown no safety issues during the study treatment in the preceding study, in the 
judgment of the investigator or sub-investigator. 
Main Criteria for Exclusion: 
 Subject has donated 400 mL or more of his or her blood volume within 90 days prior to the initiation 
of the investigational drug in this study. 
 The subject is required to receive any of the excluded medications or treatments. 
 The subject is required surgery or hospitalization for surgery during the study period. 
Main Criteria for Evaluation and Analyses: 
Primary endpoint 
 Adverse events (AEs) 
Secondary endpoints 
 Clinical laboratory test values, vital signs, electrocardiogram (ECG), and weight 
 MDS-UPDRS Part II + Part III total score 
Statistical Considerations: 
The analyses for this study will be performed using pooled data from the preceding study and this study, 
in principle, based on data obtained after administration of TVP-1012. 
[Analysis methods for the primary endpoint] 
The following analysis will be based on the safety analysis set. 
A treatment-emergent adverse event (TEAE) is defined as an adverse event whose date of onset occurs on 
or after the start of treatment period study drug in the preceding study. 
TEAEs whose date of onset occurs on or after the start of TVP-1012 will be coded using the MedDRA 
dictionary. The frequency distribution will be provided using the system organ class and the preferred 
term for each treatment group as follows: 
 All TEAEs 
 Drug-related TEAEs 
 Intensity of TEAEs 
 Intensity of drug-related TEAEs 


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CONFIDENTIAL 
 TEAEs leading to study drug discontinuation 
 Serious TEAEs 
 TEAEs over time 
Sample Size Justification: 
In the preceding study, the planned number of subjects to be randomized was a total of 240 (120 per 
group) and the planned number of subjects evaluable for the primary endpoint (change in the 
MDS-UPDRS Part II + Part III total score from baseline to Week 26 of the treatment period (LOCF)) was 
a total of 220 (110 per group). 
Since this study is a long-term extension study in patients with early Parkinson’s disease who have 
completed the 26-week treatment period in the preceding study, considering the potential dropouts in the 
preceding study, approximately 182 subjects will be enrolled in this study. 
In addition, considering the potential dropouts in this study and in the preceding study, it is estimated that 
155 subjects will be treated with 1 mg of TVP-1012 for 26 weeks and 59 subjects for 52 weeks. 
 


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CONFIDENTIAL 
3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
Cmax 
maximum observed serum concentration 
COMT 
catechol-O-methyltranferase 
CRO 
contract research organization 
CYP 
Cytochrome P-450 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
γ-GTP 
γ-glutamyl transpeptidase 
hCG 
human chorionic gonadotropin 
ICH 
International Conference on Harmonisation 
INN 
international nonproprietary name 
INR 
international normalized ratio 
LDH 
lactate dehydrogenase 
MAO 
Monoamine oxidase 
MDS 
Movement Disorders Society 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
PDQ-39 
The 39-item Parkinson’s disease questionnaire 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
preferred term 
PTE 
pretreatment event 
QOL 
quality of life 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
UPDRS 
unified Parkinson’s disease rating scale 
WHO 
World Health Organization 


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4.0 
INTRODUCTION 
4.1 
Background 
Parkinson’s disease is the second most common neurodegenerative disorder of the 
central nervous system after Alzheimer’s disease. The prevalence of Parkinson’s disease 
is estimated to be 100-150/100,000 in the Japanese population, mostly affecting elderly 
people with peak age in the late 50s to 60s [1]. A significant increase in the number of 
patients is expected as the population ages in the future. 
The 4 major symptoms of Parkinson’s disease are resting tremor, muscle rigidity 
(muscle stiffness), bradykinesia, and postural instability. These motor symptoms are 
suspected to occur due to damage or death of substantia nigra dopaminergic neurons in 
the midbrain, followed by a reduction in dopamine volume in the striatum. 
The Japanese therapeutic guideline recommends initially treating motor symptoms of 
Parkinson’s disease with levodopa or a dopamine agonist, in principle, and rich 
evidence with these drugs used as first-line therapy are available [2]. 
In clinical practice overseas, the efficacy of initial treatment with MAO-B inhibitors has 
been demonstrated in Parkinson’s disease and the therapeutic algorithm recommends 
MAO-B inhibitors as the first-line treatment for mild Parkinson’s disease in addition to 
levodopa and dopamine agonists [3][4]. In Japan, selegiline is one of the MAO-B 
inhibitors available but not approved for first-line treatment of Parkinson’s disease. If 
clinical development of MAO-B inhibitors is promoted in Japan, treatment options for 
patients with mild or early Parkinson’s disease may expand. 
TVP-1012 (INN: rasagiline) is a MAO-B inhibitor without an amphetamine structure. 
In comparison with selegiline, TVP-1012 is characterized by (1) a 5 to 10-fold MAO-B 
inhibitory effect, and (2) easy drug management due to not having an amphetamine 
structure and not being designated as ingredient in narcotics. As of September, 2014, 
rasagiline has been approved in 53 countries in Europe, the United States, and East 
Asian countries as a monotherapy for early Parkinson’s disease, and also as concomitant 
therapy with levodopa for Parkinson’s disease. Currently, clinical development for 
TVP-1012 as monotherapy for early Parkinson’s disease and as an add-on therapy to 
levodopa for Parkinson’s disease is ongoing in Japan. 
 
 
 
 


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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Summary 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Summary 
 
 
 
 
 
 
 
 
 
 


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4.2 
Rationale for the Proposed Study 
 
 
 
 
 
 
 
 
Based on these results, this study was planned to evaluate the efficacy and safety of 
long-term extension administration with TVP-1012 in Japanese patients with early 
Parkinson’s disease who have completed the preceding study (TVP-1012/CCT-001). 
The comprehensive evaluation of the efficacy and safety of TVP-1012 in early 
Parkinson’s disease will be performed based on the results of this study, Study 
TVP-1012/CCT-001, and overseas clinical studies. 
The clinical development of TVP-1012 as an add-on to levodopa for Parkinson’s 
disease is ongoing in Japan. Currently, a Phase 2/3 study (TVP-1012/CCT-002) and a 
Phase 3 study (TVP-1012/OCT-002) are underway. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective(s) 
 
To evaluate the long-term safety of TVP-1012 (1 mg/day) in Japanese patients with 
early Parkinson’s disease 
5.1.2 
Secondary Objectives(s) 
 
To evaluate the long-term efficacy of TVP-1012 (1 mg/day) in Japanese patients 
with early Parkinson’s disease 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
 
Adverse events (AEs) 
5.2.2 
Secondary Endpoints 
 Clinical laboratory test values, vital signs, electrocardiogram (ECG), and weight 
 Movement Disorder Society-Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) Part II＋Part III total score 
5.2.3 
Additional Endpoints 
 
MDS-UPDRS Part I total score 
 
MDS-UPDRS Part II total score 
 
MDS-UPDRS Part III total score 
 
MDS-UPDRS Part IV total score 
 
MDS-UPDRS tremor score 
 
MDS-UPDRS bradykinesia score 
 
MDS-UPDRS muscle rigidity score 
 
MDS-UPDRS individual score 
 
Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index scores for 
individual domain 
 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
Patients will make a total of 7 visits in this study, i.e., at Weeks 26, 29, 32, 36, 40, 46 
and 52 of the treatment period, to undergo designated tests, observations, and 
assessments. 
This is a multicenter, open-label, long-term, extension, phase 3 study to evaluate the 
safety and efficacy of long-term administration of TVP-1012 at 1 mg for another 26 
weeks in patients with early Parkinson’s disease who have completed the 26-week 
treatment period in the preceding TVP-1012/CCT-001 study. 
Among participants of the TVP-1012/CCT-001 study, those consenting to participate in 
this study prior to undergoing the tests, observations, and assessments at Week 26 of the 
treatment period (VISIT 8) in the preceding study, and fulfilling the eligibility criteria 
will be enrolled in this study. From the day after the VISIT 8 of the preceding study, 
subjects will receive TVP-1012 1 mg once daily for 26 weeks in an unblinded manner. 
The visit numbers in this study will be continued from the preceding study, and the 
study visit week will be counted from the start of the treatment period in the preceding 
study. 
This study will be conducted in the same study sites as those of the preceding study (55 
sites) and the number of subjects to be enrolled in this study is estimated to be 182 
subjects after considering dropouts in the preceding study. 
Schematic of Study Design is included as Figure 6.a. A schedule of study procedures is 
listed in Appendix A. 
 


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V: VISIT 
* Informed consent for this study must be obtained prior to tests, observations, and assessments at Week 
26 of the treatment period in the preceding study. Those who consent to participate in this study and 
fulfilling the eligibility criteria will be enrolled in this study. Subjects will start dosing from the day 
after the VISIT 8. 
Figure 6.a 
Schematic of Study Design 
 


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6.2 
Justification for Study Design, Dose, and Endpoints 
6.2.1 
Justification for Study Subject 
To evaluate the safety and efficacy of long-term administration of TVP-1012 in 
Japanese patients with early Parkinson’s disease, this study will target subjects who 
have completed the preceding study and were assessed as not demonstrating safety 
concerns in the opinion of the investigator or sub-investigator.  
6.2.2 
Justification for Study Design 
This open-label, long-term extension study has a common study design that allows for 
the evaluation of long-term safety. This study was designed as an extension study 
following the preceding study, to collect pertinent data on long-term administration in 
an efficient manner.  
See Section 13.3 for Sample Size Justification. 
6.2.3 
Justification for Dose Regimen 
 
 
 
 
 
 
 
  
In the preceding study, 1 mg of TVP-1012 or placebo was administered for 26 weeks to 
evaluate the efficacy and safety of TVP-1012 1 mg. 
In this study, the dose of 1 mg of TVP-1012 will be maintained for subjects treated with 
1 mg of TVP-1012 in the preceding study, to evaluate administration at 1 mg for 52 
weeks. In addition, subjects treated with placebo in the preceding study will be switched 
to 1 mg of TVP-1012 in this study, to evaluate administration at 1 mg for 26 weeks, for 
the purpose of evaluating a large number of subjects as much as possible.  
 
 
 
 


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6.2.4 
Justification for Treatment Period 
Parkinson’s disease is a progressive disease and long-term administration is anticipated 
when TVP-1012 is prescribed. Therefore, another 26-week extension of treatment was 
planned following the 26-week treatment in the preceding study to evaluate the 
long-term safety of TVP-1012 for 6 months and 12 months.  
6.2.5 
Justification for Endpoints 
In this study, the long-term safety and efficacy of TVP-1012 following the preceding 
study will be evaluated. As the safety and efficacy will be evaluated in pooled data from 
this and preceding studies, the same endpoints used for the preceding study were set.  
Safety evaluation is the primary objective of this study. Of the safety evaluation 
variables in the preceding study, the frequency of adverse events (AEs) will be used as 
the primary endpoint and clinical laboratory test results, vital signs, ECGs, and weight 
will be used for the assessment of secondary endpoints. 
In addition, MDS-UPDRS Part II + Part III total score, which was the primary efficacy 
endpoint in the preceding study, will be used as a secondary endpoint. The efficacy 
endpoints in the preceding study other than MDS-UPDRS Part II + Part III total score 
will be set as additional endpoints. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study. 
 
New information or other evaluation regarding the safety or efficacy of the study 
medication that indicates a change in the known risk/benefit profile for the 
compound, such that the risk/benefit is no longer acceptable for subjects 
participating in the study. 


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 
Significant violation of Good Clinical Practice (GCP) that compromises the ability 
to achieve the primary study objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the 
investigator) is found in significant violation of GCP, protocol, or contractual agreement, 
is unable to ensure adequate performance of the study, or as otherwise permitted by the 
contractual agreement. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority 
elects to terminate or suspend the study or the participation of an investigational site, a 
study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable investigational sites during the 
course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to the administration 
of the investigational drug. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria:  
1. In the opinion of the investigator or sub-investigator, the subject is capable of 
understanding and complying with protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required 
privacy authorization prior to the initiation of any study procedures. 
3. The subject has completed the preceding study (TVP-1012/CCT-001 study). 
4. The subject has shown no safety issues during the study treatment in the 
preceding study, in the judgment of the investigator or sub-investigator. 
5. A female subject of childbearing potential* who is sexually active with a 
nonsterilized* male partner agrees to use routinely adequate contraception* from 
signing of informed consent to 1 month after the last dose of the investigational 
drug. 
*Definition of female subjects of chiledbearing potential is defined in 
Section 9.1.10. 
Contraception and Pregnancy Avoidance Procedure and reporting 
responsibilities are defined in Section 9.1.11. 
 
[Justification of Inclusion Criteria] 
1, 2： 
These criteria were set to include subjects who understand the objective of 
the study and will cooperate in the study conduct. 
3： 
This criterion was set as this study is designed to conduct with subjects who 
have completed the 26-week treatment period in the preceding study. 
4： 
This criterion was set in consideration of subject safety. 
5： 
This criterion was set in consideration of safety risk associated with 
pregnancy. 
 


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7.2 
Exclusion Criteria 
Any subject who meets the following criteria will not qualify for entry into the study: 
1. The subject is an immediate family member, study site employee, or is in a 
dependant relationship with a study site employee who is involved in conduct of 
this study (e.g., spouse, parent, child, sibling) or may consent under duress. 
2. Subject has donated 400 mL or more of his or her blood volume within 90 days 
prior to the initiation of the investigational drug in this study. 
3. The subject is required to receive excluded medications or treatments. 
4. If female, the subject is intending to become pregnant during, or within 1 month 
after the last dose of the investigational drug; or intending to donate ova during 
such time period. 
5. The subject requires surgery or hospitalization for surgery during the study 
period. 
6. The subject who, in the opinion of the investigator or sub-investigator, is 
unsuitable for any other reason. 
 
[Justification of Exclusion Criteria] 
1, 5： These criteria were set as basic matters to conduct clinical studies. 
2： 
This criterion was set as basic matters to conduct clinical studies in 
consideration of subject safety. 
3： 
This criterion was set in consideration of efficacy evaluation and subject safety. 
4： 
This criterion was set to avoid the safety risk associated with pregnancy to 
pregnant woman and fetus. 
6： 
This criterion was set to exclude subjects with unknown factors which might 
influence the evaluation of efficacy. 
 
7.3 
Excluded Medications and Treatments 
The list of excluded medications and treatments is shown in Table 7.a. Subjects must be 
instructed not to take any medications, including over-the-counter products, without 
first consulting with the investigator or sub-investigator. 


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Table 7.a 
Excluded Medications and Treatments 
Medication/Treatment 
Duration 
Exception 
Excluded Medication 
(1) selegiline 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(2) pethidine, tramadol 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(3) reserpine, methyldopa 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(4) Other investigational drug From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(5) levodopa containing drug 
(6) Dopamine agonist 
(7) amantadine 
(8) Anticholinergic agent 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(9) COMT inhibitor 
(10) droxidopa 
(11) zonisamide 
(12) istradefylline 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(13) Psychoneurotic agent 
(phenothiazine, 
butyrophenone, benzamide, 
Atypical antipsychotic drug) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
Quetiapine may be 
concomitantly administrered 
without change in dose 
regimen throughout the 
study if the drug has been 
continuously administered in 
the preceding study. 
(14) Antinauseant with 
dopamine agonistic property  
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
domperidone may be 
concomitantly administered 
without change in dose 
regimen throughout the 
study if the drug has been 
continuously administered in 
the preceding study. 
(15) CYP1A2 inhibitor 
(including ciprofloxacin, 
enoxacin, fluvoxamine, 
zafirlukast) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 


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Medication/Treatment 
Duration 
Exception 
(16) dextromethorphan 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(17) Antidepressant  
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(18) St. John’s Wort 
(including supplements) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(19) Narcotic analgesic agent 
(excluding ≤ 1% of codeine, 
dihydrocodeine) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
Excluded Treatment 
(20) Neurosurgical 
intervention 
 (Pallidotomy, 
Thalamotomy, deep brain 
stimulation) 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
(21) Transcranial magnetic 
stimulation 
From VISIT 8 through VISIT 14, or the day of 
study site visit for early termination. 
－ 
 
Medications/treatments for AEs during the study period may be administered, provided 
that these treatments do not deviate from the above range. If a drug listed above is 
chosen as routine medication after study completion, this medication should be 
administered following a reasonable interval as needed, based on the precautions for use 
for each drug. 


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[Justification of Excluded Medications and Treatments] 
(1), (2), (18), (19) 
These criteria were set to ensure the safety of subjects, in consideration of  
adverse drug reactions due to concomitant use. 
(3), (13), (14) 
These criteria were set since there is a possibility of worsening Parkinsonism, 
which may affect the efficacy evaluation of TVP-1012; however, some drugs 
may be used concomitantly, if these drugs do not affect the efficacy 
evaluation of TVP-1012. 
(4)-(12), (20), (21) 
 These criteria were set because they could influence the evaluation of 
efficacy. 
(15) 
This criterion was set due to the effect on the pharmacokinetics of TVP-1012, 
considering the metabolic pathway mainly via CYP1A2. 
(16) 
This criterion was set to ensure the safety of subjects, in consideration of 
possibly elevating serotonin level due to concomitant use. 
(17) 
This criterion was set to ensure the safety of subjects and to minimize the 
effect on the efficacy evaluation due to mutually potentiated pharmacological 
action with concomitant use. 
 
7.4 
Diet, Fluid, Activity Control 
The investigator, sub-investigator, or study coordinator will give subjects the following 
instructions: 
1. 
Subjects should be punctual for visit appointments and undergo the physical 
examinations and prescribed tests. Subjects should also contact the investigator, 
sub-investigator or study coordinator promptly if they cannot visit the site as 
planned. 
2. 
Subjects should contact the investigator, sub-investigator, or study coordinator by 
telephone, etc., to ask for instructions immediately after symptoms worsen 
between planned visits. 
3. 
Subjects should follow instructions regarding treatment adherence provided by the 
investigator or sub-investigator. Subjects should visit the site after taking the 
study drug on planned visit days.* If the subject does not comply with treatment 
procedures, the subject must report this to the investigator, sub-investigator, or 


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study coordinator at the next visit. Unused study drug(s) and drug sheet(s) (blister 
sheet) should be returned at the next visit. 
* For the day the serum chemistry is scheduled, the study medication must be taken without 
having breakfast. In this case, deviation from the original dose timing (not before or after 
breakfast) will be permitted. 
4. Subjects are not allowed to take any medications other than drugs prescribed by the 
investigator or sub-investigator, including over-the-counter products, without first 
consulting with the investigator (except for emergency use). 
5. 
If a subject visits another medical institution from signing of the informed consent 
to 1 month after the last administration of the investigational drug, the investigator 
should notify the primary care physician that the subject was participating in a 
clinical study. 
6. 
If a subject visits another medical institution from signing of the informed consent 
to 1 month after the last administration of the investigational drug, the investigator 
or sub-investigator should be informed of the circumstances and therapy. 
7. 
On the days on which clinical serum chemistry tests are scheduled, blood must be 
collected in fasted state (≥ 8 hours), whenever possible. 
8. 
A female subject of childbearing potential who is sexually active with a 
nonsterilized male partner must agree to use routinely adequate contraception 
from signing of informed consent to 1 month after the last dose of the 
investigational drug. 
9. 
Excessive eating, drinking, exercise and drastic change of the meal are not 
allowed during the study period. 
10. Blood donation is not allowed from the start of the investigational drug 
administration until at least 1 month after the last administration of the 
investigational drug. Subject must immediately report the blood donation during 
this period, if any, to the investigator. 
11. Subjects should avoid driving vehicles, operating machinery, and working in high 
areas, etc., in consideration of possible treatment-emergent dizziness, or reduced 
attention, concentration, or reflex function. 


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7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study 
should be recorded in the case report form ([e]CRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.15. 
1. Pretreatment Event or AE 
The subject has experienced a pretreatment event (PTE) or AE that requires early 
termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
 Liver Function Test (LFT) Abnormalities 
 Study medication should be discontinued immediately with appropriate clinical 
follow-up until a subject’s laboratory profile has returned to normal or the value 
immediately after the informed consent (for PTEs), or the value before the initiation 
of the investigational drug* (for AEs). (See Section 9.1.9) if the following 
circumstances occur at any time during study medication treatment: 
* The value before the initiation of the study medication is defined as the value prior to the start of 
the run-in period in the preceding study for AEs occurred before first study medication 
administration in the treatment period in the preceding study, and as the value at baseline in the 
preceding study for AEs occurred after first study medication administration in the treatment 
period in the preceding study. 
 ALT or AST > 8 × ULN, or 
 ALT or AST > 5 × ULN and persists for more than 2 weeks, or 
 ALT or AST > 3 × ULN in conjunction with elevated total bilirubin >2 × ULN 
or international normalized ratio (INR) > 1.5, or 
 ALT or AST > 3 × ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
2. Significant protocol deviation 
The discovery after the first dose of study medication that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up 
The subject did not return to the clinic and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented. 
4. Voluntary withdrawal 
The subject wishes to withdraw from the study. The reason for withdrawal, if 
provided, should be recorded in the (e)CRF. 


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Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be 
recorded (i.e., withdrawal due to an AE or lack of efficacy). 
5. Study termination 
The sponsor, IRB, or regulatory agency terminates the study. 
6. Pregnancy 
The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn 
immediately. The procedure is described in Section 9.1.11. 
7. Lack of efficacy 
The investigator or sub-investigator has determined that the subject is not benefiting 
from investigational treatment; and, continued participation would pose an 
unacceptable risk to the subject. 
8. Other 
Note: The specific reasons should be recorded in the “specify” field of the (e)CRF. 
 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator or sub-investigator may terminate a subject’s study participation at any 
time during the study when the subject meets the study termination criteria described in 
Section 7.5. In addition, a subject may discontinue his or her participation without 
giving a reason at any time during the study. Should a subject’s participation be 
discontinued, the primary criterion for termination must be recorded by the investigator 
or sub-investigator. In addition, efforts should be made to perform all procedures 
scheduled for the Early Termination Visit. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, 
including important sections describing the management of clinical trial material. 
8.1 
Study Medication 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study medication refers to all or any of the drugs defined 
below. 
(1) Dosage Form and Manufacturing 
Drug substance code number: TVP-1012 
Nonproprietary name: rasagiline (INN) 
Chemical name: N-propargyl-1-(R)-aminoindan mesylate 
Table 8.a 
Study Medication 
Type of the drug 
Dosage form 
TVP-1012 1 mg tablet 
A white to yellowish white round shape tablet containing 
rasagiline, engraved with “
” on one surface. 
 
All the study medication were manufactured in 
  
(2) Packaging and Labeling 
Ten tablets of the TVP-1012 1 mg are encapsulated in an aluminum blister sheet and 19 
sheets of the TVP-1012 1 mg tablet are packed in a carton. 
The label affixed to the carton containing the investigational drug should include a 
description that the content is an investigational drug, name of the drug “TVP-1012 
1.0 mg tablet”, study number “TVP-1012/OCT-001”, the name and address of the 
sponsor, manufacturing number, number of the drugs, and storage. 
8.1.2 
Storage 
The investigational drug must be stored at 1°C to 30°C. 
All clinical trial material must be kept in an appropriate, limited-access, secure place 
until it is used or returned to the sponsor or designee for destruction. Investigational 
drug must be stored under the conditions specified on the label, and remain in the 


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original container until dispensed. A daily temperature log of the drug storage area must 
be maintained every working day. 
8.1.3 
Dose and Regimen 
The administration of the study medication will start on the day after VISIT 8 and the 
subjects will be orally administered 1 tablet of TVP-1012 1.0 mg once daily before or 
after breakfast ( at the same timing with the preceding study). 
The investigator or its designee will supply sufficient amount of the study medication 
required during the period between study visits. Subjects will be instructed to take study 
medication in the morning of study visits* and to bring unused study medications and 
blister sheets to the site at each study visit. Also, compliance of the study medication 
from the last study visit will be checked by the investigator or sub-investigator (see 
Section 9.2). 
* For the day the serum chemistry is scheduled, the study medication must be taken without having 
breakfast. In this case, deviation from the timing of dose (not before or after breakfast) will be 
permitted. 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a study subject, at a dose above that which is assigned to 
that individual subject according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an 
Overdose page of the (e)CRF, in order to capture this important safety information 
consistently in the database. AEs associated with an overdose will be documented on 
AE CRF(s) according to Section 10.0, PRETREATMENT EVENTS AND ADVERSE 
EVENTS. 
Serious adverse events (SAEs) of overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Investigational Drug Assignment and Dispensing Procedures 
The same investigational drug is used for all subjects at each study site where the study 
is conducted. The investigator or sub-investigator will assign the investigational drug 
allocated to each study site to the subjects according to the study procedure. 


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8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
Upon receipt of the procedures for handling, storage, and management of the 
investigational drug prepared by the sponsor, the investigational drug manager will 
appropriately manage all the drugs supplied by the sponsor. The investigator will also 
receive the same procedures from the sponsor. The procedures will define the processes 
necessary to ensure that receipt, handling, storage, management, and prescription of the 
sponsor-supplied drugs, as well as collection of the unused drugs from subjects and 
return to the sponsor or disposal of unused drugs should be performed appropriately and 
reliably. 
The investigational drug manager will return unused drugs to the sponsor immediately 
after the completion of the clinical study at the study site. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or sub-investigator 
whenever possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to tests, observations and evaluations at Week 
26 (VISIT 8) in the preceding study. 
The same identification code provided in the preceding study will be assigned and will 
be used throughout the study period. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
The same demographic information, medical history and medication history obtained in 
the preceding study will be used in this study. 
9.1.3 
Physical Examination Procedure 
A physical examination will consist of the following body systems:  
(1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) 
gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal 
system; (9) nervous system; (10) lymph nodes; (11) other.  
All subsequent physical examinations should assess clinically significant changes from 
the values obtained at baseline (VISIT 2). 
9.1.4 
Skin Examination 
A subject should be confirmed as not having melanoma in accordance with separately 
prepared study procedures. If melanoma is suspected, this subject must visit a 
dermatologist. 
 


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9.1.5 
Weight 
Weight will be collected in kilograms to 1 decimal place. 
9.1.6 
Vital Sign Procedure 
Vital signs will include body temperature (infra-axillary measurement), sitting 
systolic/diastolic (mmHg) blood pressure after resting more than 5 minutes, and pulse 
(bpm). 
9.1.7 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These 
may be prescribed by a physician or obtained by the subject over the counter. 
Concomitant medication is not provided by Takeda and all medication including vitamin 
supplements, over-the-counter medications, oral herbal preparations, and St. John’s 
Wort must be recorded in the (e)CRF. If any antiparkinsonian drug is taken, its dosage 
and unit per day must be obtained. 
9.1.8 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that 
are present at signing of informed consent in the preceding study. Concurrent medical 
conditions for this study are those investigated in the preceding study. 
9.1.9 
Procedures for Clinical Laboratory Samples 
Table 9.a lists the samples to be collected for each laboratory test. All samples will be 
collected after fasted for more than 8 hours, whenever possible, in accordance with 
acceptable laboratory procedures. The maximum volume of blood at any single visit is 
approximately 6 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Red blood cells 
Hemoglobin 
Hematocrit 
White blood cells with 
differential  
(neutrophil, eosinophil, 
monocyte, lymphocyte, 
and basophil) 
Platelets 
AST 
ALT 
γ-GTP 
ALP 
LDH 
Albumin 
Total protein 
Total bilirubin 
Total cholesterol 
Triglycerides 
Creatinine 
Blood urea nitrogen (BUN) 
Urine acid 
Creatine kinase 
Sodium 
Potassium 
Chlorine 
Calcium 
Phosphorus 
Protein (qualitative) 
Glucose (qualitative) 
Blood (qualitative) 
Ketone body (qualitative) 
Pregnancy Test (for female subjects of childbearing potential only) 
Urine hCG (qualitative) 
 
The central laboratory will perform laboratory tests for hematology, serum chemistries, 
and urinalysis. However, the urine hCG (qualitative) will be performed at each study 
site for women with childbearing potential. 
If subjects experience ALT or AST > 3 × ULN, follow-up laboratory tests (at a 
minimum, serum ALP, ALT, AST, total bilirubin, γ-GTP, and INR) should be performed 
within a maximum of 7 days and preferably within 48-72 hours after the abnormality 
was noted. (see Section 7.5 and 10.2.3) 
If the ALT or AST remains elevated > 3 × ULN on these 2 consecutive occasions, the 
investigator or sub-investigator must contact the sponsor for consideration of additional 
testing, close monitoring, possible discontinuation of study medication, discussion of 
the relevant subject details and possible alternative etiologies. 
The laboratory test results will be evaluated and maintained by the investigator or 
sub-investigator. And also, the investigator will maintain a copy of the reference ranges 
for the laboratory used. 


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9.1.10 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and for 1 
month after last dose of study medication, female subjects of childbearing potential 
who are sexually active or before menopause with a nonsterilized male partner must 
use adequate contraception. In addition they must be advised not to donate ova during 
this period. Subjects will be provided with information on acceptable methods of 
contraception as part of the subject informed consent process and will be asked to 
sign a consent form stating that they understand the requirements for avoidance of 
pregnancy, donation of ova during the course of the study. During the course of the 
study, regular urine hCG pregnancy tests will be performed only for women of 
childbearing potential and subjects will receive continued guidance with respect to 
the avoidance of pregnancy as part of the study procedures (Appendix A). 
Subjects also must have a negative urine hCG pregnancy test at each evaluation 
point. 
9.1.11 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued.  
If the pregnancy occurs during administration of active study medication, after the end 
of run-in period of the preceding study and within 1 month of the last dose of active 
study medication, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the Safety Information Emergency Call Center (contact listed 
specified in the appendix). 
Should the pregnancy occur during or after administration of blinded drug, the 
investigator or sub-investigator must inform the subject of their right to receive 
treatment information. If the subject chooses to receive unblinded treatment information, 
the individual blind should be broken by the investigator or sub-investigator. 
If the female subject agrees to the primary care physician (gynecologist) being informed, 
the investigator or sub-investigator should notify the primary care physician that the 
subject was participating in a clinical study at the time she became pregnant and provide 
details of treatment the subject received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome, using the pregnancy 
form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted. 


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9.1.12 ECG Procedure 
Standard 12-lead ECGs will be recorded under resting. The investigator or 
sub-investigator (or a qualified observer at the investigational site) will interpret the 
ECG using one of the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal and clinically significant. The following parameters 
will be recorded on the (e)CRF from the subject’s ECG trace: heart rate, RR interval, 
PR interval, QT interval, QRS interval, and QTcB interval. QTcF will be calculated by 
the sponsor. 
9.1.13 MDS-UPDRS 
The investigator or sub-investigator will assess the symptoms of Parkinson’s disease 
according to MDS-UPDRS (Part I: non-motor experiences of daily living, Part II: motor 
experiences of daily living, Part III: motor examination, Part IV: motor complications). 
The investigator or sub-investigator (hereinafter referred to as “evaluator”) responsible 
for evaluating MDS-UPDRS scores will undergo training on MDS evaluations prior to 
study conduct and should be accredited with a training certificate. Only evaluators with 
a training certificate are allowed to evaluate the MDS-UPDRS for the study. 
The evaluator will not evaluate subjects until he/she receives a training certificate for 
MDS evaluations. If the assigned evaluator is replaced (or added) during the study, a 
new evaluator should complete the aforementioned training and receive a training 
certificate for MDS evaluations before starting evaluations in the study. If a new 
evaluator has already received a training certificate for MDS evaluations, re-training 
will not be mandatory. 
In principle, the same subject will be evaluated by the same evaluator as in the 
preceding study throughout the study period. The evaluator will record evaluation 
results for each item in Table 9.b in the CRF. 


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Table 9.b 
MDS-UPDRS Score Sheet 
Part I 
3.1 
Speech 
(0, 1, 2, 3, 4, UR) 
 
Primary source of 
information 
□ Patient 
□ Caregiver 
□ Patient and  
   Caregiver 
3.2 
Facial expression 
(0, 1, 2, 3, 4, UR) 
3.3a 
Rigidity-Neck(b) 
(0, 1, 2, 3, 4, UR) 
3.3b 
Rigidity-RUE(b) 
(0, 1, 2, 3, 4, UR) 
1.1 
Cognitive 
impairment 
(0, 1, 2, 3, 4, UR) 
3.3c 
Rigidity-LUE(b) 
(0, 1, 2, 3, 4, UR) 
1.2 
Hallucinations and 
psychosis 
(0, 1, 2, 3, 4, UR) 
3.3d 
Rigidity-RLE(b) 
(0, 1, 2, 3, 4, UR) 
1.3 
Depressed mood 
(0, 1, 2, 3, 4, UR) 
3.3e 
Rigidity-LLE(b) 
(0, 1, 2, 3, 4, UR) 
1.4 
Anxious mood 
(0, 1, 2, 3, 4, UR) 
3.4a 
Finger tapping-Right hand (c) 
(0, 1, 2, 3, 4, UR) 
1.5 
Apathy 
(0, 1, 2, 3, 4, UR) 
3.4b 
Finger tapping-Left hand (c) 
(0, 1, 2, 3, 4, UR) 
1.6 
Features of DDS 
(0, 1, 2, 3, 4, UR) 
3.5a 
Hand movements-Right hand 
(c) 
(0, 1, 2, 3, 4, UR) 
3.5b 
Hand movements-Left hand (c) 
(0, 1, 2, 3, 4, UR) 
Questionnaire 
3.6a 
Pronation-supination 
movements-Right hand (c) 
(0, 1, 2, 3, 4, UR) 
 
Who is filling out 
this questionnaire: 
□ Patient 
□ Caregiver 
□ Patient and  
   Caregiver 
3.6b 
Pronation-supination 
movements-Left hand(c) 
(0, 1, 2, 3, 4, UR) 
3.7a 
Toe tapping-Right foot(c) 
(0, 1, 2, 3, 4, UR) 
3.7b 
Toe tapping-Left foot (c) 
(0, 1, 2, 3, 4, UR) 
1.7 
Sleep problems 
(0, 1, 2, 3, 4) 
3.8a 
Leg agility-Right leg (c) 
(0, 1, 2, 3, 4, UR) 
1.8 
Daytime sleepiness 
(0, 1, 2, 3, 4) 
3.8b 
Leg agility-Left leg(c) 
(0, 1, 2, 3, 4, UR) 
1.9 
Pain and other 
sensations 
(0, 1, 2, 3, 4) 
3.9 
Arising from chair 
(0, 1, 2, 3, 4, UR) 
3.10 
Gait 
(0, 1, 2, 3, 4, UR) 
1.10 
Urinary problems 
(0, 1, 2, 3, 4) 
3.11 
Freezing of gait 
(0, 1, 2, 3, 4, UR) 
1.11 
Constipation 
problems 
(0, 1, 2, 3, 4) 
3.12 
Postural stability 
(0, 1, 2, 3, 4, UR) 
1.12 
Light headedness 
on standing 
(0, 1, 2, 3, 4) 
3.13 
Posture 
(0, 1, 2, 3, 4, UR) 
1.13 
Fatigue 
(0, 1, 2, 3, 4) 
3.14 
Global spontaneity of 
movement(c) 
(0, 1, 2, 3, 4, UR) 
Part II 
2.1 
Speech 
(0, 1, 2, 3, 4) 
3.15a 
Postural tremor-Right hand(a) 
(0, 1, 2, 3, 4, UR) 
2.2 
Saliva and drooling 
(0, 1, 2, 3, 4) 
3.15b 
Postural tremor-Left hand(a) 
(0, 1, 2, 3, 4, UR) 
2.3 
Chewing and 
swallowing 
(0, 1, 2, 3, 4) 
3.16a 
Kinetic tremor-Right hand(a) 
(0, 1, 2, 3, 4, UR) 
2.4 
Eating tasks 
(0, 1, 2, 3, 4) 
3.16b 
Kinetic tremor-Left hand(a) 
(0, 1, 2, 3, 4, UR) 
2.5 
Dressing 
(0, 1, 2, 3, 4) 
3.17a 
Rest tremor amplitude-RUE(a) 
(0, 1, 2, 3, 4, UR) 
2.6 
Hygiene 
(0, 1, 2, 3, 4) 
3.17b 
Rest tremor amplitude-LUE(a) 
(0, 1, 2, 3, 4, UR) 
2.7 
Handwriting 
(0, 1, 2, 3, 4) 
3.17c 
Rest tremor amplitude-RLE(a) 
(0, 1, 2, 3, 4, UR) 
2.8 
Doing hobbies and 
other activities 
(0, 1, 2, 3, 4) 
3.17d 
Rest tremor amplitude-LLE(a) 
(0, 1, 2, 3, 4, UR) 
2.9 
Turning in bed 
(0, 1, 2, 3, 4) 
3.17e 
Rest tremor 
amplitude-Lip/jaw)(a) 
(0, 1, 2, 3, 4, UR) 
2.10 
Tremor(a) 
(0, 1, 2, 3, 4) 
2.11 
Getting out of bed, 
a car, or a deep 
chair 
(0, 1, 2, 3, 4) 
3.18 
Constancy of rest tremor(a) 
(0, 1, 2, 3, 4, UR) 
 
Were dyskinesias present during 
examination? 
□No 
□Yes 
2.12 
Walking and 
balance 
(0, 1, 2, 3, 4) 
 
If Yes, did these movements 
interfere with ratings? 
□No 
□Yes 
2.13 
Freezing 
(0, 1, 2, 3, 4) 
Part III 
 
Hoehn and Yahr Stage 
(0, 1, 2, 3, 4, 5) 
3a 
Is the patient on 
medication? 
□No 
□Yes  
Part IV 
4.1 
Time spent with dyskinesias 
(0, 1, 2, 3, 4) 


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3b 
Patient's clinical 
state 
□ON 
□OFF 
4.2 
Functional impact of 
dyskinesias 
(0, 1, 2, 3, 4) 
3c 
Is the patient on 
Levodopa? 
□No 
□Yes 
4.3 
Time spent in the OFF state 
(0, 1, 2, 3, 4) 
4.4 
Functional impact of 
fluctuations 
(0, 1, 2, 3, 4) 
3c1 
If yes, minutes 
since last dose: 
 
      
minutes 
4.5 
Complexity of motor 
fluctuations 
(0, 1, 2, 3, 4) 
4.6 
Painful OFF-state dystonia 
(0, 1, 2, 3, 4) 
0: Normal, 1: Slight, 2: Mild, 3: Moderate, 4: Severe, UR: Unable to Rate 
Bolded items represent MDS-UPDRS scores by category. Scores for each bolded item will be added according to 
Parts and the total score of individual Parts (I to IV) will be calculated. Scores for (a), (b), and (c) will be added 
separately and (a) tremor score, (b) muscle rigidity score, and (c) akinesia/bradykinesia score will be calculated. 
 
9.1.14 QOL assessment 
PDQ-39 is a self-administered questionnaire for QOL. Prior to the assessment, subjects 
will be provided instructions on how to record PDQ-39 and assess QOL during 1 month 
prior to the day of the assessment. Answers to all questions will be documented in the 
CRF. 
9.1.15 Documentation of Screen Failure 
The investigator should complete the (e)CRF for the subject who signed the informed 
consent and withdrawn from the study before randomization. 
For subjects discontinued the study before the initiation of the investigational drug in 
this study, the date of signing informed consent, date of birth, sex, eligibility, reason for 
withdrawal, AE assessment (if any, it must be collected as an AE occurred in the 
preceding study), concomitant medications, and the date of the last physical 
examination/evaluations must be recorded in the (e)CRF. 
The primary reason for screen failure is recorded in the (e)CRF using the following 
categories: 
• PTE/AEs 
• Did not meet inclusion criteria or did meet exclusion criteria <specify reason>. 
• Significant protocol deviation.  
• Lost to follow-up. 
• Voluntary withdrawal <specify reason>. 
• Study termination. 
• Other <specify reason>. 
Subject numbers assigned to subjects who fail screening should not be reused. 


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9.1.16 Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria 
are eligible for entrance into the study. If the subject is found to be not eligible for the 
study, the investigator or sub-investigator should record the primary reason for failure 
on the applicable (e)CRF. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be instructed to bring unused investigational drugs and blister sheets to the 
site at each study visit. Also, compliance of the study medication from the last study 
visit will be checked by the investigator or sub-investigator. 
All subjects should be instructed about the dosing requirement during study contacts. If 
a subject is persistently noncompliant with the sponsor-supplied drugs (50% of the 
allocated medication for the period since the last visit), it may be appropriate to 
withdraw the subject from the study. The authorized study personnel conducting the 
re-education must document the process in the subject source records. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix 
A. Assessments should be completed at the designated visit/time point(s). 
9.3.1 
Study Entrance/Week 26 in Treatment Period 
The subject informed consent must be obtained before initiation of 
tests/observations/evaluations scheduled at Week 26 (VISIT 8). 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria 
as described in Section 7.0, and subjects whose eligibility is confirmed will be enrolled 
in this study. See Section 9.1.15 for procedures for documenting screening failures. 
Procedures to be completed at Week 26 (VISIT 8; Day 175 - 189) include: 
• Dispense study medication 
9.3.2 
Treatment Period (Weeks 29, 32, 36, 40, and 46) 
9.3.2.1 Week 29 (Treatment Period) 
Week 29 (VISIT 9; Day 196-210) include: 
• Physical Examination Procedure 
• Vital Sign Procedure 


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• Documentation of Concomitant Medications 
• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.2.2 Week 32 (Treatment Period) 
Procedures to be completed at Week 32 (VISIT 10; Day 217-231) include: 
• Physical Examination Procedure 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 
• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 
• MDS-UPDRS 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.2.3 Week 36 (Treatment Period) 
Procedures to be completed at Week 36 (VISIT 11; Day 245-259) include: 
• Physical Examination Procedure 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 
• MDS-UPDRS 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.2.4 Week 40 (Treatment Period) 
Week 40 (VISIT 12; Day 273-287) include: 
• Physical Examination Procedure 
• Weight 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 


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• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 
• ECG Procedure 
• MDS-UPDRS 
• QOL 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.2.5 Week 46 (Treatment Period) 
Procedures to be completed at Week 46 (VISIT 13; Day 315-329) include: 
• Physical Examination Procedure 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 
• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 
• MDS-UPDRS 
• AE assessment 
• Compliance of study medication 
• Dispense investigational drug 
9.3.3 
Week 52 (Treatment Period) or Early Termination 
The following procedures will be performed in the last visit scheduled at Week 52 in the 
treatment period (VISIT 14; Day 357 - 371). For subjects who started the 
investigational drug adninistration in this study and are withdrawn from the study 
before the last visit at Week 52, the procedures scheduled at Week 52 should be 
performed within 7 days from the termination of study medication (the last 
administration day is defined as day 0), whenever possible. 
• Physical Examination Procedure 
• Skin examination 
• Weight 
• Vital Sign Procedure 
• Documentation of Concomitant Medications 
• Clinical laboratory tests (including pregnancy test for female subjects of child 
bearing potential) 


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• ECG Procedure 
• MDS-UPDRS 
• QOL 
• AE assessment 
• Compliance of study medication 
For all subjects receiving study medication, the investigator must complete the End of 
Study (e)CRF page. 
9.3.4 
Post Study Care 
The study medication will not be available upon completion of the subject’s 
participation in the study. 
 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in the preceding study but prior to 
administration of study medication of the run-in period of the preceding study; it does 
not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions underlying disease should not be 
considered PTEs or AEs.) 
• 
Necessitate therapeutic intervention. 
• 
Require an invasive diagnostic procedure. 
• 
Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
• 
Be considered unfavorable by the investigator for any reason.  
Diagnoses vs signs and symptoms: 
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 


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Laboratory values and ECG findings: 
Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs 
if they are judged to be clinically significant (i.e., if some action or intervention is 
required or if the investigator or sub-investigator judges the change to be beyond the 
range of normal physiologic fluctuation). A laboratory re-test and/or continued 
monitoring of an abnormal value are not considered an intervention. In addition, 
repeated or additional noninvasive testing for verification, evaluation or monitoring of 
an abnormality is not considered an intervention. 
If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis 
only should be reported appropriately as a PTE or as an AE. 
Pre-existing conditions (disease or symptom present before signing of the informed 
consent in the preceding study): 
Pre-existing conditions (present at the time of signing of informed consent in the 
preceding study) are considered concurrent medical conditions and should NOT be 
recorded as PTEs or AEs. Baseline evaluations (e.g., laboratory tests, ECG, X-rays etc.) 
immediately after signing of informed consent in the preceding study should NOT be 
recorded as PTEs unless related to study procedures. However, if a subject experiences 
an abnormality (e.g., internal bleeding due to blood collection) related to the procedures 
for the baseline tests/observations in the preceding study, the abnormality should be 
recorded as a PTE on the (e)CRF. If the subject experiences a worsening or 
complication of such a concurrent condition, the worsening or complication should be 
recorded appropriately as a PTE (worsening or complication occurs before start of study 
medication) or an AE (worsening or complication occurs after start of study medication). 
The investigator or sub-investigator should ensure that the event term recorded captures 
the change in the condition (e.g., “worsening of hypertension”). 
If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence 
of an episode should only be captured as a PTE/AE if the episodes become more 
frequent, serious or severe in nature, that is, the investigator or sub-investigator should 
ensure that the AE term recorded captures the change in the condition from Baseline 
(e.g. “worsening of…”). If a subject has a degenerative concurrent condition (e.g., 
cataracts, rheumatoid arthritis), worsening of the condition should only be captured as a 
PTE/AE if occurring to a greater extent to that which would be expected. Again, the 


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investigator or sub-investigator should ensure that the AE term recorded captures the 
change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
If the subject experiences a worsening or complication of a PTE after starting 
administration of the study medication, the worsening or complication should be 
recorded appropriately as an AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (e.g., worsening of…”). 
If the subject experiences a worsening or complication of an AE after any change in 
study medication (including change from a study medication for the CCT-001 study to 
that for the OCT-001), the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent in the preceding study are not considered PTEs or AEs. However, if a 
preplanned procedure is performed early (e.g., as an emergency) due to a worsening of 
the pre-existing condition, the worsening of the condition should be captured 
appropriately as a PTE or an AE. Complications resulting from any planned surgery 
should be reported as AEs. 
Elective surgeries or procedures: 
Elective procedures performed where there is no change in the subject’s medical 
condition (e.g., cosmetic surgery) should not be recorded as PTEs or AEs, but should be 
documented in the subject’s source documents. Complications resulting from an elective 
surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be 
recorded as an AE. The investigator or sub-investigator must make the distinction 
between exacerbation of pre-existing illness and lack of therapeutic efficacy. 


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Overdose: 
Cases of overdose with any medication without manifested side effects are NOT 
considered PTEs or AEs, but instead will be documented on an Overdose page of the 
(e)CRF. Any manifested side effects will be considered PTEs or AEs and will be 
recorded on the AE page of the (e)CRF. 
10.1.4 SAEs 
A SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING*. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing 
hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately 
life threatening or fatal or does not result in hospitalization. 
 Includes any event or synonym described in the Takeda Medically Significant 
AE List (Table 10.a). 
*The term “life threatening” 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. 


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Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
(ARDS) 
Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizures (including convulsion and 
epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/mucocutaneous 
syndrome (Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial pneumonia) 
Neuroleptic malignant syndrome / malignant 
hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
Confirmed or suspected transmission of infectious 
agent by a medicinal product 
Confirmed or suspected endotoxin shock 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Sections 10.2.2 and 
10.3). 
10.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s 
usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual 
activities. 
 
10.1.6 Causality of AEs 
The relationship of each AE to the investigational drug will be assessed using the 
following categories: 
 


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Term 
Definition 
Clarification 
Unrelated 
This category applies to 
those adverse events which, 
after careful consideration, 
are clearly and 
incontrovertible due to 
extraneous causes (disease, 
environment, etc.) 
This category applied to those adverse events which, after 
careful consideration, are clearly and incontrovertible due to 
extraneous causes (disease, environment, etc.) 
Unlikely 
In general, this category 
can be considered 
applicable to those adverse 
events which, after careful 
medical consideration at 
the time they are evaluated, 
are judged to be unrelated 
to the test drug. 
An adverse experience may be considered unlikely related if 
or when (must have 2): 
・ It does not follow a reasonable temporal sequence from 
administration of the drug. 
・ It could readily have been produced by the subject’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject. 
・ It does not follow a known pattern of response to the test 
drug. 
・ It does not reappear or worsen when the drug is 
re-administered. 
Possibly 
This category applies to 
those adverse events for 
which, after carful medical 
consideration at the time 
they are evaluated, a 
connection with the test 
drug administration appears 
unlikely but cannot be 
ruled out with certainty. 
An adverse experience may be considered possibly related if 
or when (at least 2 of the following): 
・ It follows a reasonable temporal sequence from 
administration of the drug. 
・ It could not readily have been produced by the subject’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject. 
・ It follows a known pattern of response to the test drug. 
Probably 
This category applies to 
those adverse events which, 
after careful medical 
consideration at the time 
they are evaluated, are felt 
with a high degree of 
certainty to be related to 
the test drug. 
An adverse experience may be considered probably related if 
or when (at least 3 of the followings): 
・ It follows a reasonable temporal sequence from 
administration of the drug. 
・ It could not be reasonable explained by the known 
characteristics of the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy 
administered to the subject. 
・ It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an adverse 
event does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists (e.g., bone 
marrow depression, fixed drug eruptions, tardive 
dyskinesia). 
・ It follows a known pattern of response to the test drug. 
 
 
 
 
 
 


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10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the 
relationship should be assessed as Not Related. 
10.1.8 Start Date 
The date of onset of a PTE or an AE will be determined according to the following 
criteria. 
PTE or AE 
Date of onset 
Signs, symptoms, and diseases 
(diagnoses) 
The date on which the subject, the investigator or sub-investigator 
first noted the signs/symptoms of an AE. 
Asymptomatic diseases 
The date on which a definitive diagnosis is obtained through tests. 
The date on which a diagnosis is confirmed should be recorded, 
even when the test result indicates an old sign(s) of the disease, or 
an approximate time of onset. 
Worsening of concurrent 
diseases or PTEs 
Worsening of AEs ovserved in 
the preceding study 
The date on which the subject, the investigator or sub-investigator 
first noted the first worsening of disease/symptom. 
For PTEs: cases in which 
normal values at the time of 
screening (i.e., the first test after 
signing of the informed 
consent) in the preceding study 
are abnormal at the subsequent 
test; 
For AEs: cases in which 
abnormal test values are found 
at the test after the start of 
administration of the 
investigational drug 
The date on which a clinically abnormal laboratory parameter is 
observed. 


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For PTEs: cases in which 
abnormal test values are found 
at the first test after signing of 
the informed consent and they 
are found to have worsened at 
the subsequent test; 
For AEs: cases in which 
abnormal test values are found 
at the test after the start of 
administration of the 
investigational drug and they 
worsen at the subsequent test 
The date on which a clinically obvious increase/decrease in a 
laboratory parameter is confirmed based on the time profile of the 
parameter. 
 
10.1.9 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event 
resolved but with sequelae or the subject died. In the event that the stop date of AE/PTE 
is not comfirmed, AE/PTE will be determined to be continuing. 
10.1.10 Frequency 
Episodic AEs/PTE (e.g., constipation, diarrhoea, vomiting) or those which occur 
repeatedly over a period of consecutive days are intermittent. All other events are 
continuous. 
10.1.11 Action Concerning Study Medication 
Actions associated with the investigational drug will be classified or defined as follows: 
Drug withdrawn 
A study medication is stopped due to the particular AE (including 
discontinuation/withdrawal based on the subject’s own judgment). 
Dose not changed 
The particular AE did not require stopping a study medication.  
Cases in which administration of the investigational drug is discontinued or the 
dose is reduced or increased because of an AE other than the particular AE. 
Cases in which administration of the investigational drug is discontinued or its 
dose is reduced for a reason other than the AE, e.g., inadvertent behavior by the 
subject. 
Unknown 
Only to be used if it has not been possible to determine what action has been 
taken because of loss of follow-up. 
Not Applicable 
A study medication was stopped for a reason other than the particular AE, or 
dosing with study medication was already stopped before the onset of the AE. 


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10.1.12 Outcome 
The outcome of a PTE or an AE will be determined according to the following criteria: 
Category 
Criteria 
Recovered/Resolved 
・The sign and symptom disappeared or resolved. 
・Subject returned to first assessment status (the value before the administration 
of the investigational drug*) in the preceding study for AEs, or the value at 
the first test after signing of the informed consent in the preceding study for 
PTEs. 
Recovering/Resolving 
・The intensity is lowered by one or more stages. 
・The diagnosis or signs/symptoms has almost disappeared. 
・The abnormal laboratory value improved, but has not returned to the normal 
range or to the value before the administration of the investigational drug* in 
the preceding study (for AEs) or the value at the first test after signing of the 
informed consent in the preceding study (for PTEs). 
・The subject died from a cause other than the particular AE/PTE with the 
condition remaining “recovering/resolving” (no need to record the date of 
death). 
Not recovered 
/not resolved 
・There is no change in the diagnosis, signs or symptoms. 
・The intensity of the diagnosis, signs/ symptoms or laboratory value on the last 
day of the observed study period has got worse than when it started. 
・Is an irreversible congenital anomaly. 
・The subject died from another cause with the particular AE/PTE state 
remaining “Not recovered/not resolved” (no need to record the date of 
death). 
Resolved with 
sequelae 
・The subject recovered from an acute AE/PTE but was left with impairment 
which interrupts the subject’s usual activities. 
Fatal 
・PTE/AE directly related to death 
“Direct relationship with the PTE/AE” means that the PTE/AE caused the 
death or apparently contributed to the death. 
・Cases in which the outcome of the PTE/AE observed in the same subject is 
determined or assumed as not having directly caused the death are not 
documented as “fatal.” 
・If the outcome of the PTE/AE is “fatal,” the date of death should be 
documented. 
Unknown 
・The course of the AE/serious PTE cannot be followed up due to hospital 
change or residence change at the end of the subject’s participation in the 
study. 
 
* “The value before the administration of the investigational drug” means the value at the start of the 
study medications in the run-in period in the preceding study for the PTE/AE occurred before the 
initiation of administration for the treatment period in the preceding study, and the value at baseline for 
the AEs occurred after initiation of the investigational drug for the treatment period in the preceding 
study. 


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10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent 
to participate in the preceding study and continue until the subject is first administered 
study medication in the run-in period in the preceding study. For subjects who 
discontinue prior to study medication administration in the run-in period in the 
preceding study, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered 
study medication in this study. Routine collection of AEs will continue until tests 
scheduled at Week 52 in the treatment period (or at early termination). 
AEs occurred between at the end of the last laboratory tests in the preceding study 
(TVP-1012/CCT-001) and before initiation of administration in this study will be 
collected as AEs occurred in the preceding study and any AEs observed in the preceding 
study will be monitored continuously throughout this study. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator or sub-investigator will assess whether any 
subjective AEs have occurred. A neutral question, such as “How have you been feeling 
since your last visit?” may be asked. Subjects may report AEs occurring at any other 
time during the study.  
Subjects experiencing a serious PTE must be monitored until the symptoms subside and 
any clinically relevant changes in laboratory values have returned to the value at the 
first laboratory test after signing of informed consent of the preceding study or there is a 
satisfactory explanation for the change (persistent, irreversible PTE). Non-serious PTEs, 
related or unrelated to the study procedure, need not to be followed-up for the purposes 
of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically 
relevant changes in laboratory values have returned to baseline (to the value at the start 
of the run-in period for AEs occurred before the initiation of the study medications in 
the treatment period in the preceding study, or the value at baseline for AEs occurred 
after administration of the study medication in the treatment period in the preceding 


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study) or until there is a satisfactory explanation for the changes observed (persistent, 
irreversible PTE). All PTEs and AEs will be documented in the PTE/AE page of the 
(e)CRF, whether or not the investigator or sub-investigator concludes that the event is 
related to the drug treatment. The following information will be documented for each 
event: 
 
Event term 
 
Start and stop date 
 
Frequency 
 
Severity 
 
Investigator’s opinion of the causal relationship between the event and 
administration of study medications (Unrelated, Unlikely, Possibly, Probably) 
 
Action concerning study medication 
 
Outcome of event 
 
Investigator’s opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure 
 
Seriousness  
AEs and serious PTEs will be followed up until they have resolved or the investigator or 
sub-investigator judges that the follow-up is no longer necessary. 
10.2.2 Collection and Reporting of SAEs 
When a SAE occurs through the AE collection period it should be reported according to 
the following procedure. PTEs that meet the criteria for SAEs described in Section 
10.1.4 will be reported in a same manner to that for SAEs. 
A SAE should be reported to Safety Information Emergency Call Center (described in 
the separate contact information list) within 1 business day of first onset or subject’s 
notification of the event. The investigator should submit the completed SAE form 
within 10 calendar days to Safety Information Emergency Call Center. Also the original 
document of a Takeda SAE form must be submitted to the sponsor. 
The information to be reported within 1 business day should be completed as fully as 
possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as 
serious 


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• Subject identification number 
• Investigator’s or sub-investigator’s name 
• Name of the study medications 
• Causality assessment (relationship with the study medication or study 
procedure) 
Any SAE spontaneously reported to the investigator or sub-investigator following the 
AE collection period should be reported to the sponsor. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST > 3 × ULN and total bilirubin > 2 × ULN for 
which an alternative etiology has not been identified, the event should be recorded as a 
SAE and reported as per Section 10.2.2. The investigator or sub-investigator must 
contact the Medical Monitor for discussion of the relevant subject details and possible 
alternative etiologies, such as acute viral hepatitis A or B, other acute liver disease, or a 
history or concurrent medical condition. Follow-up laboratory tests as described in 
Section 9.1.9 must also be performed. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later 
date, the investigator or sub-investigator should complete a follow-up SAE form or 
provide other written documentation immediately to the sponsor or Safety Information 
Emergency Call Center. Copies of any relevant data from the hospital notes (e.g., ECGs, 
laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested by the sponsor or IRB. 
All SAEs should be followed up until resolution or permanent outcome of the event. 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
investigators, IRBs, and the head of the study site, as applicable. Relative to the first 
awareness of the event by/or further provision to the sponsor or sponsor’s designee 
(CRO), SUSARs will be submitted to the regulatory authorities as expedited reports 
within 7 days for fatal and life-threatening events and 15 days for other serious events, 
unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current 


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benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration 
or in the overall conduct of the trial. The investigational site also will forward a copy of 
all expedited reports to his or her IRB. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint 
committee will be used in this study. 
 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data 
Management Plan. AEs, PTEs, medical history, and concurrent conditions will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization (WHO) Drug Dictionary. 
12.1 
CRFs (Electronic and Paper) 
Completed (e)CRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to (e)CRFs. The 
sponsor will make arrangements to train the investigator, sub-investigator, and study 
coordinator in the use of the (e)CRF. These forms are used to transmit the information 
collected in the performance of this study to the sponsor and regulatory authorities. 
(e)CRFs must be completed directly recording data in English. 
Corrections to (e)CRFs are recorded in an audit trail that captures the old information, 
the new information, identification of the person making the correction, the date the 
correction was made, and the reason for change. 
The principal investigator must review the (e)CRFs for completeness and accuracy and 
must sign and date the appropriate (e)CRFs as indicated. Furthermore, the investigator 
must retain full responsibility for the accuracy and authenticity of all data entered on the 
(e)CRFs. 
The following data will not be recorded directly into the (e)CRFs. 
1) Laboratory Test Results Measured at Central Laboratory 
After the database lock of clinical study database, any change of, modification of or 
addition to the data on the (e)CRFs should be made by the investigator sub-investigator 
with use of change and modification records of CRFs (Data Clarification Form) 
provided by the sponsor. The principal investigator must review the Data Clarification 
Form for completeness and accuracy, and must sign, or sign and seal, and date the form. 
(e)CRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by study monitors. The sponsor or its designee will be permitted to 
review the subject’s medical and hospital records pertinent to the study to ensure 
accuracy of the (e)CRFs. The completed (e)CRFs are the sole property of the sponsor 
and should not be made available in any form to third parties, except for authorized 
representatives of appropriate governmental health or regulatory authorities, without 
written permission of the sponsor. 


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12.2 
Record Retention 
The investigator or the head of the site agrees to keep the records stipulated in Section 
12.1 and those documents that include (but are not limited to) the study-specific 
documents, the identification log of all participating subjects, medical records, source 
worksheets, all original signed and dated informed consent forms, copies of all paper 
CRFs, electronic copy of (e)CRFs, including the audit trail, and detailed records of drug 
disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. In addition, the investigator and the head of the site are required to retain 
essential relevant documents until the day as 1) or 2) below, whichever comes later. 
However, if the sponsor requests a longer time period for retention, the head of the site 
should discuss how long and how to retain those documents with the sponsor.  
1) The day on which marketing approval of the investigational drug is obtained (or 
the day 3 years after the date of notification in the case that the investigation is 
discontinued.) 
2) The day 3 years after the date of early termination or completion of the clinical 
study.  
In addition, the investigator and the head of the institution should retain the essential 
relevant documents until the receipt of a sponsor-issued notification to state the 
retention is no longer required. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
The analyses for this study will be performed using pooled data from the preceding 
study and this study, in principle, based on data obtained after administration of 
TVP-1012. 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock of 
this study. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to database lock of this study. This 
review will assess the accuracy and completeness of the study database, subject 
evaluability, and appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
In this study, two kinds of analysis sets are defined: full analysis set (FAS) and safety 
analysis set. The safety analysis set, the analysis set used for safety analysis, will be 
defined as “all subjects who were received at least one dose of TVP-1012.” The 
definition of each analysis set will be described in the Handling Rules for Analysis 
Data. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the 
rules for handling data, consulting a medical expert as needed. If necessary, the 
Handling Rules for Analysis Data will be supplemented with new handling rules that 
were not discussed at the planning stage. The Handling Rules for Analysis Data must be 
finalized prior to database lock. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized overall and by 
treatment group of the preceding study using the safety analysis set. 
13.1.3 Efficacy Analysis 
(1) [Secondary endpoint and its analytical method] 
[Secondary endpoint] 
• 
MDS-UPDRS Part II＋Part III total score 
[Analysis method] 


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The following analysis will be performed for FAS. 
Descriptive statistics (number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles) and two-sided 95% confidence intervals of means will be 
provided for the MDS-UPDRS Part II + Part III total score at each visit and the change 
from baseline in the MDS-UPDRS Part II + Part III total score at each visit of the 
treatment period by treatment group in the preceding study. 
(2) Additional efficacy endpoints 
Refer to Section 5.2.3. 
(3) Method of data conversion and handling of missing data 
Details will be described in the Handling Rules for Analysis Data and the Statistical 
Analysis Plan. 
(4) Significance level and confidence coefficient 
• 
Confidence coefficient: 95% (two-sided) 
13.1.4 Safety Analysis 
(1) Primary endpoint and its analytical method 
[Primary endpoint] 
• 
Adverse events 
[Analytical methods] 
The following analyses will be based on the safety analysis set. 
A treatment-emergent adverse event (TEAE) is defined as an adverse event whose date 
of onset occurs on or after the start of treatment period study drug in the preceding 
study. 
TEAEs whose date of onset occurs on or after the start of TVP-1012 will be coded 
using the MedDRA dictionary. The frequency distribution will be provided using the 
system organ class and the preferred term for each treatment group of the preceding 
study as follows: 
 All TEAEs 
 Drug-related TEAEs 
 Intensity of TEAEs 


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 Intensity of drug-related TEAEs 
 TEAEs leading to study drug discontinuation 
 Serious TEAEs 
 TEAEs over time 
(2) Secondary endpoints and their analytical methods 
[Secondary endpoints] 
 Laboratory test results, vital signs, 12-lead ECGs and weight 
[Analytical methods] 
The following analyses will be based on the safety analysis set. 
For continuous variables, the observed values and the changes from baseline will be 
summarized by treatment group of the preceding study for each visit using descriptive 
statistics. 
Case plots will also be presented for the observed values by treatment group of the 
preceding study. 
For categorical variables, shift tables showing the number of subjects in each category 
at baseline and each post-baseline visit will be provided for each treatment group of the 
preceding study. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
Number of subjects to be enrolled in this study: approximately 182 
[Justification of Sample size] 
In the preceding study, the planned number of subjects to be randomized was a total of 
240 (120 per group) and the planned number of subjects evaluable for the primary 
endpoint (change in the MDS-UPDRS Part II + Part III total score from baseline to 
Week 26 of the treatment period (LOCF)) was a total of 220 (110 per group). 
Since this study is a long-term extension study in patients with early Parkinson’s disease 
who have completed the 26-week treatment period in the preceding study, considering 
the potential dropouts in the preceding study, approximately 182 subjects will be 
enrolled in this study. 


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In addition, considering the potential dropouts in this study and in the preceding study, 
it is estimated that 155 subjects will be treated with 1 mg of TVP-1012 for 26 weeks 
and 59 subjects for 52 weeks. 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure 
that all aspects of the protocol are followed. Source documents will be reviewed for 
verification of data recorded on the (e)CRFs. Source documents are defined as original 
documents, data, and records. The investigator and the head of the institution guarantee 
access to source documents by the sponsor or its designee and by the IRB 
All aspects of the study and its documentation will be subject to review by the sponsor 
or designee, including but not limited to the Investigator’s Binder, study medication, 
subject medical records, informed consent documentation, and review of (e)CRFs and 
associated source documents. It is important that the investigator or sub-investigator and 
other study personnel are available during the monitoring visits and that sufficient time 
is devoted to the process. 
14.2 
Protocol Deviations 
The investigator or sub-investigator can deviate and change from the protocol for any 
medically unavoidable reason, for example, to eliminate an immediate hazard to study 
subjects, without a prior written agreement with the sponsor or a prior approval from 
IRB. In the event of a deviation or change, the principal investigator should notify the 
sponsor and the head of the site of the deviation or change as well as its reason in a 
written form, and then retain a copy of the written form. When necessary, the principal 
investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the 
head of the site as soon as possible and an approval from IRB should be obtained. 
The investigator or sub-investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or 
designees. In this circumstance, the sponsor-designated auditor will contact the site in 
advance to arrange an auditing visit. The auditor may ask to visit the facilities where 
laboratory samples are collected, where the medication is stored and prepared, and any 
other facility used during the study. In addition, there is the possibility that this study 
may be inspected by regulatory agencies, including those of foreign governments (e.g., 
the FDA, the United Kingdom Medicines and Healthcare products Regulatory Agency 
[MHRA]). If the study site is contacted for an inspection by a regulatory body, the 


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sponsor should be notified immediately. The investigator and the head of the institution 
guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each 
investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the “Responsibilities of 
the Investigator” that are listed in Appendix B. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable local requirements of each 
participating region. The sponsor or designee will require documentation noting all 
names and titles of members who make up the respective IRB. If any member of the 
IRB has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the 
respective IRB for the protocol’s review and approval. This protocol, the Investigator’s 
Brochure, a copy of the informed consent form, and, if applicable, subject recruitment 
materials and/or advertisements and other documents required by all applicable laws 
and regulations, must be submitted to a central or local IRB for approval. The IRB’s 
written approval of the protocol and subject informed consent must be obtained and 
submitted to the sponsor or designee before commencement of the study (i.e., before 
shipment of the sponsor-supplied drug or before initiation of the run-in period). The 
IRB approval must refer to the study by exact protocol title, number, and version date; 
identify versions of other documents (e.g., informed consent form) reviewed; and state 
the approval date. The sponsor will notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation. Until the site receives notification no 
protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may 
include notification to the IRB regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety 
reporting requirements, reports and updates regarding the ongoing review of the study at 
intervals specified by the respective IRB, and submission of the investigator’s final 
status report to IRB. All IRB approvals and relevant documentation for these items must 
be provided to the sponsor or its designee. 


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Subject incentives should not exert undue influence for participation. Payments to 
subjects must be approved by the IRB and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described 
in the Declaration of Helsinki and the ICH Guidelines for GCP and will be in 
accordance with all applicable laws and regulations. The informed consent form and the 
subject information sheet describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information (to the third party 
including overseas) for purposes of conducting the study. The informed consent form 
and the subject information sheet further explains the nature of the study, its objectives, 
and potential risks and benefits. The informed consent form will detail the requirements 
of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the 
informed consent form and the subject information sheet. The informed consent form 
and the subject information sheet must be approved by both the IRB and the sponsor 
prior to use. 
The informed consent form and the subject information sheet must be written in a 
language fully comprehensible to the prospective subject. It is the responsibility of the 
investigator or sub-investigator to explain the detailed elements of the informed consent 
form and the subject information sheet to the subject. Information should be given in 
both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the study 
and (2) decide whether or not to participate in the study. If the subject determines he or 
she will participate in the study, then the informed consent form must be signed and 
dated by the subject at the time of consent and prior to the subject entering into the 
study. The subject should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator or sub-investigator must also sign and 
date the informed consent form at the time of consent and prior to subject entering into 
the study. 
Once signed, the original informed consent form will be stored in the investigator’s site 
file. The investigator or sub-investigator must document the date the subject signs the 


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CONFIDENTIAL 
informed consent in the subject’s medical record. Copies of the signed informed consent 
form shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects in 
the same manner as the original informed consent. The date the revised consent was 
obtained should be recorded in the subject’s medical record, and the subject should 
receive a copy of the revised informed consent form. 
 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, a subject’s source data 
will only be linked to the sponsor’s clinical study database or documentation via a 
unique identification number. As permitted by all applicable laws and regulations, 
limited subject attributes, such as sex, age, or date of birth may be used to verify the 
subject and accuracy of the subject’s unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, 
the sponsor requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (e.g., FDA, MHRA, Pharmaceuticals and 
Medical Devices Agency [PMDA]), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, 
admission and discharge summaries for hospital admissions occurring during a subject’s 
study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent process 
(see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (i.e., subject name, address, and 
other identifier fields not collected on the subject’s [e]CRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data 
derived by the investigator from the study. During the study, only the sponsor may make 
study information available to other study investigators or to regulatory agencies, except 
as required by law or regulation. Except as otherwise allowable in the clinical study site 


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Amendment 1 
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CONFIDENTIAL 
agreement, any public disclosure (including publicly accessible websites) related to the 
protocol or study results is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 
The investigator or sub-investigator needs to obtain a prior written approval from the 
sponsor to publish any information from the study externally such as to a professional 
association.  
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely 
manner and to comply with applicable law, regulation and guidance, Takeda will, at a 
minimum register all clinical trials conducted in patients that it sponsors anywhere in 
the world on publicly accessible websites, JAPIC-CTI, before trial initiation. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of this clinical trial, regardless of outcome on publicly 
accessible websites, JAPIC-CTI, as required by applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable 
to the site where the subject is participating. If a local underwriter is required, then the 
sponsor or sponsor’s designee will obtain clinical study insurance against the risk of 
injury to clinical study subjects.  
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator or sub-investigator has 
questions regarding this policy, he or she should contact the sponsor or sponsor’s 
designee. 


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CONFIDENTIAL 
16.0 
REFERENCES 
[1] 
Parkinson’s disease and related diseases (3) Parkinson’s Disease (subsidized by 
government), Japan Intractable Diseases Information Center: Japan Intractable 
Diseases Research Foundation/Japan Intractable Diseases Information Center, 
http://www.nanbyou.or.jp/entry/169 (2014/10/30 accessed) 
[2] 
Preparation Committee for Guidelines on Parkinson’s Disease, Japanese Society 
of Neurology, “Practical Guidelines for Parkinson’s Disease 2011” Igaku Shoin, 
2011. 
[3] 
Schapira AH. Treatment options in the modern management of Parkinson disease. 
Arch Neurol. 2007; 64(8): 1083-1088 
[4] 
Schapira AH. Olanow CW. Drug selection and timing of initiation of treatment in 
early Parkinson’s disease. Ann Neurol. 2008; 64(Suppl 2): S47-55 
[5] 
 
 
[6] 
 
 
 
[7] 
 
 
 
 
 
 


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CONFIDENTIAL 
Appendix A Schedule of Study Procedures 
Study Week (a) 
Treatment period 
W26 
W29 
W32 
W36 
W40 
W46 
W52/ 
Early 
Termination (b) 
VISIT Number (c) 
8 
9 
10 
11 
12 
13 
14 
Study Day(d) (Day) 
182 
203 
224 
252 
280 
322 
364 
Visit Windows (d) (Days) 
175 to 
189 
196 to 
210 
217 to 
231 
245 to 
259 
273 to 
287 
315 to 
329 
357 to  
371 
Informed consent 
X (e) 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Physical examination 
X (f) 
X 
X 
X 
X 
X 
X 
Skin examination 
X (f) 
 
 
 
 
 
X 
Weight  
X (f) 
 
 
 
X 
 
X 
Vital signs 
X (f) 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X (f) 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests (g) 
X (f) 
X 
X 
 
X 
X 
X 
ECG 
X (f) 
 
 
 
X 
 
X 
MDS-UPDRS 
X (f) 
 
X 
X 
X 
X 
X 
QOL assessment 
X (f) 
 
 
 
X 
 
X 
Drug compliance 
X (f) 
X 
X 
X 
X 
X 
X 
Dispense investigational drug 
X 
X 
X 
X 
X 
X 
 
AE assessment(h) 
X (f) 
X 
X 
X 
X 
X 
X 
(a) The study visit weeks in this study will be counted from the start of the treatment period in the 
preceding study. 
(b) For subjects withdrawn from the study after the initiation of the investigational drug in this study and 
before Week 52 of the treatment period, the tests, observations, and assessments scheduled for Week 
52 of the treatment period should be performed within 7 days following discontinuation of treatment, 
whenever possible (the day of the last dose regarded as 0 day). 
(c) Visit numbers in this study will be continued from the preceding study. 
(d) Day 1 is defined as the day of first study medication administration for the treatment period in the 
preceding study. 
(e) Informed consent for this study must be obtained prior to tests, observations, and assessments at Week 
26 of the treatment period in the preceding study. 
(f) Results of the tests, observations, and assessments at Week 26 of the treatment period in the preceding 
study will be used also for this study. 
(g) To be measured after fasting for at least 8 hours whenever possible. Women of childbearing potential 
will undergo pregnancy test as well. 
(h) AE collection in this study will begin at the initiation of the investigational drug in this study, and 
continued until Week 52 of the treatment period or early termination. AEs occurring between the final 
assessment in the preceding study and the initiation of the investigational drug in this study will be 
captured by the preceding study. AEs that occurred during the preceding study and persisted into this 
study will be followed up in this study as well. 
 
 


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CONFIDENTIAL 
Appendix B Responsibilities of the Investigator 
1. Conduct the appropriate study in accordance with the protocol and GCP 
considering the rights, safety and wellbeing of human subjects. 
2. When a part of the important activities related to the study are delegated to the 
sub-investigator or the study collaborator, prepare the lists of activities to be 
delegated and responsible personnel, submit the lists to the director of the site in 
advance to get them accepted. 
3. Prepare a written informed consent form and other written information, and update 
as appropriate. 
4. Confirm the contents of the clinical study agreement. 
5. Provide necessary information on the protocol, medications and responsibilities of 
individual personnel to the sub-investigator and study collaborator, and provide 
guidance and supervision. 
6. Screen subjects who meet the requirements of the protocol, provide the explanation 
of the study in writing and obtain the written consent. 
7. Assume responsibility for all the medical judgment related to the study. 
8. Ensure in collaboration with the director of the site that sufficient information on all 
clinically significant adverse events related to the study are provided to subjects 
throughout and beyond the period when subjects participate in the study. 
9. If a subject consults other medical institution or other department, notify the 
physician of the medical institution or department of the subject’s participation in 
the study, as well as the end and termination of the study in writing, and document 
such records. 
10. In case of urgent report of a SAE, immediately notify the director of the site and the 
sponsor in writing. 
11. Determine the need of emergency key code blinding of a subject in case of 
emergency. 
12. Prepare correct and complete (e)CRFs, and submit them to the sponsor with 
electronic signature. 
13. Check and confirm the contents of (e)CRFs prepared by the sub-investigator or 
transcribed from the source data by the study collaborator, and submit them to the 
sponsor with electronic signature. 
14. Discuss any proposal from the sponsor including update of the protocol. 
15. Notify the director of the site of the end of the study in writing. 


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CONFIDENTIAL 
Appendix C Detailed Description of Amendments to Text 
Amendments made from the first edition of this study protocol are listed below. 
 
Page 14, 4.1 Background, Safety Summary 
Existing Text 
 
 
 
Revised Text 
 
 
 
 
 
 
 
Rationale for Amendment 
To appropriately document the summary of safety results based on the information on 
the incidence of adverse events in the 2 mg of TVP-1012 monotherapy group 
 
Page 24, 7.3 Excluded Medications and Treatments 
Existing Text 
(15) CYP1A2 inhibitor 
Revised Text 
(15) CYP1A2 inhibitor (including ciprofloxacin, enoxacin, fluvoxamine, 
zafirlukast) 
Rationale for Amendment 
To specify CYP1A2 inhibitors 
 


TVP-1012 
TVP-1012/OCT-001 
Page 74 of 74
Amendment 1 
16 December 2014
 
CONFIDENTIAL 
Page 25, 7.3 Excluded Medications and Treatments 
Existing Text 
(17) Antidepressant (excluding trazodone) 
Revised Text 
(17) Antidepressant 
Rationale for Amendment 
Prohibiting concomitant use of all anti-depressants, including trazodone, was 
determined to be appropriate, considering the safety of subjects and potential effect on 
efficacy evaluations. 
 
Page 27, 7.4 Diet, Fluid, Activity Control 
Existing Text 
(No description) 
Revised Text 
11. Subjects should avoid driving vehicles, operating machinery, and working in 
high areas, etc., in consideration of possible treatment-emergent dizziness, or 
reduced attention, concentration, or reflex function. 
Rationale for Amendment 
Having judged that caution should be made in light of safety of subjects based on 
descriptions of overseas labeling information of TVP-1012 and Japanese package 
insert for Parkinson’s disease drugs. 
 

SAP_001.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable information or 
company confidential information may be removed in their entirety if it is considered that they do not add 
substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). 
Note; This document was translated into English and the language in original document was Japanese.


Protocol No. TVP-1012/OCT-001 
Statistical Analysis Plan 
 
Title of Study 
: 
A Multicenter, Open-label, Long-term, Extension, Phase 3 Study 
to Evaluate the Safety and Efficacy of TVP-1012 at 1 mg in 
Early Parkinson's Disease Patients Not Treated with Levodopa 
Study Number: 
: 
TVP-1012/OCT-001 
Sponsor: 
: 
Takeda Pharmaceutical Company Limited 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Second Version: 
Created on 11 April 2017 
 


Protocol No. TVP-1012/OCT-001 
1 
TABLE OF CONTENTS 
Considerations ...................................................................................................................................... 3 
Glossary ................................................................................................................................................ 4 
Definition of Visit Window ................................................................................................................... 5 
A) For the analyses based on the data after administration of TVP-1012 ............................................ 5 
B) For the analyses based on the data after study drug administration for the treatment period in 
the preceding study .......................................................................................................................... 8 
Others .................................................................................................................................................... 9 
1 Study Subjects, Demographics, and Other Baseline Characteristics ............................................. 11 
1.1 Disposition of Subjects .......................................................................................................... 11 
 Study Information in This Study .................................................................................... 11 
1.1.1
 All Subjects Who Did Not Enter the Treatment Period .................................................. 11 
1.1.2
 Subject Eligibility in This Study .................................................................................... 11 
1.1.3
 Number of Subjects Who Entered This Study in Each Site ............................................ 11 
1.1.4
 Disposition of Subjects ................................................................................................... 12 
1.1.5
 Study Drug Completion Status ....................................................................................... 12 
1.1.6
 Protocol Deviations and Analysis Data Set .................................................................... 13 
1.1.7
1.2 Demographic and Other Baseline Characteristics .................................................................. 14 
 Summary of Demographics and Other Baseline Characteristic ..................................... 14 
1.2.1
 Medical History and Concurrent Medical Conditions .................................................... 14 
1.2.2
 Medication History and Concomitant Medications ........................................................ 15 
1.2.3
1.3 Measurements of Treatment Compliance ............................................................................... 15 
 Exposure and Compliance of TVP-1012 ........................................................................ 15 
1.3.1
2 Efficacy Analysis ........................................................................................................................... 17 
2.1 Secondary Endpoint and Analytical Method .......................................................................... 17 
 MDS-UPDRS Part II + Part III Total Score ................................................................... 17 
2.1.1
2.2 Other Endpoints and Analytical Methods .............................................................................. 17 
 MDS-UPDRS Total Scores and Individual Scores ......................................................... 17 
2.2.1
 PDQ-39 Summary Index and Domain Scores ................................................................ 18 
2.2.2
2.3 Statistical/Analytical Issues ................................................................................................... 18 
 Adjustments for Covariates ............................................................................................ 18 
2.3.1
 Handling of Dropouts or Missing Data .......................................................................... 18 
2.3.2
 Interim Analyses and Data Monitoring .......................................................................... 18 
2.3.3
 Multicentre Studies ......................................................................................................... 18 
2.3.4
 Multiple Comparison/Multiplicity .................................................................................. 18 
2.3.5
 Use of an "Efficacy Subset" of Subject .......................................................................... 19 
2.3.6
 Active-Control Studies Intended to Show Equivalence or Non-inferiority .................... 19 
2.3.7


Protocol No. TVP-1012/OCT-001 
2 
 Examination of Subgroups ............................................................................................. 19 
2.3.8
3 Safety Analysis .............................................................................................................................. 20 
3.1 Treatment-Emergent Adverse Event ...................................................................................... 20 
 Overview of Treatment-Emergent Adverse Events ........................................................ 20 
3.1.1
 Displays of Treatment-Emergent Adverse Events .......................................................... 20 
3.1.2
 Examination of Subgroups for Treatment-Emergent Adverse Event ............................. 22 
3.1.3
3.2 Laboratory and Other Safety Data ......................................................................................... 22 
 Laboratory Test Results .................................................................................................. 22 
3.2.1
 Vital Signs, Physical Findings, and Other Observations Related to Safety .................... 23 
3.2.2
4 Significance Level and Confidence Coefficient ............................................................................ 25 
Creation History (version management) ............................................................................................. 26 
[Appendix 1] A Comparison Table for Changes in TVP-1012/OCT-001 ............................................. 1 
[Appendix 2] 
Definition of MAV Criteria ....................................................................................... 1 
[Appendix 3] 
MDS-UPDRS Score .................................................................................................. 1 
[Appendix 4] 
Modified Hoehn and Yahr Scale ............................................................................... 1 
[Appendix 5] 
PDQ-39 Score ........................................................................................................... 1 
 
 
 


Protocol No. TVP-1012/OCT-001 
3 
Considerations 
This is a multicenter, open-label, long-term, extension, phase 3 study that evaluates the safety and 
efficacy of long-term administration of TVP-1012 at 1 mg for another 26 weeks in patients with 
early Parkinson’s disease who have completed the 26-week treatment period in the preceding 
TVP-1012/CCT-001 study. 
The analyses for this study will be performed using pooled data from the preceding study and this 
study based on data obtained after administration of TVP-1012, unless otherwise specified. 


Protocol No. TVP-1012/OCT-001 
4 
Glossary 
 Descriptive statistics: 
Number of subjects, mean, standard deviation, maximum, minimum, and quartiles 
 MAV: 
Markedly Abnormal Value 
 Treatment groups in the preceding study: 
TVP-1012 1 mg and placebo groups in the preceding study. However, they are shown as 
“1 mg ->1 mg group” and “P ->1 mg group” respectively in this statistical analysis plan. 
 Study drugs for treatment period in both studies: 
Study drug for treatment period in the previous study and study drug in this study 
 Number of days after administration (days): 
A) For the analyses based on the data after administration of TVP-1012 
The day before the day of first TVP-1012 administration is shown as Day -1 and 
the day of first TVP-1012 administration as Day 1.  That is, shown as follows: 
[If the treatment group in the preceding study is 1 mg ->1 mg group] 
Day before the day of first study drug administration for the treatment period 
in the preceding study: 
Day -1 
Day of first study drug administration for the treatment period in the 
preceding study: 
Day 1 
[If the treatment group in the preceding study is P ->1 mg group] 
Day before the day of first study drug administration in this study: 
 Day -1 
Day of first study drug administration in this study: 
Day 1 
B) For the analyses based on the data after study drug administration for the treatment 
period in the preceding study 
The day before the day of the first study drug administration for the treatment 
period in the preceding study is shown as Day -1 and the day of the first study drug 
administration for the treatment period in the preceding study as Day 1.  
 Number of days after the end of administration (days): 
Day 1 is defined as the day following the later of “day of the last study drug administration 
for the treatment period in the preceding study” or the “day of the last study drug 
administration in this study.”  
 Protocol Deviations: 
Protocol deviations in this study, unless otherwise specified.  
 


Protocol No. TVP-1012/OCT-001 
5 
Definition of Visit Window 
A) For the analyses based on the data after administration of TVP-1012 
For each test, observation, and evaluation items, evaluable data (i.e., non-missing and acceptable 
according to the Handling Rules for Analysis Data) will be handled according to the following rules.  
However, the number of days after administration and number of days after the end of administration 
will be the contents of “For the analyses based on the data after administration of TVP-1012” in the 
Glossary.  
Among the evaluation points, at points other than at the end of administration, evaluable data within 
the visit window will be used.  If more than one evaluable data lies within the same visit window, 
the examinations, observation, and assessments with the Study Time closest to the scheduled Study 
Time will be used. If there are two observations equidistant to the scheduled Study Time, the later 
observation will be used. The size of difference from the Study Time will be determined based on 
the number of days after administration.  
Among the evaluation points, at the end of administration, the data with the largest number of days 
after administration will be used among the evaluable data within the visit window.  
 
MDS-UPDRS Part I, II, III, and IV Total Scores, MDS-UPDRS Part II + Part III Total Score, 
MDS-UPDRS Tremor, Muscle Rigidity, and Akinesia/Bradykinesia Scores, and MDS-UPDRS 
Individual Scores 
Visit 
Scheduled Study Time 
Visit Windows 
Number of 
days after 
administration 
Number of days 
after the end of 
administration 
Baseline (prior to TVP-1012 
administration) 
Number of days after 
administration: -1 
-22 ~ -1 
 
Week 6 
Number of days after 
administration: 42 
1 ~ 55 
< 8 
Week 10 
Number of days after 
administration: 70 
56 ~ 83 
< 8 
Week 14 
Number of days after 
administration: 98 
84 ~ 118 
< 8 
Week 20 
Number of days after 
administration: 140 
119 ~ 160 
< 8 
Week 26 
Number of days after 
administration: 182 
161 ~ 202 
< 8 
Week 32 
Number of days after 
administration: 224 
203 ~ 237 
< 8 
Week 36 
Number of days after 
administration: 252 
238 ~ 265 
< 8 
Week 40 
Number of days after 
administration: 280 
266 ~ 300 
< 8 
Week 46 
Number of days after 
administration: 322 
301 ~ 342 
< 8 
Week 52 
Number of days after 
administration: 364 
343 ~ 385 
< 8 
At end of administration 
  
1 ~ 385 
< 8 
 


Protocol No. TVP-1012/OCT-001 
6 
PDQ-39 Summary Index and Score by Domain 
Visit 
Scheduled Study Time 
Visit Windows 
Number of 
days after 
administration 
Number of days 
after the end of 
administration 
Baseline (prior to TVP-1012 
administration) 
Number of days after 
administration: -1 
-22 ~ -1 
 
Week 14 
Number of days after 
administration: 98 
1 ~ 139 
< 8 
Week 26 
Number of days after 
administration: 182 
140 ~ 230 
< 8 
Week 40 
Number of days after 
administration: 280 
231 ~ 321 
< 8 
Week 52 
Number of days after 
administration: 364 
322 ~ 385 
< 8 
At end of administration 
  
1 ~ 385 
< 8 
 
Clinical Laboratory Tests 
Visit 
Scheduled Study Time 
Visit Windows 
Number of 
days after 
administration 
Number of days 
after the end of 
administration 
Baseline (prior to TVP-1012 
administration) 
Number of days after 
administration: -1 
-22 ~ -1 
 
Week 3 
Number of days after 
administration: 21 
1 ~ 31 
< 8 
Week 6 
Number of days after 
administration: 42 
32 ~ 69 
< 8 
Week 14 
Number of days after 
administration: 98 
70 ~ 118 
< 8 
Week 20 
Number of days after 
administration: 140 
119 ~ 160 
< 8 
Week 26 
Number of days after 
administration: 182 
161 ~ 192 
< 8 
Week 29 
Number of days after 
administration: 203 
193 ~ 213 
< 8 
Week 32 
Number of days after 
administration: 224 
214 ~ 251 
< 8 
Week 40 
Number of days after 
administration: 280 
252 ~ 300 
< 8 
Week 46 
Number of days after 
administration: 322 
301 ~ 342 
< 8 
Week 52 
Number of days after 
administration: 364 
343 ~ 385 
< 8 
 


Protocol No. TVP-1012/OCT-001 
7 
Vital Signs 
Visit 
Scheduled Study Time 
Visit Windows 
Number of 
days after 
administration 
Number of days 
after the end of 
administration 
Baseline (prior to TVP-1012 
administration) 
Number of days after 
administration: -1 
-22 ~ -1 
 
Week 3 
Number of days after 
administration: 21 
1 ~ 31 
< 8 
Week 6 
Number of days after 
administration: 42 
32 ~ 55 
< 8 
Week 10 
Number of days after 
administration: 70 
56 ~ 83 
< 8 
Week 14 
Number of days after 
administration: 98 
84 ~ 118 
< 8 
Week 20 
Number of days after 
administration: 140 
119 ~ 160 
< 8 
Week 26 
Number of days after 
administration: 182 
161 ~ 192 
< 8 
Week 29 
Number of days after 
administration: 203 
193 ~ 213 
< 8 
Week 32 
Number of days after 
administration: 224 
214 ~ 237 
< 8 
Week 36 
Number of days after 
administration: 252 
238 ~ 265 
< 8 
Week 40 
Number of days after 
administration: 280 
266 ~ 300 
< 8 
Week 46 
Number of days after 
administration: 322 
301 ~ 342 
< 8 
Week 52 
Number of days after 
administration: 364 
343 ~ 385 
< 8 
 
12-lead ECG, Weight 
Visit 
Scheduled Study Time 
Visit Windows 
Number of 
days after 
administration 
Number of days 
after the end of 
administration 
Baseline (prior to TVP-1012 
administration) 
Number of days after 
administration: -1 
-22 ~ -1 
 
Week 14 
Number of days after 
administration: 98 
1 ~ 139 
< 8 
Week 26 
Number of days after 
administration: 182 
140 ~ 230 
< 8 
Week 40 
Number of days after 
administration: 280 
231 ~ 321 
< 8 
Week 52 
Number of days after 
administration: 364 
322 ~ 385 
< 8 
 


Protocol No. TVP-1012/OCT-001 
8 
B) For the analyses based on the data after study drug administration for the treatment period in the 
preceding study 
For MDS-UPDRS Part II + Part III total score among each test, observation, and evaluation items, 
evaluable data will be handled according to the following rules.  The number of days after 
administration and number of days after the end of administration is defined in “For the analyses 
based on the data after study drug administration for the treatment period in the preceding study” in 
Glossary.  
Among the visits, at visits other than baseline (at end of observation period) and Week 52 of the 
Treatment Period (LOCF), evaluable data within the visit window will be used.  If more than one 
evaluable data lies within the same visit window, the examinations, observation, and assessments 
with the Study Time closest to the scheduled Study Time will be used. If there are two observations 
equidistant to the scheduled Study Time, the later observation will be used. The size of difference 
from the Study Time will be determined based on the number of days after administration.  
Among the visits, at baseline (at end of observation period) and Week 52 of Treatment Period 
(LOCF), the data with the largest number of days after administration will be used among the 
evaluable data within the visit window.  
 
MDS-UPDRS Part II + Part III total score 
Visit 
Scheduled Study Time 
Visit Windows 
Number of 
days after 
administration 
Number of days 
after the end of 
administration 
Baseline (end of observation 
period) 
Number of days after 
administration: -1 
-22 ~ -1 
 
Week 6 (Treatment Period) 
Number of days after 
administration: 42 
1 ~ 55 
< 8 
Week 10 (Treatment Period) 
Number of days after 
administration: 70 
56 ~ 83 
< 8 
Week 14 (Treatment Period) 
Number of days after 
administration: 98 
84 ~ 118 
< 8 
Week 20 (Treatment Period) 
Number of days after 
administration: 140 
119 ~ 160 
< 8 
Week 26 (Treatment Period) 
Number of days after 
administration: 182 
161 ~ 202 
< 8 
Week 32 (Treatment Period) 
Number of days after 
administration: 224 
203 ~ 237 
< 8 
Week 36 (Treatment Period) 
Number of days after 
administration: 252 
238 ~ 265 
< 8 
Week 40 (Treatment Period) 
Number of days after 
administration: 280 
266 ~ 300 
< 8 
Week 46 (Treatment Period) 
Number of days after 
administration: 322 
301 ~ 342 
< 8 
Week 52 (Treatment Period) 
Number of days after 
administration: 364 
343 ~ 385 
< 8 
Week 52 (Treatment Period) 
(LOCF) 
  
1 ~ 385 
< 8 
 


Protocol No. TVP-1012/OCT-001 
9 
Others 
 Causality of AEs with study drug: 
Cases where the causality with the study drug cannot be ruled out, that is, “Unlikely,” 
“Possibly,” or “Probably” are handled as “Related,” and cases where the causality with the 
study drug are “Unrelated” are handled as “Not related.” 
 Smoking history: 
When the smoking history is “Current smoker,” it is handled as “Yes.” When the smoking 
history is “Never smoked” or “Ex-smoker,” it is handled as “No.” 
* 
If the category is set as [Yes or No], it is handled with the aforementioned contents.  
 Entry to this study: 
If the subject is considered eligible to enter to this study, it is handled as “Yes” and other 
cases are handled as “No.” 
 Duration of study drug administration in this study (days): 
Day of last study drug administration in this study - Day of first study drug administration 
in this study +1 
 Duration of study drug administration for the treatment period in both studies (days): 
“Day of last study drug administration for the treatment period in the preceding study” or 
“Day of last study drug administration in this study,” whichever the latest - Day of first 
study drug administration for the treatment period in the preceding study +1 
 Duration of Exposure to TVP-1012 (days): 
Day of last TVP-1012 administration - Day of first TVP-1012 administration +1 
 Compliance of TVP-1012 (%): 
(Prescribed quantity of TVP-1012 - Retrieved quantity of TVP-1012) / Duration of 
TVP-1012 administration × 100 (rounded to the first decimal place) 
 Duration of Parkinson’s disease (years): 
([Year when the consent was obtained × 12 + Month when the consent was obtained] – 
[Onset year of Parkinson’s disease × 12 + Onset month of Parkinson’s disease]) / 12 
(rounded to the first decimal place) 
* 
If the onset month of Parkinson’s disease is missing, the onset month will be imputed as 
January.  
 MDS-UPDRS score: 
See Appendix 3 of this Statistical Analysis Plan 
 Modified Hoehn and Yahr Scale: 
See Appendix 4 of this Statistical Analysis Plan 
 PDQ-39 score: 
See Appendix 5 of this Statistical Analysis Plan 


Protocol No. TVP-1012/OCT-001 
10 
 QTcF interval (msec): 
QT interval (msec) / ([RR interval (msec) / 1000])0.33 (rounded to the nearest integer) 
 


Protocol No. TVP-1012/OCT-001 
11 
1 
Study Subjects, Demographics, and Other Baseline Characteristics 
1.1 
Disposition of Subjects 
 Study Information in This Study 
1.1.1
Analysis Set: 
All Subjects Who Signed the Informed Consent Form in This Study 
Analysis Variable(s): 
Date First Subject Signed Informed Consent Form in This Study 
 
Date of Last Subject’s Last Visit/Contact in This Study 
 
MedDRA Version in this study 
 
WHO Drug Version in this study 
 
SAS Version Used for Creating the Data Sets in This Study 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables. 
 
(1) 
Display of analysis variables 
 
 All Subjects Who Did Not Enter the Treatment Period 
1.1.2
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period Among the Subjects 
Who Signed the Informed Consent Form in This Study 
Analysis Variable(s): 
Categories in parentheses (hereinafter the same) 
 
Age (years) 
[Min<= - <65, 65<= - <=Max] 
 
Gender 
[Male, Female] 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables. 
(1) 
Frequency distributions for categorical variables and descriptive 
statistics for continuous variables  
 
 Subject Eligibility in This Study 
1.1.3
Analysis Set: 
All Subjects Who Signed the Informed Consent Form in This Study 
Analysis Variable(s): 
Status of Entrance into This Study [Yes, No] 
 
Reason for Not Entering to This 
Study 
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation, Lost to 
Follow-up, Voluntary Withdrawal, 
Study Termination, Did Not Meet 
Entrance Criteria or Violation of 
Exclusion Criteria, Other] 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables. 
When calculating percentages for the primary reasons for subject not 
entering to this study, the total number of subjects who did not enter this 
study will be used as the denominator. 
 
(1) 
Frequency distributions 
 
 Number of Subjects Who Entered This Study in Each Site 
1.1.4
Analysis Set: 
All Subjects Who Entered This Study 
Analysis Variable(s): 
Status of Entrance into This Study [Yes] 
Stratified Variable(s): 
Site 
[Site numbers will be used as 
categories] 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 
by treatment group in the preceding study for each stratified item and by 
combining the treatment groups in the preceding study.  
 
(1) 
Frequency distributions 


Protocol No. TVP-1012/OCT-001 
12 
 
 Disposition of Subjects 
1.1.5
Analysis Set: 
All Subjects Who Entered This Study 
Analysis Variable(s): 
Study Drug Administration Status 
in This Study  
[No] 
 
Reason for Not Being Treated 
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation, Lost to 
Follow-up, Voluntary Withdrawal, 
Study Termination, Did Not Meet 
Entrance Criteria or Violation of 
Exclusion Criteria, Other] 
 
Study Drug Completion Status in 
This Study 
[Completed Study Drug, Prematurely 
Discontinued Study Drug] 
 
Reason for Discontinuation of 
Study Drug 
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation, Lost to 
Follow-up, Voluntary Withdrawal, 
Study Termination, Pregnancy, Lack of 
Efficacy, Other] 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 
by treatment group in the preceding study and by combining the treatment 
groups in the preceding study.  When calculating percentages for the 
primary reasons for not being treated, the total number of subjects who did 
not receive TVP-1012 will be used as the denominator and when calculating 
percentages for the primary reasons for prematurely discontinued study 
drug, the total number of subjects who did complete the study drug 
administration will be used as the denominator. 
 
(1) 
Frequency distributions 
 
 Study Drug Completion Status 
1.1.6
1.1.6.1 
Assessment of This Study 
Analysis Set: 
All Subjects Who Entered This Study 
Analysis Variable(s): 
Study Drug Completion Status in 
This Study 
[Completed Study Drug, Prematurely 
Discontinued Study Drug] 
 
Reason for Discontinuation of 
Study Drug 
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation, Lost to 
Follow-up, Voluntary Withdrawal, 
Study Termination, Pregnancy, Lack of 
Efficacy, Other] 
Categories: 
Duration of study drug 
administration in this study (days) 
[0, 1<= - <28, 28<= - <56, 56<= - <84, 
84<= - <112, 112<= - <140, 140<= - 
<168, 168<= - <=Max] 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 
by treatment group in the preceding study and by combining the treatment 
groups in the preceding study.  
 
(1) 
Frequency distributions by treatment period of study drug in this 
study 
 


Protocol No. TVP-1012/OCT-001 
13 
1.1.6.2 
Assessment of Preceding Study and This Study 
Analysis Set: 
All Subjects Who Were Randomized in the Preceding Study 
Analysis Variable(s): 
Study Drug Completion Status for the Treatment Period in Both Studies 
 
 
[Completed Study Drug, Prematurely 
Discontinued Study Drug] 
 
Reason for Discontinuation of 
Study Drug 
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation, Lost to 
Follow-up, Voluntary Withdrawal, 
Study Termination, Pregnancy, Lack of 
Efficacy, Other] 
Categories: 
Duration of study drug administration for the treatment period in both 
studies (days) 
 
 
[0, 1<= - <84, 84<= - <168, 168<= - 
<252, 252<= - <336, 336<= - <=Max] 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 
by treatment group in the preceding study and by combining the treatment 
groups in the preceding study.  
 
(1) 
Frequency distributions by treatment period of study drug 
administration for the treatment period in both studies 
 
 Protocol Deviations and Analysis Data Set 
1.1.7
1.1.7.1 
Protocol Deviations 
Analysis Set: 
All Subjects Who Entered This Study 
Analysis Variable(s): 
Protocol Deviations 
[Major GCP Violations, Deviations of 
Protocol Entry Criteria, Deviations of 
Discontinuation Criteria, Deviations 
Related to Treatment Procedure or 
Dose, Deviations Concerning Excluded 
Medication or Therapy, Deviations to 
Avoid Emergency Risk, Other 
Deviation] 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 
by treatment group in the preceding study and by combining the treatment 
groups in the preceding study.  
The number of subjects with protocol deviations will be calculated and the 
details of deviations will be shown after classifying the contents of 
deviations into the above categories.  A subject who has several categories 
will be counted once in each appropriate category.  
(1) 
Frequency distributions 
 
1.1.7.2 
Analysis Sets 
Analysis Set: 
All Subjects Who Were Randomized in the Preceding Study 
Analysis Variable(s): 
Handling of Cases in Analysis Sets and Case Data 
 
 
[Categories are based on the 
specifications in “Handling Rules 
for Analysis Data”] 
 
Inclusion/Exclusion of Analysis Set 
 


Protocol No. TVP-1012/OCT-001 
14 
 
Full Analysis Set 
[Included] 
 
Full Analysis Set 2 
[Included] 
 
Safety Analysis Set 
[Included] 
Analysis Method(s): 
The following analyses (1) and (2) will be performed for the above analysis 
variables by treatment group in the preceding study and the following 
analysis (3) will be performed by treatment group in the preceding study 
and by combining the treatment groups in the preceding study.  
For (1) and (2), a subject who has several categories will be counted once in 
each appropriate category. 
 
(1) 
Frequency distributions for handling of cases in each analysis set 
(2) 
Frequency distributions for handling of case data in each analysis set 
(3) 
Frequency distributions for number of cases included in each analysis 
set 
 
1.2 
Demographic and Other Baseline Characteristics 
 Summary of Demographics and Other Baseline Characteristic 
1.2.1
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Age (years) 
[Min<= - <65, 65<= - <=Max] 
 
Gender 
[Male, Female] 
 
Height (cm) 
 
 
Weight (kg) (Baseline (prior to TVP-1012 administration)) 
 
BMI(kg/m2) 
 
 
Smoking history 
[The subject has never smoked,  
The subject is a current smoker,  
The subject is an ex-smoker] 
 
Timing of Study Drug 
Administration 
[Before breakfast, After breakfast] 
 
Duration of Parkinson’s disease 
(years) 
[Min<= - <1.5, 1.5<= - <=Max] 
 
Modified Hoehn and Yahr Scale 
[Min<= - <2.0, 2.0<= - <3.0, 3.0<= - 
<=Max] 
 
MDS-UPDRS Part II + Part III total score (Baseline (prior to TVP-1012 
administration)) 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 
by treatment group in the preceding study and by combining the treatment 
groups in the preceding study.  
(1) 
Frequency distributions for categorical variables and descriptive 
statistics for continuous variables  
 
 Medical History and Concurrent Medical Conditions 
1.2.2
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Medical History in the Preceding 
Study 
 
 
Concurrent Medical Conditions in 
the Preceding Study 
 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 
by treatment group in the preceding study and by combining the treatment 


Protocol No. TVP-1012/OCT-001 
15 
groups in the preceding study.  
MedDRA dictionary will be used for coding. Summaries will be provided 
using SOC and PT, where SOC will be sorted alphabetically and PT will be 
sorted in decreasing frequency.   
(1) 
Frequency distributions for medical history in the preceding study 
(by SOC/PT) 
(2) 
Frequency distributions for concurrent medical conditions in the 
preceding study (by SOC/PT) 
 
The method of counting events when conducting each frequency 
distribution will be as follows: 
[Number of subjects with medical history and/or concurrent medical 
conditions] 
A subject with multiple occurrences of medical history or concurrent 
medical conditions within a SOC will be counted only once in that SOC.  
A subject with multiple occurrences of medical history or concurrent 
medical conditions within a PT will be counted only once in that PT. 
 
 Medication History and Concomitant Medications 
1.2.3
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Medication History in the 
Preceding Study 
 
 
Concomitant Medications in the Preceding Study and This Study 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 
by treatment group in the preceding study and by combining the treatment 
groups in the preceding study.  
The WHO Drug dictionary will be used for coding. Summaries will be 
provided using Preferred Names and sorted in decreasing frequency based 
on the number of reports.  
A subject who has been administered multiple doses of the same medication 
(Preferred Name) will be counted only once for that medication (Preferred 
Name). 
(1) 
Frequency distributions for medication history in the preceding study 
(2) 
Frequency distributions for concomitant medications that the subject 
started to use prior to study drug administration for the treatment 
period in the preceding study and also used during the treatment 
period, and concomitant medications that the subject started to use 
after study drug administration for the treatment period in the 
preceding study 
 
1.3 
Measurements of Treatment Compliance 
 Exposure and Compliance of TVP-1012 
1.3.1
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Duration of Exposure to 
TVP-1012 (days) 
[1<= - <84, 84<= - <168, 168<= - 
<252, 252<= - <336, 336<= - <=Max] 
 
Compliance of TVP-1012 (%) 
[Min<= - <50.0, 50.0<= - <70.0, 
70.0<= - <90.0, 90.0<= - <=Max] 
Analysis Method(s): 
The following analysis will be performed for the above analysis variables 


Protocol No. TVP-1012/OCT-001 
16 
by treatment group in the preceding study and by combining the treatment 
groups in the preceding study.  
(1) 
Frequency distributions for categorical variables and descriptive 
statistics for continuous variables  


Protocol No. TVP-1012/OCT-001 
17 
2 
Efficacy Analysis 
2.1 
Secondary Endpoint and Analytical Method 
 MDS-UPDRS Part II + Part III Total Score 
2.1.1
2.1.1.1 
Analysis based on the data after administration of TVP-1012 
Analysis Set: 
Full Analysis Set 
Analysis Variable(s): 
MDS-UPDRS Part II + Part III total score 
Visit: 
Baseline (prior to TVP-1012 administration), Week 6, Week 10, Week 14, 
Week 20, Week 26, Week 32, Week 36, Week 40, Week 46, Week 52, End of 
Treatment 
Analysis Method(s): 
Descriptive statistics and two-sided 95% confidence intervals of means at 
each visit by treatment group in the preceding study will be provided for the 
MDS-UPDRS Part II + Part III total score at each visit and the change from 
baseline (prior to TVP-1012 administration) in the MDS-UPDRS Part II + 
Part III total score at each visit of the treatment period (at each visit during 
the treatment period (Week 6 to End of Treatment)-Baseline (prior to 
TVP-1012 administration)).  Furthermore, the means and standard 
deviations by treatment group in the preceding study will be shown in 
graphical display for the MDS-UPDRS Part II + Part III total score at each 
visit, and the change from baseline (prior to TVP-1012 administration) in 
the MDS-UPDRS Part II + Part III total score at each visit of the treatment 
period. 
 
2.1.1.2 
Analysis based on the data after study drug administration for the treatment period 
in the preceding study 
Analysis Set: 
Full Analysis Set 2 
Analysis Variable(s): 
MDS-UPDRS Part II + Part III total score 
Visit: 
Baseline (at end of observation period), Week 6, Week 10, Week 14, Week 
20, Week 26, Week 32, Week 36, Week 40, Week 46, Week 52 of Treatment 
Period, Week 52 of Treatment Period (LOCF) 
Analysis Method(s): 
The same analysis as 2.1.1.1 will be performed for the above analysis 
variables. 
Furthermore, the point estimates of the mean differences between treatment 
groups (1 mg -> 1 mg group-P -> 1 mg group) and the two-sided 95% 
confidence intervals at each visit by treatment group in the preceding study 
will be provided for the change from baseline (at end of observation period) 
in the MDS-UPDRS Part II + Part III total score at each visit during the 
treatment period (at each visit during the treatment period (Week 6 to Week 
52 of Treatment Period (LOCF))-Baseline (at end of observation period)). 
 
2.2 
Other Endpoints and Analytical Methods 
 MDS-UPDRS Total Scores and Individual Scores 
2.2.1
Analysis Set: 
Full Analysis Set 
Analysis Variable(s): 
MDS-UPDRS Part I total score 
 
MDS-UPDRS Part II total score 
 
MDS-UPDRS Part III total score 
 
MDS-UPDRS Part IV total score 


Protocol No. TVP-1012/OCT-001 
18 
 
MDS-UPDRS tremor score 
 
MDS-UPDRS bradykinesia score 
 
MDS-UPDRS muscle rigidity score 
 
MDS-UPDRS individual scores 
Visit: 
Baseline (prior to TVP-1012 administration), Week 6, Week 10, Week 14, 
Week 20, Week 26, Week 32, Week 36, Week 40, Week 46, Week 52, End of 
Treatment 
Analysis Method(s): 
The same analysis as 2.1.1.1 will be performed for the above analysis 
variables. However, the graphical display of the mean and standard 
deviation is excluded. 
 
 PDQ-39 Summary Index and Domain Scores 
2.2.2
Analysis Set: 
Full Analysis Set 
Analysis Variable(s): 
PDQ-39 Summary Index 
 
PDQ-39 domain scores 
Visit: 
Baseline (prior to TVP-1012 administration), Week 14, Week 26, Week 40, 
Week 52, End of Treatment 
Analysis Method(s): 
The same analysis as 2.1.1.1 will be performed for the above analysis 
variables. However, the graphical display of the mean and standard 
deviation is excluded. 
 
2.3 
Statistical/Analytical Issues 
 Adjustments for Covariates 
2.3.1
Not applied in this study. 
 
 Handling of Dropouts or Missing Data 
2.3.2
Missing test results and data determined to be non-evaluable according to the Handling Rules for 
Analysis Data and this statistical analysis plan will not be used for hypothesis testing and estimations.  
Values below/less than or equal to the lower limit of quantification will be treated as zero when 
calculating the descriptive statistics. Values above/greater than or equal to the upper limit of 
quantification will be treated as the upper limit of quantification when calculating the descriptive 
statistics. 
 
 Interim Analyses and Data Monitoring 
2.3.3
No interim analysis is planned. 
 
 Multicentre Studies 
2.3.4
Not applied in this study. 
 
 Multiple Comparison/Multiplicity 
2.3.5
Not applied in this study. 
 


Protocol No. TVP-1012/OCT-001 
19 
 Use of an "Efficacy Subset" of Subject 
2.3.6
Not applicable in this study. 
 
 Active-Control Studies Intended to Show Equivalence or Non-inferiority 
2.3.7
Not applicable in this study. 
 
 Examination of Subgroups 
2.3.8
2.3.8.1 
Examination of Subgroups for Secondary Endpoint 
Analysis Set: 
Full Analysis Set 
Analysis Variable(s): 
Change from baseline (prior to TVP-1012 administration) in the 
MDS-UPDRS Part II + Part III total score at end of treatment (at end of 
treatment-baseline (prior to TVP-1012 administration)) 
Subgroup(s): 
Age (years) 
[Min<= - <65, 65<= - <=Max] 
 
Gender 
[Male, Female] 
 
Smoking history 
[Yes, No] 
 
Timing of Study Drug 
Administration 
[Before breakfast, After breakfast] 
 
Duration of Parkinson’s disease 
(years) 
[Min<= - <1.5, 1.5<= - <=Max] 
 
Modified Hoehn and Yahr Scale 
[Min<= - <2.0, 2.0<= - <3.0, 3.0<= - 
<=Max] 
Analysis Method(s): 
Descriptive statistics and two-sided 95% confidence intervals of means will 
be provided for the above each subgroup by treatment group in the 
preceding study. 
 
 


Protocol No. TVP-1012/OCT-001 
20 
3 
 Safety Analysis 
Of the safety evaluation variables in this study, the frequency of adverse events (AEs) will be used as 
the primary endpoint, and clinical laboratory test results, vital signs, ECGs, and weight will be used 
for the assessment of secondary endpoints.  
 
3.1 
Treatment-Emergent Adverse Event 
 Overview of Treatment-Emergent Adverse Events 
3.1.1
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
TEAEs that occurred after administration of TVP-1012 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analysis Method(s): 
The following summaries will be provided for each treatment group in the 
preceding study. 
 
(1) 
Overview of TEAEs 
 
1) 
All TEAEs (number of events, number and percentage of 
subjects)  
 
2) 
Relationship of TEAEs to study drug (number of events, number 
and percentage of subjects) 
 
3) 
Intensity of TEAEs (number of events, number and percentage 
of subjects) 
 
4) 
TEAEs leading to study drug discontinuation (number of events, 
number and percentage of subjects) 
 
5) 
Serious TEAEs (number of events, number and percentage of 
subjects) 
 
6) 
Relationship of serious TEAEs to study drug (number of events, 
number and percentage of subjects) 
 
7) 
Serious TEAEs leading to study drug discontinuation (number of 
events, number and percentage of subjects) 
 
8) 
TEAEs resulting in death (number of events, number and 
percentage of subjects) 
 
TEAEs will be counted according to the rules below. 
[Number of subjects with TEAEs] 
• In case of “frequency distributions by relationship to study drug” 
A subject with occurrences of a TEAE in both categories (i.e., Related 
and Not Related) will be counted once in the Related category. 
• In case of “frequency distributions by intensity” 
A subject with multiple occurrences of a TEAE will be counted once for 
the TEAE with the maximum intensity. 
• In case of distributions other than the above 
A subject with multiple occurrences of a TEAE will be counted only 
once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 
 Displays of Treatment-Emergent Adverse Events 
3.1.2
Analysis Set: 
Safety Analysis Set 


Protocol No. TVP-1012/OCT-001 
21 
Analysis Variable(s): 
TEAEs that occurred after administration of TVP-1012 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Time of Onset (days) 
[1<= - <84, 84<= - <168, 168<= - <252, 252<= - 
<336, 336<= - <=Max] 
Analysis Method(s): 
The following summaries will be provided for each treatment group in the 
preceding study. 
TEAEs will be coded using MedDRA and will be summarized using SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency for tables provided by SOC and PT. SOC and PT will 
be sorted in decreasing frequency for tables provided by SOC only or PT 
only. 
 
(1) 
All TEAEs by SOC and PT 
 
(2) 
All TEAEs by SOC 
 
(3) 
All TEAEs by PT 
 
(4) 
Drug-Related TEAEs by SOC and PT 
 
(5) 
Intensity of All TEAEs by SOC and PT 
 
(6) 
Intensity of Drug-Related TEAEs by SOC and PT 
 
(7) 
TEAEs Leading to Study Drug Discontinuation by SOC and PT 
 
(8) 
Serious TEAEs by SOC and PT 
 
(9) 
TEAEs by SOC and PT Over Time 
 
The methods of counting events and calculating the percentage of subjects 
when conducting each frequency distribution will be as follows: 
[Number of subjects with TEAEs] 
• In case of “frequency distributions by SOC and PT, by SOC only, or PT 
only” 
A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC. 
A subject with multiple occurrences of TEAE within a PT will be 
counted only once in that PT. 
When calculating percentages for TEAE, the number of subjects in the 
safety analysis set will be used as the denominator. 
• In case of “frequency distributions by SOC and PT” 
A subject with multiple occurrences of a TEAE within a SOC or a PT 
will be counted only once for the TEAE with the maximum intensity. 
When calculating percentages for TEAE, the number of subjects in the 
safety analysis set will be used as the denominator. 
• In case of “frequency distributions by time of onset by SOC and PT” 
For each time interval, a subject with multiple occurrences of TEAE 
within a SOC or a PT will be counted only once in that SOC or PT. When 
calculating the onset rate of TEAEs for each time interval, the number of 
subjects among the safety analysis set (i.e., subjects who either have an 
exposure or have an occurrence of a TEAE, during or after the 
corresponding time interval) will be used as the denominator and the 
number of subjects whose onset of any one of the TEAEs is within the 
time interval will be used as the numerator. 
 


Protocol No. TVP-1012/OCT-001 
22 
 Examination of Subgroups for Treatment-Emergent Adverse Event 
3.1.3
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
TEAEs that occurred after administration of TVP-1012 
Subgroup(s): 
Age (years) 
[Min<= - <65, 65<= - <=Max] 
 
Gender 
[Male, Female] 
 
Smoking history 
[Yes, No] 
 
Timing of Study Drug 
Administration 
[Before breakfast, After breakfast] 
Analysis Method(s): 
The following summaries will be provided for above each subgroup by 
treatment group in the preceding study.  
TEAEs will be coded using MedDRA and will be summarized using SOC 
and PT, where SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency.   
 
(1) 
All TEAEs by SOC and PT 
 
(2) 
Drug-Related TEAEs by SOC and PT 
 
The methods of counting events and calculating the percentage of subjects 
when conducting each frequency distribution will be as follows: 
[Number of subjects with TEAEs] 
• A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC.  
A subject with multiple occurrences of TEAE within a PT will be 
counted only once in that PT. 
When calculating percentages for TEAE, the number of subjects in each 
stratified item in the safety analysis set will be used as the denominator. 
 
3.2 
Laboratory and Other Safety Data 
 Laboratory Test Results 
3.2.1
3.2.1.1 
Hematology and Serum Chemistry 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Hematology 
 
RBC 
Hemoglobin 
Hematocrit 
 
WBC 
 
 
 
WBC Differentials (Neutrophil, Eosinophil, Monocyte, Lymphocyte, and 
Basophil) 
 
Platelets 
 
 
 
Serum Chemistry 
 
AST 
ALT 
γ-GTP 
 
ALP 
LDH 
Albumin 
 
Total Protein 
Total Bilirubin 
Total Cholesterol 
 
Triglycerides 
Creatinine 
 
 
Blood Urea Nitrogen (BUN) 
Urine Acid 
 
Creatine Kinase 
Sodium 
 
Potassium 
Chlorine 
Calcium 
 
Phosphorus 
 
 
Categories: 
Results of determination based on reference values 
 
 
[Below lower limit of reference value, Within the range of 
reference value, Over upper limit of reference value] 


Protocol No. TVP-1012/OCT-001 
23 
Visit: 
Baseline (prior to TVP-1012 administration), Week 3, Week 6, Week 14, 
Week 20, Week 26, Week 29, Week 32, Week 40, Week 46, Week 52 
Analysis Method(s): 
The following summaries will be provided for each treatment group in the 
preceding study. 
 
(1) 
Descriptive statistics for observed values for each visit and changes 
(each visit after administration [Week 3 to Week 52] - baseline [prior 
to TVP-1012 administration]) will be provided. 
 
(2) 
Case Plots 
 
(3) 
A shift table for baseline (prior to TVP-1012 administration) and 
each visit after administration will be provided for the results of 
determination based on the reference values.  
 
3.2.1.2 
Urinalysis 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Protein 
[-,  +-,  1+,  2+,  3+,  4+] 
 
Glucose 
[-,  1+,  2+,  3+,  4+,  5+] 
 
Blood 
[-,  +-,  1+,  2+,  3+] 
 
Ketone Body 
[-,  +-,  1+,  2+,  3+,  4+] 
Visit: 
Baseline (prior to TVP-1012 administration), Week 3, Week 6, Week 14, 
Week 20, Week 26, Week 29, Week 32, Week 40, Week 46, Week 52 
Analysis Method(s): 
The following summaries will be provided for each treatment group in the 
preceding study. 
 
(1) 
A shift table for baseline (prior to TVP-1012 administration) and 
each visit after administration (Week 3 to Week 52) will be provided. 
 
 Vital Signs, Physical Findings, and Other Observations Related to Safety 
3.2.2
3.2.2.1 
Vital Signs 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Body temperature 
 
 
Systolic blood pressure 
 
 
Diastolic blood pressure 
 
 
Pulse rate 
 
Visit: 
Baseline (prior to TVP-1012 administration), Week 3, Week 6, Week 10, 
Week 14, Week 20, Week 26, Week 29, Week 32, Week 36, Week 40, Week 
46, Week 52 
Analysis Method(s): 
The following summaries will be provided for each treatment group in the 
preceding study. 
If a vital sign parameter has both lower and upper MAV criteria, analysis 
will be performed for each.  Definitions of parameters subject to this 
analysis and MAV criteria are given in Appendix 2 of this Statistical 
Analysis Plan. 
 
(1) 
Descriptive statistics for observed values for each visit and changes 
(each visit after administration [Week 3 to Week 52] - baseline [prior 
to TVP-1012 administration]) will be provided. 
 
(2) 
Case Plots 
 
(3) 
Overall frequency distributions of MAV after the administration of 
TVP-1012 will be provided.  


Protocol No. TVP-1012/OCT-001 
24 
 
3.2.2.2 
12-Lead ECG 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Heart Rate 
 
 
RR Interval 
 
 
PR Interval 
 
 
QT Interval 
 
 
QRS Interval 
 
 
QTcB Interval 
 
 
QTcF Interval 
 
 
12-Lead ECG Interpretation [Within Normal Limits, Abnormal but Not 
Clinically Significant, Abnormal and 
Clinically Significant] 
Visit: 
Baseline (prior to TVP-1012 administration), Week 14, Week 26, Week 40, 
Week 52 
Analysis Method(s): 
For each variable other than 12-lead ECG interpretations, summaries (1) 
and (2) will be provided by treatment group in the preceding study.  
For 12-lead ECG interpretation, summary (3) will be provided by treatment 
group in the preceding study.  
 
(1) 
Descriptive statistics for observed values for each visit and changes 
(each visit after administration (Week 14 to Week 52)-baseline (prior 
to TVP-1012 administration) will be provided. 
 
(2) 
Case Plots 
 
(3) 
A shift table for baseline (prior to TVP-1012 administration) and 
each visit after administration will be provided. 
 
3.2.2.3 
Weight 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Weight 
 
Visit: 
Baseline (prior to TVP-1012 administration), Week 14, Week 26, Week 40, 
Week 52 
Analysis Method(s): 
The following summaries will be provided for each treatment group in the 
preceding study. 
 
(1) 
Descriptive statistics for observed values for each visit and changes 
(each visit after administration (Week 14 to Week 52)-baseline (prior 
to TVP-1012 administration) will be provided. 
 
(2) 
Case Plots 
 


Protocol No. TVP-1012/OCT-001 
25 
4 
Significance Level and Confidence Coefficient 
 Confidence coefficient: 
95% (two-sided) 


Protocol No. TVP-1012/OCT-001 
26 
Creation History (version management) 
 
Version 
Date 
Created/Modified by 
Comments 
1 
2016.09.30 
 
Creation of first version 
2 
2017.04.11 
 
Creation of second version 
 


Protocol No. TVP-1012/OCT-001 
1 
[Appendix 1] A Comparison Table for Changes in TVP-1012/OCT-001 
Amendment from First Version (Created on 30 September 2016) to Second Version (Created on 11 April 2017) 
Page 
Existing Text 
Revised Text 
Rationale for Amendment 
22 
3.1.3 Examination of Subgroups for 
Treatment-Emergent Adverse Event 
Stratified Variable(s): 
Smoking history 
[Yes, No] 
Timing of Study Drug Administration 
[Before breakfast, After breakfast] 
3.1.3 Examination of Subgroups for 
Treatment-Emergent Adverse Event 
Stratified Variable(s): 
Age (years) 
[Min<= - <65, 65<= - <=Max] 
Gender 
[Male, Female] 
Smoking history 
[Yes, No] 
Timing of Study Drug Administration 
[Before breakfast, After breakfast] 
Modified after examining it with related 
functional departments. 
 
 


Protocol No. TVP-1012/OCT-001 
1 
[Appendix 2] 
Definition of MAV Criteria 
(1) MAV Criteria 
1) 
Vital Signs 
For each test item, those obtained until 7 days after the administration of TVP-1012 (including 7 
days after the end of TVP-1012 administration and evaluable data [i.e., non-missing and acceptable 
according to the Handling Rules for Analysis Data]) will be subject and the determination on MAV 
will be conducted according to the following table.  The LLN and ULN in the following table will 
be the lower limit and upper limit of reference values within the normal range of each test item.  
 
Vital Signs 
Test item 
Gender 
Age 
MAV Criteria 
Lower 
Upper 
Body Temperature (°C) 
- 
- 
<35.6 
>37.7 
Systolic Blood Pressure (mmHg) 
- 
- 
<90 
>180 
Diastolic Blood Pressure (mmHg) 
- 
- 
<50 
>100 
Pulse Rate (bpm) 
- 
- 
<45 
>120 
 
Overall determination after administration of TVP-1012 
The presence or absence of MAV for each subject will be determined for each test item according to 
the rules (1) to (3).  If a test item has both lower and upper MAV criteria, analysis will be 
performed for each.  
[1] If it is determined that at least 1 item among the evaluable data after the administration of 
TVP-1012 “meets the MAV Criteria,” it will be determined as “Yes.” 
[2] If it does not correspond to [1] and it is determined that at least 1 item among the evaluable data 
after the administration of TVP-1012 “does not meet the MAV Criteria,” it will be determined 
as “No.” 
[3] If it corresponds to neither [1] nor [2], it will be excluded from the analysis for the results of the 
determination.  
 
 


Protocol No. TVP-1012/OCT-001 
1 
[Appendix 3] 
MDS-UPDRS Score 
 MDS-UPDRS individual score 
Part I 
Number 
Variable 
Score 
1.1 
Cognitive impairment 
(0, 1, 2, 3, 4, UR) 
1.2 
Hallucinations and psychosis 
(0, 1, 2, 3, 4, UR) 
1.3 
Depressed mood 
(0, 1, 2, 3, 4, UR) 
1.4 
Anxious mood 
(0, 1, 2, 3, 4, UR) 
1.5 
Apathy 
(0, 1, 2, 3, 4, UR) 
1.6 
Features of DDS 
(0, 1, 2, 3, 4, UR) 
1.7 
Sleep problems 
(0, 1, 2, 3, 4) 
1.8 
Daytime sleepiness 
(0, 1, 2, 3, 4) 
1.9 
Pain and other sensations 
(0, 1, 2, 3, 4) 
1.10 
Urinary problems 
(0, 1, 2, 3, 4) 
1.11 
Constipation problems 
(0, 1, 2, 3, 4) 
1.12 
Light headedness on standing 
(0, 1, 2, 3, 4) 
1.13 
Fatigue 
(0, 1, 2, 3, 4) 
 
Part II 
Number 
Variable 
Score 
2.1 
Speech 
(0, 1, 2, 3, 4) 
2.2 
Saliva and drooling 
(0, 1, 2, 3, 4) 
2.3 
Chewing and swallowing 
(0, 1, 2, 3, 4) 
2.4 
Eating tasks 
(0, 1, 2, 3, 4) 
2.5 
Dressing 
(0, 1, 2, 3, 4) 
2.6 
Hygiene 
(0, 1, 2, 3, 4) 
2.7 
Handwriting 
(0, 1, 2, 3, 4) 
2.8 
Doing hobbies and other activities 
(0, 1, 2, 3, 4) 
2.9 
Turning in bed 
(0, 1, 2, 3, 4) 
2.10 
Tremor 
(0, 1, 2, 3, 4) 
2.11 
Getting out of bed, a car, or a deep chair 
(0, 1, 2, 3, 4) 
2.12 
Walking and balance 
(0, 1, 2, 3, 4) 
2.13 
Freezing 
(0, 1, 2, 3, 4) 
 
 
 


Protocol No. TVP-1012/OCT-001 
2 
Part III 
Number 
Variable 
Score 
3.1 
Speech 
(0, 1, 2, 3, 4, UR) 
3.2 
Facial expression 
(0, 1, 2, 3, 4, UR) 
3.3a 
Rigidity-Neck 
(0, 1, 2, 3, 4, UR) 
3.3b 
Rigidity-RUE 
(0, 1, 2, 3, 4, UR) 
3.3c 
Rigidity-LUE 
(0, 1, 2, 3, 4, UR) 
3.3d 
Rigidity-RLE 
(0, 1, 2, 3, 4, UR) 
3.3e 
Rigidity-LLE 
(0, 1, 2, 3, 4, UR) 
3.4a 
Finger tapping-Right hand 
(0, 1, 2, 3, 4, UR) 
3.4b 
Finger tapping-Left hand 
(0, 1, 2, 3, 4, UR) 
3.5a 
Hand movements-Right hand 
(0, 1, 2, 3, 4, UR) 
3.5b 
Hand movements-Left hand 
(0, 1, 2, 3, 4, UR) 
3.6a 
Pronation-supination movements-Right hand 
(0, 1, 2, 3, 4, UR) 
3.6b 
Pronation-supination movements-Left hand 
(0, 1, 2, 3, 4, UR) 
3.7a 
Toe tapping-Right foot 
(0, 1, 2, 3, 4, UR) 
3.7b 
Toe tapping-Left foot 
(0, 1, 2, 3, 4, UR) 
3.8a 
Leg agility-Right leg  
(0, 1, 2, 3, 4, UR) 
3.8b 
Leg agility-Left leg  
(0, 1, 2, 3, 4, UR) 
3.9 
Arising from chair 
(0, 1, 2, 3, 4, UR) 
3.10 
Gait 
(0, 1, 2, 3, 4, UR) 
3.11 
Freezing of gait 
(0, 1, 2, 3, 4, UR) 
3.12 
Postural stability 
(0, 1, 2, 3, 4, UR) 
3.13 
Posture 
(0, 1, 2, 3, 4, UR) 
3.14 
Global spontaneity of movement 
(0, 1, 2, 3, 4, UR) 
3.15a 
Postural tremor-Right hand 
(0, 1, 2, 3, 4, UR) 
3.15b 
Postural tremor-Left hand 
(0, 1, 2, 3, 4, UR) 
3.16a 
Kinetic tremor-Right hand 
(0, 1, 2, 3, 4, UR) 
3.16b 
Kinetic tremor-Left hand 
(0, 1, 2, 3, 4, UR) 
3.17a 
Rest tremor amplitude-RUE 
(0, 1, 2, 3, 4, UR) 
3.17b 
Rest tremor amplitude-LUE 
(0, 1, 2, 3, 4, UR) 
3.17c 
Rest tremor amplitude-RLE 
(0, 1, 2, 3, 4, UR) 
3.17d 
Rest tremor amplitude-LLE 
(0, 1, 2, 3, 4, UR) 
3.17e 
Rest tremor amplitude-Lip/jaw 
(0, 1, 2, 3, 4, UR) 
3.18 
Constancy of rest tremor 
(0, 1, 2, 3, 4, UR) 
 


Protocol No. TVP-1012/OCT-001 
3 
Part IV 
Number 
Variable 
Score 
4.1 
Time spent with dyskinesias 
(0, 1, 2, 3, 4) 
4.2 
Functional impact of dyskinesias 
(0, 1, 2, 3, 4) 
4.3 
Time spent in the OFF state 
(0, 1, 2, 3, 4) 
4.4 
Functional impact of fluctuations 
(0, 1, 2, 3, 4) 
4.5 
Complexity of motor fluctuations 
(0, 1, 2, 3, 4) 
4.6 
Painful OFF-state dystonia 
(0, 1, 2, 3, 4) 
 
0: Normal, 1: Slight, 2: Mild, 3: Moderate, 4: Severe, UR: Unable to Rate 
 
 Each total score based on scores of each MDS-UPDRS variable 
The score will be calculated according to the following rules for evaluable data (i.e., non-missing 
and acceptable according to the Handling Rules for Analysis Data). 
MDS-UPDRS Part I total score: 
Total of variable 1.1 to variable 1.13 
MDS-UPDRS Part II total score: 
Total of variable 2.1 to variable 2.13 
MDS-UPDRS Part III total score: 
Total of variable 3.1 to variable 3.18 
MDS-UPDRS Part IV total score: 
Total of variable 4.1 to variable 4.6 
MDS-UPDRS Part II + Part III total score: 
 
 
Total of variable 2.1 to variable 2.13 and variable 3.1 
                                to variable 3.18 
MDS-UPDRS tremor score:  
Total of variable 2.10, variable 3.15a to variable 3.18 
MDS-UPDRS muscle rigidity score: 
Total of variable 3.3a to variable 3.3e 
MDS-UPDRS bradykinesia score: 
Total of variable 3.4a to variable 3.8b and variable 
                                3.14 
* 
The score will be calculated using the variable on the same day of the assessment. 
* 
If a missing or “UR” value is contained in the variable used for calculation, the score will 
not be calculated.  
 
 


Protocol No. TVP-1012/OCT-001 
1 
[Appendix 4] 
Modified Hoehn and Yahr Scale 
 Each Severity Classification of Modified Hoehn and Yahr Scale 
The score that corresponds to each severity classification will be used according to the following 
table. 
Severity 
Classification 
Variable 
Score 
Stage 0 
No Parkinsonism 
0 
Stage 1 
Unilateral Parkinsonism 
1 
Stage 1.5 
Unilateral Parkinsonism and axial involvement 
1.5 
Stage 2 
Bilateral Parkinsonism without impairment of balance 
2 
Stage 2.5 
Mild bilateral Parkinsonism with recovery on 
retropulsion (pull) test   
2.5 
Stage 3 
Mild to moderate Parkinsonism with impairment of 
balance but physically independent 
3 
Stage 4 
Severe Parkinsonism; still able to walk or stand 
unassisted 
4 
Stage 5 
Wheelchair bound or bedridden unless aided 
5 
 
 


Protocol No. TVP-1012/OCT-001 
1 
[Appendix 5] 
PDQ-39 Score 
 PDQ-39 individual score 
Number 
Variable 
Score 
1 
Had difficulty doing the leisure activities which you 
would like to do? 
(0, 1, 2, 3, 4) 
2 
Had difficulty looking after your home, e.g. DIY, 
housework, cooking? 
(0, 1, 2, 3, 4) 
3 
Had difficulty carrying bags of shopping? 
(0, 1, 2, 3, 4) 
4 
Had problems walking half a mile? 
(0, 1, 2, 3, 4) 
5 
Had problems walking 100 yards? 
(0, 1, 2, 3, 4) 
6 
Had problems getting around the house as easily as 
you would like? 
(0, 1, 2, 3, 4) 
7 
Had difficulty getting around in public? 
(0, 1, 2, 3, 4) 
8 
Needed someone else to accompany you when you 
went out? 
(0, 1, 2, 3, 4) 
9 
Felt frightened or worried about falling over in 
public? 
(0, 1, 2, 3, 4) 
10 
Been confined to the house more than you would like? 
(0, 1, 2, 3, 4) 
11 
Had difficulty washing yourself? 
(0, 1, 2, 3, 4) 
12 
Had difficulty dressing yourself? 
(0, 1, 2, 3, 4) 
13 
Had problems doing up your shoe laces? 
(0, 1, 2, 3, 4) 
14 
Had problems writing clearly? 
(0, 1, 2, 3, 4) 
15 
Had difficulty cutting up your food? 
(0, 1, 2, 3, 4) 
16 
Had difficulty holding a drink without spilling it? 
(0, 1, 2, 3, 4) 
17 
Felt depressed? 
(0, 1, 2, 3, 4) 
18 
Felt isolated and lonely? 
(0, 1, 2, 3, 4) 
19 
Felt weepy or tearful? 
(0, 1, 2, 3, 4) 
20 
Felt angry or bitter? 
(0, 1, 2, 3, 4) 
21 
Felt anxious? 
(0, 1, 2, 3, 4) 
22 
Felt worried about your future? 
(0, 1, 2, 3, 4) 
23 
Felt you had to conceal your Parkinson's from people? 
(0, 1, 2, 3, 4) 
24 
Avoided situations which involve eating or drinking in 
public? 
(0, 1, 2, 3, 4) 
25 
Felt embarrassed in public due to having Parkinson's 
disease? 
(0, 1, 2, 3, 4) 


Protocol No. TVP-1012/OCT-001 
2 
26 
Felt worried by other people's reaction to you? 
(0, 1, 2, 3, 4) 
27 
Had problems with your close personal relationships? 
(0, 1, 2, 3, 4) 
28 
Lacked support in the ways you need from your 
spouse or partner? 
(0, 1, 2, 3, 4, 5) 
29 
Lacked support in the ways you need from your 
family or close friends? 
(0, 1, 2, 3, 4) 
30 
Unexpectedly fallen asleep during the day? 
(0, 1, 2, 3, 4) 
31 
Had problems with your concentration, e.g. when 
reading or watching TV? 
(0, 1, 2, 3, 4) 
32 
Felt your memory was bad? 
(0, 1, 2, 3, 4) 
33 
Had distressing dreams or hallucinations? 
(0, 1, 2, 3, 4) 
34 
Had difficulty with your speech? 
(0, 1, 2, 3, 4) 
35 
Felt unable to communicate with people properly? 
(0, 1, 2, 3, 4) 
36 
Felt ignored by people? 
(0, 1, 2, 3, 4) 
37 
Had painful muscle cramps or spasms? 
(0, 1, 2, 3, 4) 
38 
Had aches and pains in your joints or body? 
(0, 1, 2, 3, 4) 
39 
Felt unpleasantly hot or cold? 
(0, 1, 2, 3, 4) 
 
0: Never, 1: Occasionally, 2: Sometimes, 3: Often, 4: Always (or cannot do at all), 5: If you do 
not have a spouse or partner tick here. 
 
 PDQ-39 score by domain (rounded to the first decimal place) 
The score will be calculated according to the following rules for evaluable data (i.e., non-missing 
and acceptable according to the Handling Rules for Analysis Data). 
Mobility: 
(Total of variable 1 to variable 10) / (4×10) × 100 
Activities of daily living: 
 (Total of variable 11 to variable 16) / (4×6) × 100 
Emotional well-being: 
(Total of variable 17 to variable 22) / (4×6) × 100 
Stigma: 
(Total of variable 23 to variable 26) / (4×4)×100 
Social support: 
[In the case when variable 28 is other than 5 
(Total of variable 27 to variable 29) / (4×3)×100 
[In the case when variable 28 is 5] 
(Total of variables 27 and 29) / (4×2) × 100 
Cognitions: 
(Total of variable 30 to variable 33) / (4×4)×100 
Communication: 
(Total of variable 34 to variable 36) / (4×3)×100 
Bodily discomfort: 
(Total of variable 37 to variable 39) / (4×3) × 100 
* 
The score will be calculated using the variable on the same day of the assessment. 
* 
If a missing value is contained in the variable used for calculation, the score will not be 
calculated.  
 
 PDQ-39 Summary Index (rounded to the first decimal place) 


Protocol No. TVP-1012/OCT-001 
3 
The score will be calculated according to the following rules for evaluable data (i.e., non-missing 
and acceptable according to the Handling Rules for Analysis Data). 
(Total of PDQ-39 Score by Domain Mobility-Bodily discomfort) / 8 
* 
The score will be calculated using the variable on the same day of the assessment. 
* 
If a missing value is contained in the variable used for calculation, the score will not be 
calculated.