Clinical trial NCT05312632
Conditions: Parkinson Disease
Sponsor: Eisai Korea Inc.
Start date: 2022-04-05; Completion date: 2023-05-25
Enrollment: 201 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of this study is to evaluate the change at the 18th week from baseline in daily "off" time measured by participant diary and Parkinson's Disease Questionnaire-39 (PDQ-39) in participants with Parkinson's Disease who are receiving levodopa.

Detailed description:

Arms: arm 1: Participants with parkinson's disease will be administered Safinamide Mesilate 50 milligram (mg) tablet, orally, once daily as add-on therapy to levodopa for up to 2 weeks. After 2 weeks, at the discretion of an investigator, dose of Safinamide Mesilate will be increased to 100 mg tablets (two tablets of 50 mg each), orally, once daily for up to 18 weeks.
Interventions: intervention 1: Safinamide Mesilate
Intervention descriptions: intervention 1: Safinamide Mesilate oral tablets.

Protocol documents:
Prot_SAP_000.pdf: 


 
 
 
 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.: ME2125 
Name of Active Ingredient: safinamide mesilate 
Study Protocol Title 
A multi-center, open-label phase 4 study evaluating the efficacy and safety of safinamide mesilate as 
add-on therapy to levodopa in Parkinson’s Disease patients with motor fluctuation in South Korea 
Sites 
Approximately 20 sites 
Study Period and Phase of Development 
Approximately 13 months (may be shortened or extended depending on registration status) 
Phase 4 
Objectives 
Primary Objective 
To evaluate the change at the 18th week from baseline in daily “off” time measured by subject diary 
and Parkinson’s Disease Questionnaire-39 (PDQ-39) in patients with Parkinson’s Disease who are 
receiving levodopa. 
 
Secondary Objective 
● 
To evaluate the change at the 18th week from baseline in below assessments:  
- 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) Part 3 
- 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) Part 4 
- 
King’s Parkinson’s disease Pain Scale (KPPS)  
- 
Mini-Mental State Examination (MMSE) 
● 
To evaluate the safety of safinamide mesilate in Parkinson’s Disease patients who are receiving 
levodopa 
● 
To evaluate the change at the 18th week from baseline in daily “on” time without dyskinesia in 
patients with Parkinson’s Disease who are receiving levodopa 
Study Design 
This is a multi-center, open-label, single-arm, interventional study in Parkinson’s Disease patients who 
are receiving levodopa.  
After providing written informed consent, subjects will enter the Screening Period for maximum 21 
days and then Baseline Period for 1 day. If subjects are eligible, Treatment Period will begin in which 
subjects will be treated with safinamide mesilate (hereinafter, study drug) for 18 weeks.  
 
After the Treatment Period, subjects’ participation in the study will be completed after the completion 
of Visit 4 (EOT), which is the End of Treatment Visit. At Visit 4(EOT), the subjects who require 
tapering will enter a Taper Period for 1 week. The Taper Period may be omitted if the subject’s daily 
dose of study drug at the end of treatment is 50mg, if subjects will continue to take the study drug after 
the completion of the trial, or if it is considered not required by an investigator. 
 


 
 
 
 
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[Screening Period] 
At Visit 1(Screening), informed consent will be obtained after the study has been fully explained to 
each subject and before the conduct of any screening procedures or assessments. A medical history 
interview, identification of prior and concomitant medications, identification of concomitant therapies, 
height, weight, physical examination, urine pregnancy test (females of childbearing potential only), 12-
lead electrocardiogram (ECG; if deemed necessary by the investigator), vital signs, clinical laboratory 
tests (hematology, chemistry, and urinalysis), and adverse events (AE) assessment will be conducted 
for evaluation of eligibility criteria, and will include confirmation that the subject meets diagnostic 
criteria for Parkinson’s Disease. 
 
At Visit 1(Screening), subjects perform the Mini-Mental State Examination (MMSE) among the 
efficacy assessments. Also, a diary will be handed out to subjects and/or their caregivers, and 
investigator will train them how to complete the diary. Subjects who meet the eligibility criteria of the 
study will be instructed to complete the diary for 3 consecutive days prior to Visit 2 (Baseline).  
 
If subjects have previously taken medications such as Catechol-O-methlytransferase (COMT) 
inhibitor and/or Monoamine oxidase-B (MAO-B) inhibitor, they have to take appropriate wash-out 
period for each medication (3 days for COMT inhibitor; 14 days for MAO-B inhibitor). 
 
[Baseline Period] 
At Visit 2 (Baseline), subjects will return to the site after they have completed the diary for at least 3 
consecutive days. At Visit 2 (Baseline), safety assessments including AE assessment, vital signs, 
weight (if deemed necessary by an investigator), and physical examination will be conducted.  
 
Efficacy assessments including Parkinson’s Disease Questionnaire-39 (PDQ-39), Movement Disorder 
Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3 and Part 4, and King’s 
Parkinson’s disease Pain Scale (KPPS) will be conducted. Investigators will also review the completed 
subject diary with subjects.  
 
The study drug will be distributed to the subjects who meet the eligibility criteria at Visit 2 (Baseline). 
Subjects will be instructed to take the study drug every day starting from the day after Visit 2 
(Baseline).  
 
[Treatment Period] 
Subjects will take the study drug daily for 18 weeks.  
 
The dose of the study drug is 50 mg once a day for 2 weeks (14 days) starting from the next day after 
Visit 2 (Baseline), and 100 mg once a day afterwards. Subjects who need to increase the dose at the 
discretion of an investigator shall visit the site (unscheduled) prior to the dose increase. 
 
Subjects whose dose cannot be increased to 100 mg/day within 4 weeks following Visit 2 (Baseline) 
will be dropped out from the clinical trial. 
 


 
 
 
 
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If Adverse Events (AE) occur in subjects who have increased the dose, the dose may be reduced back 
to 50 mg/day at the discretion of an investigator through unscheduled site visit or phone visit. After 
reduction from 100mg/day to 50mg/day, the dose may be increased back to 100 mg/day at the 
discretion of an investigator. 
 
Subjects will return to the site at 8 weeks and 18 weeks for Visit 3 and Visit 4 (EOT), respectively. The 
“windows” permitted for Visit 3 (8 weeks) will be -4 weeks and +2 weeks; for Visit 4 (18 weeks: EOT) 
will be +/- 2 weeks. Safety assessments including AE assessment, 12-lead ECG (if deemed necessary 
by an investigator), vital signs, weight, physical examination, clinical laboratory tests (hematology, 
chemistry, and urinalysis), and urine pregnancy test (females of childbearing potential only) will be 
conducted according to the schedule for each visit during Treatment Period. Efficacy assessments 
including PDQ-39, MDS-UPDRS Part 3 and Part 4, KPPS, and MMSE will be conducted at Visit 4 
(EOT). Subjects will complete the diary for at least 3 consecutive days prior to Visit 4 (EOT), and 
investigators will review the completed diary together with subjects at Visit 4 (EOT). 
 
[Taper Period] 
Of the subjects who have completed 18 weeks of treatment, those who require tapering will enter a 
Taper Period for 1 week. After the completion of the Taper Period, subjects will return to the site for 
Visit 5. At Visit 5, safety assessments including AE assessment, vital signs, weight (if deemed 
necessary by an investigator), and physical examination will be conducted. For those subjects 
participating in the Taper Period, their participation in the study will be completed after the completion 
of Visit 5. 
 
Taper Period may be omitted if the subject’s daily dose of the study drug at the end of treatment is 
50mg, if subjects will continue to take the study drug after the completion of the trial, or if it is 
considered not required by an investigator. For the subjects who do not require the Taper Period, their 
participation in the study will be completed after the completion of Visit 4 (EOT). 
 
Premature Discontinuation of Study Drug 
A subject who prematurely discontinues taking the study drug should return to the site as soon as 
practicable after discontinuing study drug (preferably within 7 days) to complete Premature 
Discontinuation Visit. Following the completion of Premature Discontinuation Visit, subjects who 
require taper will undergo a Taper Period for 1 week. Then the subjects will return to the site for Visit 
5. For the subjects who do not require the Taper Period, Premature Discontinuation Visit would be 
their last visit in the study. 
Number of Subjects 
Approximately 199 subjects will be enrolled in the trial.  
Inclusion Criteria 
To be eligible for inclusion into this trial, the subjects must fulfill all of the following criteria: 
1. Male or female, age ≥19 years at the time of informed consent 
2. Patients who meet the clinical diagnostic criteria of Movement Disorder Society (MDS) 
diagnosis criteria 2015 for Parkinson's disease, have motor fluctuations with ≥1.5 hours of “off” 






 
 
 
 
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Subject Diary 
Information on daily “off” time and “on” time will be collected by subject diary.  
Subjects will complete the diary for at least 3 consecutive days prior to each visit where completed 
diary review is conducted (Visit 2, Visit 4) and the diary will be maintained by the subject over a 24-
hour period each day the diary is being completed. At 30-minute intervals throughout the period, the 
subject/caregiver will record whether the subject is currently 1) in an “on” phase 2) in an “on” phase 
with dyskinesia, 3) in an “off” phase, or 4) asleep. Subjects will also check when they take their 
levodopa throughout the day.  
An “off” phase will be defined as lack of mobility, bradykinesia, or akinesia whereas in an “on” phase, 
the subject will be functioning as well as can be expected for that subject, irrespective of whether or 
not he/she is having dyskinesia. 
The daily “off” time is defined as the mean of the total daily “off” time during the last two 24-hour 
diary recording periods prior to the visit. The daily “on” time is defined as the mean of the total daily 
“on” time during the last two 24-hour diary recording periods prior to the visit. 
 
Investigators will review the completed subject diary with subjects at Visit 2 (Baseline) and Visit 4 
(EOT).  
 
PDQ-39 
To assess the efficacy of non-motor symptoms and motor symptoms in subjects, PDQ-39 will be used. 
The PDQ-39 comprises 39 questions measuring eight dimensions of health: mobility, activities of daily 
living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. 
Dimension scores are coded on a scale of 0 (perfect health as assessed by the measure) to 100 (worst 
health as assessed by the measure). A summary index score can also be calculated. The contents of the 
instrument were developed on the basis of exploratory in-depth interviews with subjects with 
Parkinson's Disease, and the reliability, validity and sensitivity to change of the instrument were then 
assessed in a number of large-scale surveys. The questionnaire will be provided in Korean to the 
subjects. 
 
MDS-UPDRS Part 3 
To assess the efficacy of motor symptoms in subjects, MDS-UPDRS Part 3 will be used. The MDS-
UPDRS is a rating tool used to follow the longitudinal course of Parkinson’s Disease. It is made up of 
four parts that assess the following: Part 1 – Non-motor Aspects of Experiences of Daily Living; Part 
2 – Motor Aspects of Experiences of Daily Living; Part 3 – Motor Examination; and Part 4 – Motor 
Complications. The information for these ratings is obtained through an interview with the subject and 
caregiver if available. 
 
MDS-UPDRS Part 3 evaluates the motor function of the subject. This section of the scale consists of 
18 items with 33 separate ratings being performed on a scale from 0 (normal) to 4 (severe). Specific 
instructions are provided for the testing of each item, which should be followed in all instances. Raters 
demonstrate while describing tasks the subject is to perform and rate function immediately thereafter. 
The subject’s speech, facial expressions, ability to arise from a chair, posture, gait, postural stability 
(retropulsion test), and body bradykinesia are assessed. In addition, tremor at rest, action or postural 
tremor of hands, rigidity, finger taps, hand movements (open/close), rapid alternating movements of 
hands (pronation/supination), and leg agility are assessed.  


 
 
 
 
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MDS-UPDRS Part 4 
In MDS-UPDRS Part 4, raters use historical and objective information to assess two motor 
complications, dyskinesias and motor fluctuations that include OFF-state dystonia. Raters will use all 
information from patient, caregiver, and the examination to answer the six questions that summarize 
function over the past week including today. This section has instructions for the raters and also 
instructions to be read to the patient, and integrates patient-derived information with the rater’s 
clinical observations and judgments. In Part A, the duration of, disability caused by, and functional 
impact of any dyskinesias experienced by the subject are rated on a scale from 0 to 4. Clinical 
fluctuations are assessed in Part B, which includes time spent in the “off” state (estimation of the 
proportion of the waking day spent in the “off” state), functional impact of fluctuations, the 
predictability and timing of the subject’s “off” periods, and proportion of the “off” state having 
painful dystonia. 
 
KPPS 
To assess pain scale in subjects, KPPS will be used. KPPS is Parkinson’s Disease-specific pain scale. 
Its seven domains include 14 items; each item is scored by severity (0-3) multiplied by frequency (0-
4), resulting in a subscore of 0 to 12 with a total possible score range from 0 to 168. 
 
MMSE 
To assess cognition in subjects, MMSE will be used. The MMSE is a brief practical screening test for 
cognitive dysfunction. The test consists of relevant items (awareness of time, awareness of location, 
memory, attention, ability to calculate, ability to recall, ability to name names, repetition, 
understanding, reading, writing, and drawing) and has a total possible score of 30. It is useful as a quick 
method to assess the severity of cognitive dysfunction. 
 
Safety Assessment 
Safety assessment will consist of determining and recording all adverse events (AEs) and other events 
of special interests including pregnancy, breast feeding, overdose, abuse or misuse, lack of therapeutic 
efficacy, medication error, off label use, occupational exposure, and suspected transmission of an 
infectious agent; regular clinical laboratory evaluation for hematology, blood chemistry, and urine 
values; periodic measurement of vital signs and ECGs; and the performance of physical examinations.  
Statistical Methods 
Details of statistical methods and analyses will be specified in the statistical analysis plan (SAP). 
 
Study Endpoints 
Co-Primary Endpoints 
● 
Change at the 18th week from baseline in daily “off” time 
● 
Change at the 18th week from baseline in PDQ-39 score 
 
Secondary Endpoints 
● 
Change at the 18th week from baseline in below assessments:  
- 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) Part 3 


 
 
 
 
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- 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) Part 4 
- 
King’s Parkinson’s disease Pain Scale (KPPS)  
- 
Mini-Mental State Examination (MMSE) 
● 
Safety of safinamide mesilate  
● 
Change at the 18th week from baseline in daily “on” time without dyskinesia 
 
Analysis Set 
Safety Analysis Set (SAS) 
The SAS is the group of subjects who received at least 1 dose of study drug and completed at least 1 
post-dose safety assessment. 
 
Full Analysis Set (FAS) 
The FAS is the group of subjects who received at least 1 dose of study drug and had at least 1 post-
dose daily “off” time or PDQ-39. 
 
Per Protocol Set (PPS) 
It is intended for subjects who have fully complied with the study protocol. The details of the 
evaluability criteria will be determined prior to database lock and will be specified in the statistical 
analysis plan. 
 
Efficacy Analyses 
All efficacy analysis will use FAS as the primary population and PPS as the secondary population. 
 
Primary efficacy analyses 
● 
To evaluate the change at the 18th week from baseline in daily “off” time 
The daily “off” time will be analyzed using paired t-test on the change at the 18th week from 
baseline. The descriptive statistics for the daily “off” time will be summarized by each visit. 
● 
To evaluate the change at the 18th week from baseline in PDQ-39 
The PDQ-39 will be analyzed using a paired t-test on the change at the 18th week from 
baseline.  
The descriptive statistics for the PDQ-39 will be summarized by each visit. 
Secondary efficacy analyses 
For the following items, the descriptive statistics will be summarized by each visit and it will be 
analyzed using a paired t-test on the change at the 18th week from baseline.  
● 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) Part 3 
● 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) Part 4 
● 
King’s Parkinson's disease Pain Scale (KPPS) 
● 
Mini-Mental State Examination (MMSE) 
● 
Daily “on” time without dyskinesia  
 


 
 
 
 
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Safety Analyses 
All safety analyses will be performed on the SAS. Safety data will be summarized using descriptive 
statistics (e.g., n, mean, standard deviation, median, minimum, maximum for continuous variables; n 
[%] for categorical variables). Safety data that will be evaluated include extent exposure, AEs, clinical 
laboratory results, weights, and vital signs. 
 
Other Analyses 
Levodopa dose during the study will be summarized using descriptive statistics (e.g., n, mean, 
standard deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
variables). Efficacy analyses will be performed in subgroups based on levodopa dose and details will 
be described in the SAP. 
Sample Size Rationale 
The sample size was calculated assuming the efficacy of this study at 18 weeks is comparable to the 
efficacy of phase 3 clinical study at 24 weeks. The sample size is calculated using each 2 primary 
endpoints, and a larger sample size is selected conservatively. The sample size for each evaluation 
variable is as follows: 
 
● 
Endpoint 1: Paired t-test for “off” time 
Based on the above assumptions, to calculate the number of subjects for the comparison of 
the “off” time mean change after 24 weeks compared to baseline, sample size was calculated 
assuming average change (-1.56) and standard deviation (2.35). 
The results were performed through PASS (version 2020), the sample sizes of 31 achieve 90% 
power and the significance level (alpha) is 0.025. 
● 
Endpoint 2: Paired t-test for PDQ-39 score 
Based on the above assumptions, to calculate the number of subjects for the comparison of 
the PDQ-39 score mean change after 24 weeks compared to baseline, sample size was 
calculated assuming average change (-3.17) and standard deviation (10.86). 
The results were performed through PASS (version 2020), the sample sizes of 149 achieve 
90% power and the significance level (alpha) is 0.025. 
 
According to the above two endpoints, the sample sizes are 31, 149 at each assumption. The sample 
size of endpoint 2 is larger than endpoint 1. Therefore, the final sample size obtained considering the 
drop-out rate of 25% during the study period is 199. 
 


 
 
 
 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................11 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................16 
5 
ETHICS............................................................................................................................18 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................18 
5.2 
Ethical Conduct of the Study .................................................................................18 
5.3 
Subject Information and Informed Consent ...........................................................18 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................20 
7 
INTRODUCTION ...........................................................................................................20 
7.1 
Compound Overview .............................................................................................20 
7.2 
Clinical Experience ................................................................................................20 
7.3 
Study Rationale ......................................................................................................22 
8 
STUDY OBJECTIVES ....................................................................................................22 
8.1 
Primary Objective ..................................................................................................22 
8.2 
Secondary Objective ..............................................................................................22 
9 
INVESTIGATIONAL PLAN ..........................................................................................24 
9.1 
Overall Study Design and Plan ..............................................................................24 
9.1.1 
Screening Period ..........................................................................................25 
9.1.2 
Baseline Period ............................................................................................25 
9.1.3 
Treatment Period ..........................................................................................26 
9.1.4 
Taper Period .................................................................................................26 
9.2 
Discussion of Study Design ...................................................................................27 
9.3 
Selection of Study Population ................................................................................27 
9.3.1 
Inclusion Criteria .........................................................................................27 
9.3.2 
Exclusion Criteria ........................................................................................28 
9.3.3 
Removal of Subjects from Therapy or Assessment .....................................28 
9.4 
Treatment ...............................................................................................................29 
9.4.1 
Treatment Administered ..............................................................................29 
9.4.2 
Identity of Investigational Products .............................................................30 
9.4.2.1 
Study drug code: ME2125 Chemical Name of ME2125 .....................30 
9.4.2.2 
Labeling for Study Drug ......................................................................30 
9.4.2.3 
Storage Conditions ...............................................................................31 
9.4.3 
Method of Assigning Subjects to Treatment Group ....................................31 
9.4.4 
Selection of Doses and Method of Administration in the Study .................31 
9.4.5 
Timing of Study Drug Administration .........................................................31 


 
 
 
 
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9.4.6 
Blinding........................................................................................................32 
9.4.7 
Prior and Concomitant Medications / Concomitant Therapy ......................32 
9.4.7.1 
Drug-Drug Interactions ........................................................................32 
9.4.7.2 
Prohibited Concomitant Medications and Therapies ...........................32 
9.4.8 
Treatment Compliance .................................................................................33 
9.4.9 
Drug Supplies and Accountability ...............................................................33 
9.5 
Study Assessments .................................................................................................34 
9.5.1 
Assessments .................................................................................................34 
9.5.1.1 
Screening/Baseline Assessments .........................................................34 
9.5.1.1.1 
Demography ...................................................................................34 
9.5.1.1.2 
Height .............................................................................................34 
9.5.1.1.3 
Medical History .............................................................................34 
9.5.1.2 
Efficacy Assessments ...........................................................................35 
9.5.1.2.1 
Subject Diary .................................................................................35 
9.5.1.2.2 
PDQ-39 ..........................................................................................35 
9.5.1.2.3 
MDS-UPDRS Part 3 ......................................................................36 
9.5.1.2.4 
MDS-UPDRS Part 4 ......................................................................36 
9.5.1.2.5 
KPPS ..............................................................................................36 
9.5.1.2.6 
MMSE ............................................................................................37 
9.5.1.3 
Safety Assessments ..............................................................................37 
9.5.1.3.1 
Adverse Events ..............................................................................37 
9.5.1.3.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................40 
9.5.1.3.3 
Laboratory Measurements .............................................................41 
9.5.1.3.4 
Vital Signs and Weight Measurements ..........................................41 
9.5.1.3.5 
Physical Examinations ...................................................................41 
9.5.1.3.6 
Electrocardiograms ........................................................................41 
9.5.2 
Schedule of Procedures/Assessments ..........................................................42 
9.5.2.1 
Schedule of Procedures/Assessments ..................................................42 
9.5.2.2 
Description of Procedures/Assessments Schedule ...............................46 
9.5.2.2.1 
Visit 1 (Screening, -3 weeks ~ -1 day) ..........................................46 
9.5.2.2.2 
Visit 2 (Baseline, 0 week) ..............................................................47 
9.5.2.2.3 
Visit 3 (8 weeks, -4/+2 weeks) ......................................................47 
9.5.2.2.4 
Visit 4 (EOT; 18 weeks, +/-2 weeks) ............................................48 
9.5.2.2.5 
Visit 5 (19 weeks, +1 week) ..........................................................49 
9.5.2.2.6 
Unscheduled Visit ..........................................................................49 
9.5.3 
Appropriateness of Measurements ...............................................................50 


 
 
 
 
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9.5.4 
Reporting of Serious Adverse Events and Events Associated with 
Special Situations .........................................................................................50 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................50 
9.5.4.2 
Reporting of Events Associated with Special Situations .....................51 
9.5.4.2.1 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................51 
9.5.4.2.2 
Reporting of Lack of Efficacy .............................................................52 
9.5.4.2.3 
Reporting of Adverse Events Associated with Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................52 
9.5.4.3 
Expedited Reporting ............................................................................53 
9.5.4.4 
Regulatory Reporting of Adverse Events ............................................53 
9.5.5 
Completion/Discontinuation of Subjects .....................................................53 
9.6 
Data Quality Assurance .........................................................................................53 
9.6.1 
Data Collection ............................................................................................54 
9.6.2 
Clinical Data Management ..........................................................................54 
9.7 
Statistical Methods .................................................................................................54 
9.7.1 
Statistical and Analytical Plans ....................................................................54 
9.7.1.1 
Study Endpoints ...................................................................................54 
9.7.1.1.1 
Primary Endpoints .........................................................................54 
9.7.1.1.2 
Secondary Endpoints .....................................................................55 
9.7.1.2 
Definitions of Analysis Sets.................................................................55 
9.7.1.3 
Subject Disposition ..............................................................................55 
9.7.1.4 
Demography .........................................................................................56 
9.7.1.5 
Medical History ...................................................................................56 
9.7.1.6 
Prior and Concomitant Medications ....................................................56 
9.7.1.7 
Efficacy Analyses ................................................................................56 
9.7.1.7.1 
Primary Efficacy Analyses ............................................................57 
9.7.1.7.2 
Secondary Efficacy Analyses ........................................................57 
9.7.1.8 
Safety Analyses ..............................................................................57 
9.7.1.8.1 
Extent of Exposure .........................................................................57 
9.7.1.8.2 
Adverse Events ..............................................................................57 
9.7.1.8.3 
Laboratory Values ..........................................................................59 
9.7.1.8.4 
Vital Signs and Weight ..................................................................59 
9.7.2 
Determination of Sample Size .....................................................................59 
9.7.3 
Interim Analysis ...........................................................................................60 
10 
REFERENCE LIST .........................................................................................................61 
11 
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......62 
11.1 
Changes to the Protocol .........................................................................................62 


 
 
 
 
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11.2 
Adherence to the Protocol ......................................................................................62 
11.3 
Monitoring Procedures...........................................................................................62 
11.4 
Recording of Data ..................................................................................................63 
11.5 
Identification of Source Data .................................................................................63 
11.6 
Retention of Records ..............................................................................................63 
11.7 
Auditing Procedures and Inspection ......................................................................63 
11.8 
Handling of Study Drug .........................................................................................63 
11.9 
Publication of Results ............................................................................................64 
11.10 Disclosure and Confidentiality ..............................................................................64 
11.11 Discontinuation of Study .......................................................................................64 
11.12 Subject Insurance and Indemnity ...........................................................................65 
 
 
 


 
 
 
 
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LIST OF IN-TEXT TABLES 
Table 1. Incidence of patients with adverse reaction in safinamide mesilate 50mg/day 
and 100 mg/day groups compared to placebo in clinical 
trials 
 
22 
Table 2. Incidence of patients with AEs and adverse drug reaction 
22 
Table 3. Schedule of Procedures/Assessments in Study ME2125-M082-401 
 44 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
245 
 
LIST OF APPENDICES 
Appendix 1 
Administration Instructions for Clinical Trial Study Drug 
Appendix 2 
Clinical Trial Subject Consent Form, Explanation for Consent 
Appendix 3 
Subject Diary 
Appendix 4 
Parkinson’s Disease Questionnaire (PDQ-39) 
Appendix 5 
The Movement Disorder Society-Sponsored Revision of the Unified 
Parkinson's Disease Rating Scale (MDS-UPDRS) Part 3, Part 4 
Appendix 6 
King’s Parkinson’s Pain Scale 
Appendix 7 
Mini-Mental State Examination 
 


 
 
 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
BUN 
CDR 
Blood Urea Nitrogen 
Clinical Dementia Rating  
COMT 
Catechol O-methyltransferase  
CPK 
Creatine phosphokinase 
CRA 
Clinical Research Associates  
CRF  
Case Report Form 
CRO 
Contract Research Organization  
ECG 
Electrocardiogram 
EOT 
End of Treatment  
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration  
GCP 
GDS 
Good Clinical Practice 
Global Deterioration Scale 
ICF 
Informed Consent Form  
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IP 
Investigational Products  
IRB 
Institutional Review Board  
ISF 
Investigator Study File 
IxRS 
Interactive Voice/Web Response System 
KGCP 
Korean Good Clinical Practice 
KPPS 
King's Parkinson’s disease Pain Scale  
LAR 
Legally Acceptable Representative 
LLT 
Lower Level Term 
NICE 
National Institute for Health and Care Excellence  


 
 
 
 
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Abbreviation 
Term 
MAO-B 
MDS 
MDS-UPDRS 
Monoamine oxidase-B 
Movement Disorder Society 
Movement Disorder Society-Unified Parkinson’s Disease 
Rating Scale   
MedDRA 
Medical Dictionary for Regulatory Activities 
MFDS 
Ministry of Food and Drug Safety 
MMSE 
Mini-Mental State Examination 
PDQ-39 
Parkinson’s Disease Questionnaire-39  
PPS  
PT 
Per Protocol Set  
Preferred Term 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set  
Statistical Analysis System 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
TEAE 
Treatment-Emergent Adverse Event 
WBC 
White Blood Cell 
γ-GTP 
γ-glutamyl transpeptidase 
 


 
 
 
 
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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice, GCP), Section 3, Korea Good Clinical Practice (KGCP), and any local regulations. 
Any protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review 
and approval.  
Documented study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4). If the IRB/IEC decides to suspend 
or terminate the study, the investigator will immediately send the notice of study suspension 
or termination by the IRB/IEC to the sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by an investigator or 
sponsor, depending on local regulatory obligations. If an investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report. The 
investigator or the sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB/IEC of any reportable Adverse Events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice. Upon completion of the study, the investigator will provide the 
IRB/IEC with a brief report of the outcome of the study, if required. 
In the case of early termination/temporary halt of the study, an investigator should notify the 
IRB/IEC within the timeline required by each IRB’s Standard Operating Procedures (SOP) 
and a detailed written explanation of the reasons for the termination/halt should be given. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures of the sponsor 
(or designee), which are designed to ensure adherence to GCP guidelines as required by the 
following: 
● 
Principles of the World Medical Association Declaration of Helsinki 2013 
● 
ICH E6 Guideline for GCP  
● 
KGCP 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigators must explain to each 
subject or legally acceptable representative, the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, any potential 
discomfort, potential alternative procedure or course of treatment available to the subject, and 


 
 
 
 
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the extent of maintaining confidentiality of the subject’s records. Each subject must be 
informed that participation in the study is voluntary, that he/she may withdraw from the study 
at any time, and that withdrawal of consent will not affect his/her subsequent medical treatment 
or relationship with the treating investigator. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language. The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document. If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and explained 
to the subject or the subject’s legally acceptable representative, and after the subject or the 
subject’s legally acceptable representative has orally consented to the subject’s participation 
in the study and, if capable of doing so, has signed and personally dated the ICF, the witness 
should sign and personally date the consent form. The subject will be asked to sign an ICF at 
Visit 1 (Screening) before any study-specific procedures are performed. No subject can enter 
the study before his/her informed consent has been obtained. 
Each subject must sign an approved ICF before study participation. The form must be signed 
and dated by the appropriate parties. The original, signed ICF for each subject will be verified 
by the sponsor or sponsor’s representative and kept on file according to local procedures at the 
site.  
The subject or the subject’s legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness 
to continue participation in the study. The communication of this information should be 
documented. 
 
 


 
 
 
 
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6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai Korea 
Inc. at approximately 20 investigational sites in South Korea. 
The name and telephone and fax numbers of contact personnel at the sponsor and of the 
Contract Research Organization (CRO) are listed in the Investigator Study File (ISF) provided 
to each site. 
7 
INTRODUCTION 
7.1 
Compound Overview 
Levodopa is one of the effective treatments for motor symptoms of Parkinson’s Disease.1, 2 
Long-term and high doses of levodopa treatment increase the wearing-off and dyskinesia. 
Parkinson’s Disease patients often need add-on therapy to improve motor fluctuations without 
dyskinesia to reduce motor and functional disability.1, 2 Wearing-off is usually improved by 
dopamine agonist, Monoamine Oxidase-B (MAO-B) inhibitor, and Catechol O-
methyltransferase (COMT) inhibitors administered together with dopamine precursor, 
levodopa.1, 2  
Safinamide mesilate is a novel oral therapy in the treatment of Parkinson’s Disease as an 
adjunct to levodopa. Mechanism of action of safinamide mesilate includes inhibition of MAO-
B, sodium (Na1) channel blockade, and modulation of stimulated release of glutamate.1-3 By 
inhibiting the metabolism of dopamine, Safinamide mesilate enhances endogenous residual 
dopamine and subsequently increases dopaminergic activity in the brain.1-3 
7.2 
Clinical Experience 
Clinical trials with safinamide mesilate, which were 24-week, phase III, double-blind, parallel-
group, randomized, multi-center, and multinational trials, demonstrated efficacy and safety in 
Parkinson’s Disease patients with mid-to-late stage experiencing motor fluctuations 
(NCT01187966 and NCT 00627640).1,3 According to approved Food and Drug Administration 
(FDA) label, most common adverse reactions associated with safinamide mesilate treatment 
in which the incidence for Safnamide mesilate 100 mg/day was at least 2% greater than the 
incidence for placebo were dyskinesia, fall, nausea, and insomnia (Table 1).4 
Table 1. Incidence of patients with adverse reaction in the safinamide mesilate 
50mg/day and 100 mg/day groups compared to placebo in clinical trials 
 
Safinamide mesilate 
50 mg/day (N=223) 
Safinamide mesilate 
100 mg/day (N=498) 
Placebo 
(N=497) 
Adverse reaction 
(%) 
(%) 
(%) 
Dyskinesia 
21 
17 
9 
Fall  
4 
6 
4 
Nausea  
3 
6 
4 


 
 
 
 
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Safinamide mesilate 
50 mg/day (N=223) 
Safinamide mesilate 
100 mg/day (N=498) 
Placebo 
(N=497) 
Adverse reaction 
(%) 
(%) 
(%) 
Insomnia 
1 
4 
2 
Orthostatic hypotension 
2 
2 
1 
Anxiety 
2 
2 
1 
Cough  
2 
2 
1 
Dyspepsia 
0 
2 
1 
 
In addition, phase II/III clinical trials in Japan indicated the efficacy and safety of safinamide 
mesilate as add-on therapy to levodopa in Parkinson’s Disease patients.2 In this clinical trial, 
the most common AEs were nasopharyngitis, dyskinesia, and fall. Among these, the most 
common adverse drug reaction were dyskinesia and visual hallucinations (Table 2).2 
Table 2. Incidence of patients with AEs and adverse drug reaction  
 
Adverse events 
Adverse drug reaction 
Placebo 
(N=141) 
Safinamide mesilate 
Placebo 
(N=141) 
Safinamide mesilate 
50 mg/day 
(N=133) 
100 mg/day 
(N=132) 
50 mg/day 
(N=133) 
100 mg/day 
(N=132) 
 
Nasopharyngitis 
11.3 
6.8 
12.9 
- 
- 
- 
Dyskinesia 
2.1 
8.3 
10.6 
2.1 
8.3 
10.6 
Fall  
5.0 
5.3 
6.8 
2.1 
1.5 
0.8 
Contusion 
2.8 
3.0 
5.3 
- 
- 
- 
Visual 
hallucinations 
1.4 
3.0 
4.5 
1.4 
3.0 
4.5 
Back pain 
3.5 
0.8 
3.8 
- 
- 
- 
Nausea  
0.7 
3.0 
3.0 
0.7 
2.3 
2.3 
Conjunctivitis 
0.7 
- 
3.0 
- 
- 
- 
Excoriation 
- 
- 
3.0 
- 
- 
- 
Headache 
0.7 
3.8 
1.5 
- 
2.3 
1.5 
 
 
 


 
 
 
 
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7.3 
Study Rationale 
Safinamide mesilate was approved by the U.S. Food and Drug Administration (FDA) in March 
2017 based on phase III clinical trials (NCT01187966 and NCT 00627640) as adjunctive 
treatment to levodopa in patients with Parkinson’s Disease experiencing off episodes.1, 3, 4 In 
addition, safinamide mesilate was approved by the Ministry of Food and Drug Safety (MFDS) 
in June 2020 as adjunctive therapy with levodopa-containing products in patients with end of 
dose motor fluctuations.6 Previous studies demonstrated that adjunctive therapy of safinamide 
mesilate to levodopa improves Parkinson’s Disease symptoms and “off” time. 7 
The National Institute for Health and Care Excellence (NICE) guideline 2017 regarding 
managing symptoms of Parkinson’s Disease recommends only to add adjuvant therapy to a 
levodopa regimen, under specialist advice.5 Subjects with various daily doses of levodopa from 
315 mg to 1,273 mg per day were included even in the global phase 3 clinical SETTLE study, 
so there is no clear agreement on the optimal adjuvant therapy compared to the dose.2,5  
Furthermore, only limited number of centers and patients from South Korea participated in 
previous global studies that evaluated the efficacy and safety of safinamide mesilate as an add-
on therapy in Parkinson’s Disease patients; only 27 Parkinson’s Disease patients from 4 centers 
in South Korea had experienced safinamide mesilate as add-on therapy to stable dose of 
levodopa.7 In this situation, to assess the efficacy and safety of safinamide mesilate according 
to the daily dose of levodopa is needed for Parkinson’s Disease patients who need combination 
therapy with levodopa in South Korea. 1 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
To evaluate the change at the 18th week from baseline in daily “off” time measured by subject 
diary and Parkinson’s Disease Questionnaire-39 (PDQ-39) in patients with Parkinson’s 
Disease who are receiving levodopa.  
8.2 
Secondary Objective 
● To evaluate the change at the 18th week from baseline in below assessments: 
- 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS)   
Part 3 
- 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS)   
Part 4 
- 
King’s Parkinson’s disease Pain Scale (KPPS)  
- 
Mini-Mental State Examination (MMSE) 
 
● To evaluate the safety of safinamide mesilate in Parkinson’s Disease patients who are 
receiving levodopa  


 
 
 
 
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● To evaluate the change at the 18th week from baseline in daily “on” time without 
dyskinesia in patients with Parkinson’s Disease who are receiving levodopa 
 
 




 
 
 
 
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9.1.1 
Screening Period 
The purpose of the Screening Period is to obtain informed consent and to establish protocol 
eligibility. Informed consent will be obtained after the study has been fully explained to each 
subject and before the conduct of any screening procedures or assessments. Procedures to be 
followed when obtaining informed consent are detailed in Section 5.3. 
Subjects must have a diagnosis of Parkinson’s Disease and receive levodopa at a stable dose 
for at least 4 weeks prior to the screening visit. After signed informed consent is obtained from 
the subject or for subjects from Legally Acceptable Representatives (LARs), a medical history 
interview, identification of prior and concomitant medications, identification of concomitant 
therapies, height, weight, physical examination, urine pregnancy test (females of childbearing 
potential only), 12-lead electrocardiogram (ECG; if deemed necessary by an investigator), vital 
signs, clinical laboratory tests (hematology, chemistry, and  urinalysis), and Adverse Events 
(AE) assessment will be conducted for evaluation of eligibility criteria, and will include 
confirmation that the subject meets diagnostic criteria for Parkinson’s Disease. 
At Visit 1 (Screening), subjects will perform the Mini-Mental State Examination (MMSE) 
among the efficacy assessments. Also, a daily will be handed out to subjects and/or their 
caregivers, and investigator will train them how to complete the diary. Subjects who meet the 
eligibility criteria of the study will be instructed to complete the diary for 3 consecutive days 
prior to Visit 2 (Baseline).  
 
If subjects have previously taken medication such as COMT inhibitor and/or MAO-B inhibitor, 
they have to undergo an appropriate wash-out period for each medication (3 days for COMT 
inhibitor; 14 days for MAO-B inhibitor). 
9.1.2 
Baseline Period 
At Visit 2 (Baseline), subjects will return to the site after they complete the diary for at least 3 
consecutive days. At Visit 2 (Baseline), safety assessments including AE assessment, vital 
signs, weight (if deemed necessary by an investigator), and physical examination will be 
conducted.  
Efficacy assessments including Parkinson’s Disease Questionnaire-39 (PDQ-39), Movement 
Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3 and Part 
4, and King’s Parkinson’s disease Pain Scale (KPPS) will be conducted. The investigators will 
also review the completed subject diary with subjects.  
The study drug will be distributed to subjects who meet the eligibility criteria at Visit 2 
(Baseline). The subjects will be instructed to take the study drug every day starting from the next 
day after Visit 2 (Baseline). 
 


 
 
 
 
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9.1.3 
Treatment Period 
Subjects whose screening assessments including the wash-out period and evaluations are 
completed and reviewed by the investigators and who continue to meet all of the 
inclusion/exclusion criteria will enter the Treatment Period. Subjects will take the study drug 
every day for 18 weeks. 
The dose of the study drug is 50 mg once a day for 2 weeks (14 days) starting from the next day after 
Visit 2 (Baseline), and 100 mg once a day afterwards. Subjects who need to increase the dose at the 
discretion of an investigator shall visit the site (unscheduled) prior to the dose increase.  
 
Subjects whose dose cannot be increased to 100 mg/day within 4 weeks following Visit 2 (Baseline) 
will be dropped out from the clinical trial. 
 
If Adverse Events (AE) occur in subjects who have increased the dose, the dose may be reduced back 
to 50 mg/day at the discretion of an investigator through unscheduled site visit or phone visit. After 
reduction from 100mg/day to 50mg/day, the dose may be increased back to 100 mg/day at the discretion 
of an investigator. 
 
Subjects will return to the site at 8 weeks and 18 weeks for Visit 3 and Visit 4 (EOT), respectively. The 
“windows” permitted for Visit 3 (8 weeks) will be -4 weeks and +2 weeks; for Visit 4 (18 weeks: EOT) 
will be +/- 2 weeks. Safety assessments including AE assessment, 12-lead ECG (if deemed necessary 
by an investigator), vital signs, weight, physical examination, clinical laboratory tests (hematology, 
chemistry, and urinalysis), and urine pregnancy test (females of childbearing potential only) will be 
conducted according to the schedule for each visit during Treatment Period. Efficacy assessments 
including PDQ-39, MDS-UPDRS Part 3 and Part 4, KPPS, and MMSE will be conducted at Visit 4 
(EOT). Subjects will complete the diary for at least 3 consecutive days prior to Visit 4 (EOT), and the 
investigators will review the completed diary together with subjects at Visit 4 (EOT). 
 
9.1.4 
Taper Period 
Of the subjects who have completed 18 weeks of treatment, those who require tapering will enter a 
Taper Period for 1 week. After the completion of the Taper Period, subjects will return to the site for 
Visit 5. At Visit 5, safety assessments including AE assessment, vital signs, weight (if deemed 
necessary by an investigator), and physical examination will be conducted. For those subjects 
participating in the Taper Period, their participation in the study will be completed after the completion 
of Visit 5. 
 
The Taper Period may be omitted if the subject’s daily dose of the study drug at the end of treatment is 
50mg, if subjects will continue to take the study drug after the completion of the trial, or if it is 
considered not required by an investigator. For the subjects who do not require the Taper Period, their 
participation in the study will be completed after the completion of Visit 4 (EOT). 
 




 
 
 
 
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9.3.2 
Exclusion Criteria 
To be eligible for inclusion into this trial, the subjects must not meet any of the following 
criteria:  
1. Females who are planning for pregnancy, pregnant or breastfeeding 
2. Prior use of safinamide 
3. If patients have previously taken medication such as COMT inhibitor and/or MAO-B 
inhibitor, they have to take appropriate wash-out period for each medication.(3 days for 
COMT inhibitor; 14 days for MAO-B inhibitor) 
4. Use of medications for depression or psychosis within 5 weeks prior to Screening Visit 
5. History of allergic response to levodopa, or other anti-Parkinsonian agent 
6. Hypersensitivity or contraindications to MAO-B inhibitors  
7. Confirmed ophthalmologic history including any of the following conditions: albino 
subjects, family history of hereditary retinal disease, progressive and/or severe 
diminution of visual acuity (i.e., 20/70 on Snellen Chart), retinitis pigmentosa, retinal 
pigmentation due to any cause, any active retinopathy or ocular inflammation (uveitis), 
or diabetic retinopathy. 
8. Patients who did not consent to having at least 7 days of washout period prior to Visit 2, 
if known to take narcotic analgesics 7 days prior to Screening Visit (eg, pethidine 
hydrochloride-containing products, tramadol hydrochloride, or tapentadol hydrochloride) 
9. History of serotonergic medications administration (eg, tricyclic antidepressants, 
tetracyclic antidepressants, selective serotonin reuptake inhibitors, serotonin–
noradrenaline reuptake inhibitors, selective noradrenaline reuptake inhibitor, or 
noradrenergic and serotonergic antidepressant) within 5 weeks prior to the Screening 
Visit 
10. Administering central nervous system stimulants (eg, methylphenidate hydrochloride, 
lisdexamfetamine mesilate)  
11. Administering dextromethorphan 
12. Patients with clinically significant liver function abnormalities defined as > 1.5 times of 
the upper limit of the normal range of total bilirubin or > 3 times of the upper limit of the 
normal range of ALT or AST; re-examination and re-screening are allowed once within 
the screening period 
13. Have a history of hypersensitivity to any of the ingredients of the product 
14. Currently enrolled in another clinical trial or used any investigational drug/biologics or 
device within 30 days or 5 × the half-life, whichever is longer, preceding informed 
consent 
9.3.3 
Removal of Subjects from Therapy or Assessment 
The investigators may withdraw the subjects from the study at any time for safety or 
administrative reasons and noncompliance with study procedures (e.g., omission of efficacy 
evaluation, omission of subject diary completion, use of prohibited medication or therapy, 
deviation from the dose limitation of concomitant medication, deviation from the dose increase 


 
 
 
 
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schedule of study drug, etc.) Also, subjects whose dose of study drug cannot be increased to 
100 mg/day within 4 weeks of Visit 2 (Screening) will be withdrawn from the study. Subjects 
may stop the study drug administration or withdraw from the study at any time for any reason.  
Subjects who prematurely discontinue the administration of the study drug should visit the site 
as soon as practicable (preferably within 7 days) to complete the Premature Discontinuation 
Visit. 
9.4 
Treatment 
9.4.1 
Treatment Administered 
Subjects who are enrolled in this study will be treated with the study drug for approximately 
18 weeks. The dose and administration of the study drug is as follow:  
The dose of the study drug is 50 mg once a day for 2 weeks (14 days) starting from the next day after 
Visit 2 (Baseline), and 100 mg once a day afterwards. Subjects who need to increase the dose at the 
discretion of an investigator shall visit the site (unscheduled) prior to the dose increase. 
If Adverse Events (AE) occur in subjects who have increased the dose, the dose may be reduced back 
to 50 mg/day at the discretion of an investigator through unscheduled site visit or phone visit. After 
reduction from 100mg/day to 50mg/day, the dose may be increased back to 100 mg/day at the discretion 
of an investigator. 
 
If, following the dose increase to 100mg/day, moderate or severe hepatic impairment occurs according 
to Child-Pugh classification, study drug should be administered as per below guideline. 
● 
Moderate hepatic impairment (Child-Pugh B): Do not exceed 50 mg once daily 
● 
Severe hepatic impairment (Child-Pugh C): Contraindicated (Termination of study 
drug required) 
[Child-Pugh Classification]8 
Parameter 
Abnormal value or degree 
Grade Score 
Encephalopathy* 
None 
1 and 2 
3 and 4 
1 
2 
3 
Ascites 
None 
Mild 
Moderate 
1 
2 
3 
Total bilirubin (mg/dL) 
< 2 
2 - 3 
> 3 
1 
2 
3 


 
 
 
 
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Albumin (g/dL) 
> 3.5 
2.8 - 3.5 
< 2.8 
1 
2 
3 
Prothrombin Time (seconds) < 4 
4 - 6 
> 6 
1 
2 
3 
*Grade 0: Normal values for cognition, behavior, neurological examination and ECG 
Grade 1: Anxiety, sleep disorder, easily irritated/excited, tremor, dysgraphia, 5 cps wave 
Grade 2: Narcolepsy, confusion of time, inappropriate behavior, asterixis, ataxia, decreased 
triphasic wave 
Grade 3: Narcosis, stupor, confusion of sense of space, excessive reflection, contracture, 
decreased brain wave 
Grade 4: Coma, lack of personality/action, decerebrate rigidity, slow delta wave of 2-3 cps  
Total Score 
Class 
Seriousness 
5 - 6 
A 
Mild 
7 - 9 
B 
Moderate 
10 -15 
C 
Severe 
 
9.4.2 
Identity of Investigational Products 
Study drug will be provided in a strength of 50 mg only. Subjects whose daily dose of study 
drug is 100 mg will be instructed to take 2 tablets of study drug at once daily. No comparator 
will be used in this study. 
9.4.2.1 
Study drug code: ME2125 Chemical Name of ME2125 
Generic name: safinamide mesylate 
Chemical name: (S)-2- [[4-[(3-fluorophenyl) methoxy]phenyl]methyl]aminopropanamide 
methanesulfonate 
Molecular formula: C17H19FN2O2•CH4O3S 
Molecular weight: 398.45 
9.4.2.2 
Labeling for Study Drug 
The label of study drug will include the following information as per local regulation: 
 
● 
“For clinical trial use only” or similar wording  


 
 
 
 
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● 
Name/identifier of study drug including formulation, route of administration, 
quantity of dose units, strength, etc. as required.   
● 
Lot number/batch number 
● 
Name, address, and contact number of the sponsor 
● 
Expiration date 
● 
Storage conditions 
● 
“Keep out of the reach of children” statement 
● 
Reference code to identify the clinical trial  
● 
Subject identification number and treatment number 
● 
Special precautions for storage and handling according to the approved label  
9.4.2.3 
Storage Conditions 
Study drug will be stored in accordance with the approved label as follow:  
Storage conditions: tight container, store at room temperature (1°C to 30°C) 
Temperature monitoring is required at the storage location to ensure that the study drug is 
maintained within an established temperature range. The investigators or designee is 
responsible for ensuring that the temperature is monitored throughout the total duration of the 
study and that records are maintained; the temperature should be monitored continuously by 
using either an in-house validated data acquisition system, a mechanical recording device, such 
as a calibrated chart recorder, or by manual means such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. 
9.4.3 
Method of Assigning Subjects to Treatment Group 
This is a multi-center, open-label, single-arm, interventional study. All subjects who provide 
signed informed consent to participate in this study and satisfy all eligibility requirements (see 
Section 9.3) will be assigned to receive the study drug daily for approximately 18 weeks as 
add-on therapy to levodopa. There is no randomization in this study. 
9.4.4 
Selection of Doses and Method of Administration in the Study 
The dose of the study drug will start with 50 mg administered orally once daily for 2 weeks 
(14 days) starting from the next day after Visit 2 (Baseline) and will be increased to 100 mg 
once daily afterwards. 
The study drug is provided in the form of a 50 mg tablet. If administering 50 mg/day, 
administer 1 tablet once daily. If administering 100 mg/day, administer 2 tablets once daily. 
9.4.5 
Timing of Study Drug Administration 
The study drug will be taken at the same time each day without regard to meals. 




 
 
 
 
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- 
Acetylcholinesterase inhibitors 
- 
COMT inhibitor 
- 
Any investigational drugs/biologics  
- 
All the contraindicated medications listed on the approved label of study drug 
(Appendix 1)  
 
Prohibited therapies:  
- 
DBS(Deep brain stimulation) 
- 
Surgical treatment 
- 
LCIG(Levodopa-carbidopa intestinal gel) therapy  
 
Concomitant medications and therapies listed above will be prohibited during the trial 
participation. Nevertheless, if continuous use of any prohibited medication/therapy is indicated 
for treatment of the subject during the trial, in the judgment of an investigator who treats the 
subject’s other medical symptoms, the subject must discontinue the trial immediately, and the 
details should be recorded in the Case Report Form (CRF). 
 
9.4.8 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study. Clinical 
Research Associates (CRA) will review treatment compliance during site visits and at the 
completion of the study. 
At 8 weeks and 18 weeks during the Treatment Period, and if applicable, at 19 weeks during 
the Tapering Period, at unscheduled visits, or at premature termination visit, unused study 
drugs received at last visit will be returned to the investigators or designee. The medication 
will be inventoried, and the percent compliance will be calculated by dividing the number of 
doses administered by subjects by the number of days of the treatment period.  
9.4.9 
Drug Supplies and Accountability 
The investigators or the designee will be responsible for the accountability of all study drugs 
(dispensing, inventory, and record-keeping) following the sponsor’s instructions and 
adherence to Good Clinical Practice (GCP) guidelines as well as local requirements. 
Under no circumstances will the investigators allow the study drugs to be used other than as 
directed by this protocol. Study drugs will not be dispensed to any individual who is not 
enrolled in the study.   
The site must maintain an accurate and timely record of the following: receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 


 
 
 
 
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reconciled study drugs at the site. This includes, but may not be limited to: (a) documentation 
of receipt of study drugs (b) study drugs dispensing/return reconciliation log, (c) study drugs 
accountability log, (d) all shipping service receipts, (e) documentation of returns to the 
sponsor, and (f) certificates of destruction for any destruction of study drugs that occurs at 
the site. All forms will be provided by the sponsor. Any comparable forms that the site 
wishes to use must be approved by the sponsor. 
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority. As 
applicable, all unused study drugs and empty and partially empty containers from used study 
drugs are to be returned to the investigators or the designee by the subject and, together with 
unused study drugs that were shipped to the site but not dispensed to subjects, are to be 
returned to the sponsor’s designated depot during the study or at the conclusion of the study, 
unless provision is made by the sponsor for destruction of study drugs and containers at the 
site. Destruction at the site will only occur under circumstances where regulation or supply 
type prohibits the return of study drugs to the depot. Approval for destruction to occur at the 
site must be provided by the sponsor in advance. Upon completion of drug accountability and 
reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated depot 
must be boxed, sealed, and shipped back to the depot following all local regulatory 
requirements. Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor. 
Drug accountability will be reviewed during site visits and at the completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
9.5.1.1 
Screening/Baseline Assessments 
9.5.1.1.1 
Demography  
Subject demographic information will be collected at Visit 1 (Screening). Demography 
information includes year and month of birth (or age) and sex. 
9.5.1.1.2 
Height  
Height will be collected at Visit 1 (Screening).  
9.5.1.1.3 
Medical History 
Medical and surgical history and current medical conditions will be recorded at Visit 1 
(Screening). All medical history within 6 months and surgical history within 3 years must be 
recorded on the medical history CRF.  


 
 
 
 
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9.5.1.2 
Efficacy Assessments 
The procedure for the efficacy assessments consists of the subject diary and questionnaire 
examination. Each questionnaire test below (PDQ-39, MDS-UPDRS part 3 and part 4, KPPS, 
MMSE) is to be performed in the “on” state of the subject, and is tested in the “off” state 
only when it is difficult to evaluate it in the “on” state. 
9.5.1.2.1 
Subject Diary 
Information on daily “off” time and “on” time will be collected by subject diary. Subjects 
and/or their caregivers will receive a subject diary, and investigator will train them how to 
complete the diary at Visit 1 (Screening).  
Subjects will complete the diary for at least 3 consecutive days prior to each visit where 
completed diary review is conducted (Visit 2, Visit 4) and the diary will be maintained by the 
subject over a 24-hour period each day the diary is being completed. At 30-minute intervals 
throughout the period, the subject/caregiver will record whether the subject is currently 1) in 
an “on” phase, 2) in an “on” phase with dyskinesia, 3) in an “off” phase, or 4) asleep. 
Subjects will also check when they take their levodopa throughout the day.  
An “off” phase will be defined as lack of mobility, bradykinesia, or akinesia whereas in an 
“on” phase, the subject will be functioning as well as can be expected for that subject, 
irrespective of whether or not he/she is having dyskinesia. 
The daily “off” time is defined as the mean of the total daily “off” time during the last two 
24-hour diary recording periods prior to the visit. The daily “on” time is defined as the mean 
of the total daily “on” time during the last two 24-hour diary recording periods prior to the 
visit.  
Investigators will review the completed subject diary with subjects at Visit 2 (Baseline) and 
Visit 4 (EOT) and record the results of the subject diary in CRF. At Visit 4 (EOT), subjects 
will submit the subject diary to clinical trial staff or investigators.  
9.5.1.2.2 
PDQ-39 
To assess the efficacy of non-motor symptoms and motor symptoms in subjects, Parkinson’s 
Disease Questionnaire (PDQ-39) will be used. The PDQ-39 consists of 39 questions measuring 
eight dimensions of health: mobility, activities of daily living, emotional well-being, stigma, 
social support, cognition, communication, and bodily discomfort. Dimension scores are coded 
on a scale of 0 (perfect health as assessed by the measure) to 100 (worst health as assessed by 
the measure). A summary index score can also be calculated. The contents of the instrument 
were developed on the basis of exploratory in-depth interviews with subjects with Parkinson's 
Disease, and the reliability, validity and sensitivity to change of the instrument were then 
assessed in a number of large-scale surveys. The questionnaire will be provided in Korean to 
the subjects. 
Once a subject completes PDQ-39, the investigators will record the result in CRF. 


 
 
 
 
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9.5.1.2.3 
MDS-UPDRS Part 3  
To assess the efficacy of motor symptoms in subjects, The Movement Disorder Society-
Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 3 
will be used. The MDS-UPDRS is a rating tool used to follow the longitudinal course of 
Parkinson’s Disease. It is made up of four parts that assess the following: Part 1 – Non-motor 
Aspects of Experiences of Daily Living; Part 2 – Motor Aspects of Experiences of Daily 
Living; Part 3 – Motor Examination; and Part 4 – Motor Complications. The information for 
these ratings is obtained through an interview with the subject and caregiver if available. 
MDS-UPDRS Part 3 evaluates the motor function of the subject. This section of the scale 
consists of 18 items, with 33 separate ratings being performed on a scale from 0 (normal) to 4 
(severe). Specific instructions are provided for the testing of each item, which should be 
followed in all instances. Raters demonstrate while describing tasks the subject is to perform 
and rate function immediately thereafter. The subject’s speech, facial expressions, ability to 
arise from a chair, posture, gait, postural stability (retropulsion test), and body bradykinesia 
are assessed. In addition, tremor at rest, action or postural tremor of hands, rigidity, finger taps, 
hand movements (open/close), rapid alternating movements of hands (pronation/supination), 
and leg agility are assessed.  
After completing MDS-UPDRS Part 3, the investigators will record the result in CRF.  
9.5.1.2.4 
MDS-UPDRS Part 4 
In MDS-UPDRS Part 4, raters use historical and objective information to assess two motor 
complications, dyskinesias and motor fluctuations that include OFF-state dystonia. Raters 
will use all information from patient, caregiver, and the examination to answer the six 
questions that summarize function over the past week including today. This section has 
instructions for the raters and also instructions to be read to the patient, and integrates 
patient-derived information with the rater’s clinical observations and judgments. In Part A, 
the duration of, disability caused by, and functional impact of any dyskinesias experienced 
by the subject are rated on a scale from 0 to 4. Clinical fluctuations are assessed in Part B, 
which includes time spent in “off” state (estimation of the proportion of the waking day spent 
in the “off” state), functional impact of fluctuations, the predictability and timing of the 
subject’s “off” periods, and proportion of the “off” state having painful dystonia. 
 
After completing MDS-UPDRS Part 4, the investigators will record the result in CRF.  
9.5.1.2.5 
KPPS 
To assess pain scale in subjects, King’s Parkinson’s Disease Pain Scale KPPS will be used. 
KPPS is Parkinson’s Disease-specific pain scale. Its seven domains include 14 items; each 
item is scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 
12 with a total possible score range from 0 to 168. 
After completing KPPS, the investigators will record the result in CRF.  


 
 
 
 
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9.5.1.2.6 
MMSE 
To assess cognition in subjects, the Mini-Mental State Examination (MMSE) will be used. The 
MMSE is a brief practical screening test for cognitive dysfunction. The test consists of relevant 
sections (awareness of time, awareness of location, memory, attention, as well as ability to 
calculate, ability to recall, ability to name names, repetition, understanding, reading, writing, 
and drawing) and has a total possible score of 30. It is useful as a quick method to assess the 
severity of cognitive dysfunction. 
After completing the MMSE, the investigators will record the result in CRF.   
9.5.1.3 
Safety Assessments 
Safety assessment will consist of determining and recording all adverse events (AEs) and other 
events of special interests including pregnancy, breast feeding, overdose, abuse or misuse, lack 
of therapeutic efficacy, medication error, off label use, occupational exposure, and suspected 
transmission of an infectious agent; regular clinical laboratory evaluation for hematology, 
blood chemistry, and urine values; periodic measurement of vital signs and ECGs; and the 
performance of physical examinations as detailed in Table 3. 
 
9.5.1.3.1 
Adverse Events 
Adverse Event (AE) refers to an unfavorable and unintended sign (e.g. abnormal laboratory 
finding) associated with administration/use of study drug, symptom, or disease, whether or not 
related to the medicinal (investigational) product. For this study, the study drug is safinamide 
mesilate.  
The criteria for identifying AEs in this study are: 
● 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note: Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE) 
● 
Any new disease or exacerbation of an existing disease.  
● 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (e.g., ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug. 
● 
Recurrence of an intermittent medical condition (e.g., headache) not present 
pretreatment (baseline). 
● 
An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, withdrawal of study drug, or 
withholding of study drug, whether prescribed in the protocol or not. 


 
 
 
 
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All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
after Visit 1 (Screening) through the last visit. Refer to Section 9.5.4.1 for the time period after 
the end of treatment for SAE collection.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE. It is the responsibility of the 
investigators to review all laboratory findings in all subjects and determine if they constitute 
an AE. Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE. Any laboratory abnormality considered 
to constitute an AE should be reported on the Adverse Event CRF.  
All AEs must be followed until the end of the study (subject’s last visit). All Serious Adverse 
Events (SAEs) must be followed to resolution or, if resolution is unlikely, to stabilization. 
Every effort must be made by the investigators to categorize each AE according to its 
severity and its relationship to the study drug. 
Assessing Severity of Adverse Events 
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF. The definitions are as follows: 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating, with inability to work or to perform normal daily activity 
The criteria for assessing severity are different from those used for seriousness (see Section 
9.5.1.3.2 for the definition of an SAE). 
Assessing Relationship to Study Drug 
Items to be considered when assessing the relationship of an AE to the study drug are: 
● Temporal relationship of the onset of the event to the initiation of the study drug 
● The course of the event, especially the effect of discontinuation of study drug or 
reintroduction of study drug, as applicable 
● Whether the event is known to be associated with the study drug or with other similar 
treatments 
● The presence of risk factors in the study subject known to increase the occurrence of 
the event 
● The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event 


 
 
 
 
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Classification of Causality 
In this study, the evaluation of the relationship between the drug and each adverse event 
according to the following evaluation criteria shall be recorded in the CRF. 
Causality 
Description  
Certain 
① The relationship before and after with the 
administration∙use of the drug is reasonable, and it 
is not explained by other medicines, chemicals, or 
concomitant diseases. 
② Showing a clinically reasonable response when the 
drug administration is discontinued. 
Probable/likely 
① The temporal relationship with the 
administration∙use of the drug is reasonable, and it 
does not appear to be related to other medicines, 
chemicals, or concomitant diseases. 
② Showing a clinically reasonable response when the 
drug administration is discontinued. 
Possible 
① The temporal relationship with the 
administration∙use of the drug is reasonable, but it is 
also explained as depending on other drugs, 
chemicals, or concomitant diseases. 
② In case information regarding discontinuation of the 
drug is insufficient or unclear 
Unlikely 
① Temporary cases that are unlikely to have a causal 
relationship with the administration∙use of the drug. 
② In case a reasonable explanation of the occurrence is 
possible with other drugs, chemicals, or potential 
diseases 
Conditional/unclassified 
① In case more data is needed for proper evaluation or 
when additional data is being reviewed 
Unassessable/unclassifiable 
① In case it cannot be determined as information is 
insufficient or conflicting, and it cannot be 
supplemented or verified 
 
Outcome of Adverse Events 
● Recovered 
● Recovering 
● Not recovered 
● Recovered with side effects 


 
 
 
 
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● Death 
● Unknown 
 
9.5.1.3.2 
Serious Adverse Events and Events Associated with Special Situations 
SAE is any untoward medical occurrence that at any dose: 
● Results in death 
● Is life-threatening (i.e., the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
● Results in inpatient hospitalization 
● Requires prolongation of existing hospitalization 
● Results in persistent or significant disability/incapacity 
● Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
● Is a medically significant event 
Other important medical events that may not be immediately life-threatening or result in death 
or hospitalization but, when based on appropriate medical judgment, may jeopardize the 
subject or may require intervention to prevent one of the outcomes in the definition of SAE 
listed above should also be considered SAEs. Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in such situations.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to the study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error; lack of efficacy. These events associated with special 
situations are to be captured using the SAE procedures but are to be considered as SAEs only 
if they meet one of the above criteria. All AEs associated with special situations are to be 
reported on the CRF whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “AE” (i.e., 
there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care  
● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that 
was in place before study entry 


 
 
 
 
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9.5.1.3.3 
Laboratory Measurements 
Laboratory tests to be performed according to the guideline of each site. In case that laboratory 
test is performed, laboratory abnormality may meet the criteria to qualify as an AE as described 
in this protocol (see Section 9.5.1.3.1). In these instances, the AE corresponding to the 
laboratory abnormality will be recorded on the Adverse Event CRF. 
Category 
Parameters 
Hematology 
hematocrit, hemoglobin, platelets, RBC count, and WBC count with differential 
(bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
Chemistry 
Na, K, Ca, Cl, CPK, BUN, Creatinine, Uric acid, Total bilirubin, Albumin, Total 
protein, ALT, AST, γ-GTP, Alkaline phosphatase 
Urinalysis 
Specific gravity, pH, Protein, Glucose, Bilirubin, Ketones, RBC, WBC, Creatinine 
9.5.1.3.4 
Vital Signs and Weight Measurements 
Vital sign measurements (i.e., systolic and diastolic blood pressure [mmHg], pulse [beats per 
minute], body temperature [in centigrade]), and weight (kg) will be obtained at the visits 
designated in Table 3 by a validated method.  
Vital signs will include blood pressure, pulse, and body temperature. Blood pressure and pulse 
will be measured after the subject has been sitting for 5 minutes. All blood pressure 
measurements should be performed on the same arm, preferably by the same person.  
Documentation of vital signs will be included in the source documentation at the site. Clinically 
significant abnormal findings at Visit 1 (Screening) will be recorded on the medical history 
CRF. Only changes from screening vital signs findings that meet the definition of an AE will 
be recorded on the Adverse Event CRF. 
9.5.1.3.5 
Physical Examinations 
Physical examinations will be performed as designated in Table 3. Documentation of the 
physical examination will be included in the source documentation at the site. Clinically 
significant abnormal findings at Visit 1 (Screening) will be recorded on the medical history 
CRF. Only changes from screening physical examination findings that meet the definition of 
an AE will be recorded on the Adverse Event CRF. 
9.5.1.3.6 
Electrocardiograms 
ECG will be performed as designated in Table 3. An ECG abnormality may meet the criteria 
of an AE as described in this protocol (see Section 9.5.1.3.1). In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Event CRF. 
 


 
 
 
 
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9.5.2 
Schedule of Procedures/Assessments  
9.5.2.1 
Schedule of Procedures/Assessments 
Table 3 presents the schedule of procedures/assessments for this study.






 
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Any concomitant medications and therapies during this study (starting at the date of informed consent) will be recorded at each visit  The information on concomitant medications (including levodopa) will include the name 
of product or ingredient, dose and administration (daily dose and dose unit), administration period (start date and end date), and purpose of administration  The information on concomitant therapies should include the name 
of therapy, therapy period (start date and end date), and purpose of therapy  Any Adverse Events or medical status shall be recorded during the administration of concomitant medication or use of concomitant therapy   
g  
Clinical laboratory tests to be performed according to the guideline of each site   
At Visit 3 and Visit 5, clinical laboratory tests will only be performed if considered necessary by an investigator based on the subject’s symptoms   
In case of tests related to liver function, a re-test or re-screening is allowed once during the Screening period   
h  
ECG will only be performed if considered necessary by an investigator based on the subject’s symptoms   
i  
Vital signs will include blood pressure, pulse, and body temperature  Vital signs will be measured preferably after the subject has rested comfortably for 5 minutes at each visit    
j  
Females of childbearing potential only  A dipstick will be used for urine pregnancy testing   
k  
Subjects will administer the study drug at the dose prescribed at regular visits from the next day after that visit to the day of the next regular visit  
*It is not necessary to distribute the study drug at Visit 4 (EOT) or Premature Discontinuation Visit to subjects who do not proceed with the tapering period  
l  
Study drug will be distributed to subjects who continue to meet the eligibility criteria at Visit 2 (baseline), and they are instructed to take the study drug daily for the next 18 weeks from the next day after Visit 2 (baseline)  
The dose of the study drug is started at 50 mg once a day for 2 weeks (14 days) starting from the next day after Visit 2 (Baseline) and is increased to 100 mg once a day afterwards  Subjects who need to increase the dose at 
the discretion of an investigator shall visit the site (unscheduled) prior to the dose increase  If an Adverse Event occurs following the increase in dose, the investigator may reduce the dose back to 50 mg/day through 
unscheduled site visit or phone visit  After reduction from 100mg/day to 50mg/day, the dose may be increased back to 100 mg/day at the discretion of the investigator  
m  
All adverse events (AEs) should be recorded after Visit 1 (Screening) to the last visit, regardless of relevance to the study drug or the procedure, and all AEs should be followed up until the end of the study (subject's last 
visit)   During the AE evaluation, events associated with special situations listed in Section 9 5 4 2 are also evaluated   
All serious adverse events (SAEs) should be followed up until resolution or, if no resolution is possible, until stabilization  
n  
At Visit 2 (Baseline) and Visit 4 (EOT), the investigators will review the completed subject diary with subjects  Subjects must completed the diary at least three consecutive days prior to each visit where completed diary 
review is conducted (Visit 2, Visit 4)  At Visit 4 (EOT), subjects shall submit the diary to the investigators or other clinical trial staff  
* Subjects and/or their caregivers will receive a subject diary and investigator will train them how to complete the diary at Visit 1 (Screening)  Subjects who meet the eligibility criteria of the study will be instructed to 
complete the diary for 3 consecutive days prior to Visit 2 (Baseline)  
o  
The result from MMSE conducted at Visit 1 (Screening) will be the baseline result  If MMSE was not conducted at Visit 1 (Screening), it can be performed at Visit 2 (Baseline) and then the MMSE result from Visit 2 
(Baseline) will be considered as baseline result  In other words, if MMSE is conducted at either Visit 1 (Screening) or Visit 2 (Baseline), the subject will be considered to have completed the MMSE


 
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9.5.2.2 
Description of Procedures/Assessments Schedule 
9.5.2.2.1 
Visit 1 (Screening, -3 weeks ~ -1 day) 
All procedures will be conducted after obtaining informed consent from subjects who want to 
participate in this clinical trial. After obtaining informed consent, the following procedures 
will be performed to establish eligibility for the trial: 
• Demography 
• Height 
• Weight 
• Medical history 
• Prior and concomitant medications 
• Concomitant therapies 
• Clinical laboratory tests 
• 12-lead ECG: if deemed necessary by an investigator based on subject’s symptoms 
• Vital signs 
• Urine pregnancy test 
• Physical examinations 
• AE assessment 
• Subjects and/or their caregivers receive a subject diary and investigator will train 
them how to complete a diary. 
• Conduct the MMSE among the efficacy assessments. 
During Screening Period, if subjects have previously taken medication such as COMT inhibitor 
and/or MAO-B inhibitor, they have to undergo an appropriate wash-out period for each 
medication.  
Subjects who meet the eligibility criteria of the study will be instructed to complete the diary 
for 3 consecutive days prior to Visit 2 (Baseline). 
 
 


 
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9.5.2.2.2 
Visit 2 (Baseline, 0 week) 
At Visit 2 (Baseline), the following procedures will be performed:  
• Reconfirmation of eligibility assessment 
• Weight: if deemed necessary by an investigator 
• Concomitant medications 
• Concomitant therapies 
• Vital signs 
• Physical examinations 
• Study drug dispensation  
• AE assessment 
• Efficacy assessments including PDQ-39, MDS-UPDRS Part 3 and Part 4, and KPPS, 
are performed. The completed subject diary will be reviewed by an investigator 
together with a subject. 
If MMSE was not conducted at Visit 1 (Screening), it can be performed at Visit 2 
(Baseline). If MMSE is conducted at either Visit 1 (Screening) or Visit 2 (Baseline), the 
subject will be considered to have completed the MMSE.  
9.5.2.2.3 
Visit 3 (8 weeks, -4/+2 weeks) 
At Visit 3, the following procedures will be performed:  
• Weight: if deemed necessary by an investigator 
• Concomitant medications 
• Concomitant therapies 
• Clinical laboratory tests 
• 12-lead ECG: if deemed necessary by an investigator based on subject’s symptoms 
• Vital signs 
• Physical examinations 


 
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• Study drug dispensation 
• Unused study drug return  
• Study drug compliance check  
• AE assessment   
9.5.2.2.4 
Visit 4 (EOT; 18 weeks, +/-2 weeks) 
At Visit 4 (EOT), the following procedures will be performed:  
• Weight 
• Concomitant medications 
• Concomitant therapies 
• Clinical laboratory tests 
• 12-lead ECG: if deemed necessary by an investigator based on subject’s symptoms 
• Vital signs 
• Urine pregnancy test 
• Physical examinations 
• Dispensation of study drug(only if tapering period is conducted)  
• Return of unused study drug  
• Check compliance of the study drug  
• AE assessment  
• Efficacy assessments including PDQ-39, MDS-UPDRS Part 3 and Part 4, KPPS, and 
MMSE are performed. The completed subject diary will be reviewed by an 
investigator with a subject.   
Of the subjects who have completed Visit 4(EOT), those who require tapering will enter a 
Taper Period for 1 week. After the completion of the Taper Period, subjects will return to the 
site for Visit 5. 
The Taper Period may be omitted if the subject’s daily dose of study drug at the end of 
treatment is 50mg, if subjects will continue to take the study drug after the completion of the 
trial, or if it is considered not required by an investigator. For the subjects who do not require 


 
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the Taper Period, their participation in the study will be completed after Visit 4, the End of 
Treatment Visit. 
If a subject is withdrawn from the study before Visit 4 (EOT), Premature Discontinuation Visit 
should be completed as soon as practicable after discontinuing study drug (preferably within 7 
days). Following the completion of Premature Discontinuation Visit, subjects who require 
taper will undergo a Taper Period for 1 week. Then the subjects will return to the site for Visit 
5. For the subjects who do not require a Taper Period, Premature Discontinuation Visit would 
be their last visit in the study. 
9.5.2.2.5 
Visit 5 (19 weeks, +1 week) 
After the completion of Taper Period, subjects will undergo the following examinations at 
Visit 5: 
• Weight: if deemed necessary by an investigator 
• Concomitant medications 
• Concomitant therapies 
• Clinical laboratory tests: if deemed necessary by an investigator based on subject’s 
symptoms 
• 12-lead ECG: if deemed necessary by an investigator based on subject’s symptoms 
• Vital signs 
• Physical examinations 
• Unused study drug return 
• Study drug compliance check 
• AE assessment   
9.5.2.2.6 
Unscheduled Visit 
Subjects can additionally visit separately from a scheduled visit if medical treatment is needed 
in case of abnormal test result or AE occurs, or follow-up is needed after the occurrence of AE.  
Subjects may conduct an unscheduled visit after Visit 2 (Baseline) if examination is required 
prior to increasing the dose of study drug (from 50 mg/day to 100 mg/day). 
If the dose reduction (from 100mg/day to 50mg/day) is required due to events such as AE, 
the dose may be reduced back to 50mg/day at the discretion of an investigator through 


 
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unscheduled site visit or phone visit. In the case of a phone visit, the information such as date 
of study drug dose change (start date of dose reduction) and relevant Adverse Events shall be 
collected. 
If subjects need to increase the dose back to 100mg/day after the reduction to 50mg/day, they 
may conduct an unscheduled site visit and the dose may be increased back to 100mg/day at 
the discretion of an investigator.  
9.5.3 
Appropriateness of Measurements 
All clinical assessments performed in this study are standard measurements commonly used 
in studies of Parkinson’s Disease.  
 
9.5.4 
Reporting of Serious Adverse Events and Events Associated with Special 
Situations 
9.5.4.1 
Reporting of Serious Adverse Events 
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study drug, must 
be reported on a completed SAE form as soon as possible but no later than 24 hours from 
the date an investigator becomes aware of the event. 
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. Any SAE 
judged by the investigators to be related to the study drug or any protocol-required procedure 
should be reported to the sponsor regardless of the length of time that has passed since study 
completion. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File. 
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File.  
It is very important that the SAE report form be filled out as completely as possible at the time 
of the initial report. This includes an investigator’s assessment of causality. 
Any relevant follow-up information received on SAEs should be forwarded within 24 hours of 
its receipt. If the relevant follow-up information changes the investigator’s assessment of 
causality, this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions, 
including copies of site case reports, autopsy reports, and other documents requested by the 
sponsor. 


 
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9.5.4.2 
Reporting of Events Associated with Special Situations 
The following special situations must be collected and reported in the same manner as SAEs 
regardless of occurrence of adverse events. 
• Pregnancy: paternal/maternal exposure 
• Breastfeeding 
• Lack of therapeutic efficacy 
• Drug interactions 
• Suspected transmission of infectious agents 
• Overdose, abuse, off-label use, misuse, mediation error, and occupational exposure 
• Suspected or confirmed falsified medicinal product 
9.5.4.2.1 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding 
Any pregnancy in a female subject in which the estimated date of conception is either before 
the last visit or within 28 days from the last day of administration of the study drug, or any 
exposure to study drug through breastfeeding during study treatment or within 28 days from 
the last day of administration of the study drug, must be reported. If an adverse outcome of a 
pregnancy is suspected to be related to study drug exposure, this should be reported regardless 
of the length of time that has passed since the exposure to study treatment. 
A congenital anomaly, death during perinatal period, a spontaneous abortion, or an induced 
abortion done due to safety concerns for either mother or fetus are considered to be an SAE 
and should be reported in the same time frame and in the same format as all other SAEs (refer 
to Section 9.5.4.1). 
Pregnancies or exposure to the study drug through breastfeeding must be reported as soon as 
possible but no later than 24 hours from the date an investigator becomes aware of the 
pregnancy. The contact information for the reporting of pregnancies and exposure to the study 
drug through breastfeeding is provided in the Investigator Study File. The Pregnancy Report 
Form must be used for reporting. All pregnancies must be followed to outcome. The outcome 
of the pregnancy must be reported as soon as possible but no later than 24 hours from the date 
the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study. A subject who becomes 
pregnant may remain in the study if an investigator judges that the potential benefit to the 
subject outweighs any potential risk to the subject or the fetus, and the subject gives informed 
consent for further participation. 


 
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9.5.4.2.2 
Reporting of Lack of Efficacy 
"Efficacy" is defined as:  
 The ability of an intervention to produce desired beneficial effect in expert hands and 
under ideal circumstances  
 In pharmacology, the ability of a drug, biologic, or device to produce desired 
therapeutic effect independent of potency (amount of the product needed for desired 
effect).  
"Effect" is defined as the result produced by an action. Lack of efficacy/effect is, therefore 
evidence of less than the expected effect of a product. There might be subpopulations that 
have a higher risk for lack of efficacy/effect; in order to identify such cases, one needs to 
consider the types of events that may be reported in such situations for the specific product 
and indication. 
All AEs associated with lack of efficacy should be collected on the Adverse Event CRF and 
reported in an expedited manner using the SAE form regardless of seriousness. 
9.5.4.2.3 
Reporting of Adverse Events Associated with Study Drug Overdose, 
Misuse, Abuse, or Medication Error 
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer 
to AEs associated with uses of the study drug outside of that specified by the protocol. 
Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose  
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the protocol. Intentional and inappropriate use of study drug not in 
accordance with the prescribed or authorized dose, route of 
administration, or indication(s) or use of prescription-only study drug 
without a prescription  
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site 
personnel or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of Serious 
Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria. Abuse and 
Intentional Overdose, even if asymptomatic, are always to be captured as an AE. If the AE 
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it must still be reported using the SAE form and in an expedited manner but should be noted 
as nonserious on the SAE form and the Adverse Event CRF. 
9.5.4.3 
Expedited Reporting 
The sponsor must inform the investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (i.e., within specific 
time frames). For this reason, it is imperative that sites provide complete SAE information in 
the manner described above. 
9.5.4.4 
Regulatory Reporting of Adverse Events 
AEs will be reported by the sponsor or a third party acting on behalf of the sponsor to regulatory 
authorities in compliance with local law and established guidance. The format of these reports 
will be dictated by the local requirements. 
9.5.5 
Completion/Discontinuation of Subjects 
In this study, subjects are assumed to have completed the clinical trial upon their completion 
of Visit 4 (EOT). 
A subject may elect to discontinue the study at any time for any reason. All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated in 
Table 3. 
An investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject. A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for the following reasons: 
AE, lost to follow-up, withdrawal of consent by subject, lack of efficacy, noncompliance with 
study procedure, impossibility to increase study drug dose, pregnancy, study terminated by 
sponsor, or other.  
A subject removed from the study for any reason may not be replaced. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines. Site audits may be 
made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, which 
is an independent function from the study team responsible for conduct of the study.  


 
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9.6.1 
Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements. As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines. The investigators have ultimate responsibility for the collection and reporting of 
all clinical data entered on the CRF.  
The investigators must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness. 
Completed, original CRFs are the sole property of Eisai Korea Inc. and should not be made 
available in any form to third parties without written permission from Eisai Korea Inc., except 
for authorized representatives of Eisai Korea Inc. or appropriate regulatory authorities. 
9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements. All 
data, both CRF and external data (e.g., laboratory data), will be entered into a clinical system. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released. Statistical analyses will be performed 
using SAS software or other validated statistical software as required. Details of the 
statistical analyses will be included in a separate statistical analysis plan (SAP). 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of this study data are described in this section. Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock. 
The descriptive statistics for continuous variables are the numbers of subjects, mean, 
standard deviation, median, minimum, maximum, and for categorical variables are the 
numbers of subjects and percentage. The statistical testing for efficacy endpoints is 
conducted using the two-sided test at a 2.5% significance level. 
9.7.1.1 
Study Endpoints 
9.7.1.1.1 
Primary Endpoints 
• Change at the 18th week from baseline in daily “off” time 


 
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• Change at the 18th week from baselines in PDQ-39 score 
9.7.1.1.2 
Secondary Endpoints 
● Change at the 18th week from baseline in below assessments: 
- 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) 
Part 3 
- 
Movement Disorder Society-Unified Parkinson’s Disease Rating (MDS-UPDRS) 
Part 4 
- 
King’s Parkinson’s disease Pain Scale (KPPS) 
- 
Mini-Mental State Examination (MMSE) 
● Safety of safinamide mesilate  
● Change at the 18th week from baseline in daily “on” time without dyskinesia 
 
9.7.1.2 
Definitions of Analysis Sets 
The Safety Analysis Set (SAS) is the group of subjects who received at least 1 dose of study 
drug and completed at least 1 post-dose safety assessment. The Full Analysis Set (FAS) is the 
group of subjects who received at least 1 dose of study drug and had at least 1 post-dose daily 
“off” time or PDQ-39. The Per Protocol Set (PPS) is for subjects who have fully complied with 
the study protocol. The details of the evaluability criteria will be determined prior to database 
lock and will be specified in the statistical analysis plan. 
 
9.7.1.3 
Subject Disposition 
The disposition of subjects will be tabulated as follows:  
• Number of screened subjects 
• Number of screening failed subjects and reasons for screening failure 
• Number of discontinued subjects and reasons for discontinuation 
• Number of subjects who completed the study 
The analysis set of subjects will be tabulated as follows:  
• Number of subjects for the SAS 
• Number of subjects who were excluded from the SAS and reasons 
• Number of subjects for the FAS 
• Number of subjects who were excluded from the FAS and reasons 


 
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• Number of subjects for the PPS 
• Number of subjects who were excluded from the PPS and reasons 
9.7.1.4 
Demography 
Demography for the SAS and FAS will be summarized using descriptive statistics. 
Continuous demographic and baseline variables include age, height, weight; categorical 
variables include sex, age group. 
9.7.1.5 
Medical History  
All investigator terms for medical history recorded in the CRF will be coded by System 
Organ Class (SOC) and Preferred Term (PT) using the Medical Dictionary for Regulatory 
Activities (MedDRA).  
The number (percentage) of subjects who have medical history will be summarized using 
descriptive statistics on the SAS. The medical history will be classified by SOC and PT. 
Surgical history will be performed on the SAS. The number (percentage) of subjects with 
surgical history will be summarized. The history of surgical operation will be classified 
according to SOC and PT. 
9.7.1.6 
Prior and Concomitant Medications 
All investigator terms for medications recorded in the CRF will be coded to the Anatomical 
Therapeutic Chemical (ATC) code. The number (percentage) of subjects who took prior and 
concomitant medications will be summarized on the SAS by ATC class. If the SAS and FAS 
differ substantially, then the prior and concomitant medications summaries will be repeated 
on the FAS. 
Prior medications will be defined as medications that stopped before the first dose of study 
drug. 
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and are continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug up to Visit 4 (EOT) Visit. All medications will 
be presented in subject data listings. 
9.7.1.7 
Efficacy Analyses 
All efficacy analysis will use FAS as the primary population and PPS as the secondary 
population. Efficacy data will be summarized using descriptive statistics (e.g., n, mean, 
standard deviation, median, minimum, maximum for continuous variables; n [%] for 
categorical variables). Each variable and the difference from baseline will be used for 
summary statistics. 


 
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9.7.1.7.1 
Primary Efficacy Analyses 
Two primary efficacy parameters, which are daily “off” time and PDQ-39, will be analyzed. 
The daily “off” time will be analyzed using a paired t-test on the change at the 18th week from 
baseline. The descriptive statistics for the daily “off” time will be summarized by each visit. 
The PDQ-39 will be analyzed using a paired t-test on the change at the 18th week from 
baseline. The descriptive statistics for the PDQ-39 will be summarized by each visit.  
9.7.1.7.2 
Secondary Efficacy Analyses 
For the following items, the descriptive statistics will be summarized by each visit, and it will 
be analyzed using a paired t-test on the change at the 18th week from baseline. 
● MDS-UPDRS Part 3 
● MDS-UPDRS Part 4 
● KPPS 
● MMSE 
● 
Daily “on” time without dyskinesia  
9.7.1.8 
SAFETY ANALYSES 
All safety analyses will be performed on the SAS. Safety data will be summarized using 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables). Safety variables include Treatment-
Emergent Adverse Events (TEAEs), clinical laboratory parameters, and vital signs.  
9.7.1.8.1 
Extent of Exposure 
Descriptive statistics for the extent of exposure during the study period will be summarized. 
The extent of exposure to the study drug should be characterized according to the number of 
subjects exposed, the duration of exposure, and the dose to which they were exposed. 
Compliance for the study drug will be calculated on the basis of the number of tablets 
dispensed, lost and returned. Summaries will provide descriptive summary statistics and 
number (percentage) of subjects below 80%, between 80% and 120%, and greater than 
120%. 
9.7.1.8.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
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(MedDRA). AEs will be coded to the MedDRA (Version 23.0 or higher) Lower Level Term 
(LLT) closest to the verbatim term. The linked MedDRA PT and primary SOC are also 
captured in the database. 
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or  
● Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or  
● Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous. 
Only those AEs that are treatment-emergent will be included in summary tables. All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within SOC and PT, even if the subject 
experienced more than 1 TEAE within a specific SOC and PT. The number (percentage) of 
subjects with TEAEs will also be summarized by maximum severity (mild, moderate, or 
severe). 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]). 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT. Treatment-related TEAEs include those events considered by the investigators 
to be related to the study drug. The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe). 
AEs will be summarized using the SAS. The number of AEs and number and incidence (%) 
of subjects with AEs will be summarized by dose level and overall. To obtain the incidence 
(%), the number of subjects with at least 1 event and the percentage of subjects with AEs by 
SOC and PT will be calculated. Incidence (%) by causal relationship with study drug and by 
severity will also be calculated. For clinically significant events, time of onset, and recovery 
will be reported. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT. A subject data listing of all AEs leading to death will be provided. 
The number (percentage) of subjects with treatment-emergent Serious Adverse Events 
(SAEs) will be summarized by MedDRA SOC and PT. A subject data listing of all SAEs will 
be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from the study 
drug will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading 
to discontinuation from the study drug will be provided. 


 
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9.7.1.8.3 
Laboratory Values 
For all quantitative parameters listed in Section 9.5.1.3.3, the actual value and the change at 
the 18th week from baseline will be summarized using descriptive statistics. Qualitative 
parameters listed in Section 9.5.1.3.3 will be summarized using frequencies (number and 
percentage of subjects), and changes at the 18th week from baseline will be reported using 
shift tables. Percentages will be based on the number of subjects with both non-missing 
baseline and 18 weeks results. 
9.7.1.8.4 
Vital Signs and Weight 
Descriptive statistics for the vital sign parameters (systolic and diastolic blood pressure, 
pulse, body temperature) and weight will be presented by each visit. 
9.7.1.9 
Other Analyses 
Levodopa dose administered during the study will be summarized using descriptive statistics 
(e.g., n, mean, standard deviation, median, minimum, maximum for continuous variables; n 
[%] for categorical variables). Efficacy analyses will be performed in subgroups based on 
levodopa dose, and details will be described in the SAP.  
9.7.2 
Determination of Sample Size 
The sample size is calculated under assumption the efficacy of this study at 18 weeks is 
comparable to the efficacy of phase 3 clinical study at 24 weeks.7 
The sample size is calculated using each 2 primary endpoints, and a larger sample size is 
selected conservatively. The sample size for each evaluation variable is as follows. 
1) Endpoint 1: Paired t-test for “off” time 
Based on the above assumptions, to calculate the number of subjects for the comparison of 
the “off” time mean change 24 weeks after Baseline, the sample size was calculated 
assuming average change (-1.56) and standard deviation (2.35). 
The results were performed through PASS (version 2020), the sample sizes of 31 achieve 
90% power and the significance level (alpha) is 0.025. 
2) Endpoint 2: Paired t-test for PDQ-39 score 
Based on the above assumptions, to calculate the number of subjects for the comparison of 
the PDQ-39 score mean change 24 weeks after Baseline, the sample size was calculated 
assuming average change (-3.17) and standard deviation (10.86). 
The results were performed through PASS (version 2020), the sample sizes of 149 achieve 
90% power, and the significance level (alpha) is 0.025. 


 
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According to the above two endpoints, the sample sizes are 31, 149 at each assumption. The 
sample size of endpoint 2 is larger than endpoint 1. Therefore, the final sample size obtained, 
considering the drop-out rate of 25% during the study period is 199. 
9.7.3 
Interim Analysis 
No interim analysis is planned for this study. 
 


 
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10 REFERENCE LIST 
1. Cattaneo C, Sardina M, Bonizzoni E. Safinamide as Add-On Therapy to Levodopa in Mid- 
to Late-Stage Parkinson’s Disease Fluctuating Patients: Post hoc Analyses of Studies 016 
and SETTLE. J Parkinsons Dis. 2016;6(1):165-73.  
2. Hattori N, Tsuboi Y, Yamamoto A, Sasagawa Y, Nomoto M, Nomoto M. Efficacy and 
safety of safinamide as an add-on therapy to L-DOPA for patients with Parkinson’s 
Disease: A randomized, double-blind, placebo-controlled, phase II/III study. Parkinsonism 
Relat Disord. 2020;75:17-23. 
3. Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt M, et al. Randomized trial of 
safinamide add-on to levodopa in Parkinson’s Disease with motor fluctuations. Mov 
Disord. 2014;29(2):229-37. 
4. XADAGO (safinamide) tablets, for oral use Initial U.S. Approval: 2017 
5. National Institute for Health and Care Excellence. Parkinson’s disease in adults. Published: 
19 July 2017. 
6. Equfina Tab. 50 mg (safinamide mesilate), for oral use South Korea. Approval: 2020 
7. Schapira AH, Fox SH, Hauser RA, Jankovic J, Jost WH, et al. Assessment of Safety and 
Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and 
Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017 Feb 1;74(2):216-
224.  
8. Guidelines for Clinical Trials Targeting Patients with Hepatopathy. National Institute of 
Food and Drug Safety Evaluation. Digestive Medicine Department, Drug Evaluation 
Division. December 2015. 


 
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11 PROCEDURES 
AND 
INSTRUCTIONS 
(ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation. These requirements should in no 
way prevent any immediate action from being taken by the investigators, or by the sponsor, in 
the interest of preserving the safety of all subjects included in the study. If the investigators 
determine that an immediate change to or deviation from the protocol is necessary for safety 
reasons to eliminate an immediate hazard to the subjects, the sponsor’s representative or 
appropriate study team member and the IRB/IEC for the site must be notified immediately.  
11.2 Adherence to the Protocol 
The investigators will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5, and KGCP). 
11.3 Monitoring Procedures 
The CRO’s CRA will maintain contact with the investigators and designated staff by 
telephone, letter, or email between study visits. Monitoring visits to each site will be conducted 
by the assigned CRA as described in the monitoring plan. The investigators will allow the CRA 
to inspect the clinical, laboratory, and pharmacy facilities to assure compliance with GCP and 
local regulatory requirements. The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals. These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations. All records at the site are subject to inspection by the local 
auditing agency and to IRB/IEC review. 
In accordance with ICH E6, Section 1.52, source documents may include, but are not limited 
to, the following:  
● 
Clinic, office, or hospital charts 
● 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
● 
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports regardless of how these images are stored, including microfiche and 
photographic negatives 
● 
Subject diary, PDQ-39, MMSE, MDS-UPDRS Part 3 and Part 4, and KPPS completed 
by the subjects or investigators 
● 
Records of telephone contacts 
● 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
● 
Laboratory results and other laboratory test outputs  


 
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● 
Correspondence regarding a study subject’s treatment between physicians or 
memoranda sent to the IRBs/IECs 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel. All data on the CRF must reflect the corresponding source document, except when 
a section of the CRF itself is used as the source document. Any correction to entries made on 
the CRF must be documented in a valid audit trail where the correction is dated, the individual 
making the correction is identified, the reason for the change is stated, and the original data are 
not obscured. Only data required by the protocol for the purposes of the study should be 
collected. 
The investigators must sign each CRF. The investigators will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents. 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the investigators 
are responsible for retaining all study documents, including but not limited to the protocol, 
copies of CRFs, Investigator and Site Information Form, ICFs, and IRB/IEC correspondence. 
The site should plan to retain study documents, as directed by the sponsor, for at least 5 years 
following the completion of the study. 
It is requested that at the completion of the required retention period, or should an investigator 
retire or relocate, the investigator contacts the sponsor, allowing the sponsor the option of 
retaining the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department may conduct audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations. If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately. 
11.8 Handling of Study Drug 
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor. Drug supplies must be kept in an appropriate secure area (e.g., locked cabinet) 
and stored according to the conditions specified on the drug label. The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of the 


 
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study drug in a drug accountability ledger, a copy of which must be given to the sponsor at the 
end of the study. An accurate record of the date and amount of study drug dispensed to each 
subject must be available for inspection at any time. The CRA will visit the site and review 
these documents along with all other study conduct documents at appropriate intervals once 
study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose. The 
investigator (or site personnel) must not destroy any drug label or any partly used or unused 
drug supply before approval to do so by the sponsor. At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form to 
the sponsor’s CRA or designated contractor or, when approval is given by the sponsor, will 
destroy supplies and containers at the site. 
11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor in advance of submission pursuant 
to the terms and conditions set forth in the executed Clinical Trial Agreement among the 
sponsor, CRO, and the institution/investigators. The review is aimed at protecting the sponsor’s 
proprietary information existing either at the date of the commencement of the study or 
generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the Clinical Trial 
Agreement among the sponsor, CRO, and the institution/investigators. 
11.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study should 
be kept confidential by the investigators, the investigators’ staff, and the IRB/IEC and will not 
be disclosed in whole or in part to others, or used for any purpose other than reviewing or 
performing the study, without the written consent of the sponsor. No data collected as part of 
this study will be used in any written work, including publications, without the written consent 
of the sponsor. These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in either the Confidentiality Agreement or Clinical Trial Agreement 
executed among the sponsor, CRO, and the institution/investigators. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed among the sponsor, CRO, and the institution/investigators. 
11.11 Discontinuation of Study 
The sponsor reserves the right to discontinue the study for medical reasons or any other reason 
at any time. If a study is prematurely terminated or suspended, the sponsor will promptly 
inform the investigators/institutions of the termination or suspension and the reasons for the 


 
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Eisai 
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Confidential 
Page 65 of 65 
 
termination or suspension. The IRB/IEC will also be informed promptly and provided the 
reasons for the termination or suspension by the sponsor or by the investigators/institution, as 
specified by the applicable regulatory requirements. 
The investigators reserve the right to discontinue the study should his/her judgment dictate. If 
the investigators terminate or suspend a study without prior agreement of the sponsor, the 
investigators should inform the institution where applicable, and the investigators/institution 
should promptly inform the sponsor and the IRB/IEC and provide the sponsor and the IRB/IEC 
with a detailed written explanation of the termination or suspension. Study records must be 
retained as noted above. 
11.12 Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.