A Prospective, Observational Study to Evaluate Changes in Non-Motor Symptoms and Other Clinical Outcome Assessments of Parkinson's Disease Patients Treated With XADAGO (Safinamide)Tablets
Conditions: Idiopathic Parkinson Disease
Sponsor: Supernus Pharmaceuticals, Inc.

PRODUCT: XADAGO (Safinamide) 
PROTOCOL NUMBER / AMENDMENT: USWM-SA1-4001 / 02  
 
  
SPONSOR: 
MDD US Operations, LLC, a subsidiary of Supernus Pharmaceuticals, Inc. 
9715 Key West Avenue 
Rockville, Maryland 20850 
 
 
TITLE: 
A Prospective, Observational Study to Evaluate Changes in Non-Motor Symptoms and other 
Clinical Outcome Assessments of Parkinson’s Disease Patients Treated with XADAGO 
(safinamide) Tablets 
 
 
DOCUMENT DATE: 12OCT2018 
IND NUMBER: N/A 
NCT NUMBER: NCT03944785 

Protocol No. USWM-SA1-4001 
 
12 October 2018 (Amendment 2; Final) 
  
Confidential Information 
 
Page 1 of 108 
CLINICAL STUDY PROTOCOL 
A Prospective, Observational Study to Evaluate Changes in Non-Motor Symptoms and other 
Clinical Outcome Assessments of Parkinson’s Disease Patients Treated with XADAGO 
(safinamide) Tablets 
 
Protocol Number: 
USWM-SA1-4001 
Product: 
XADAGO (safinamide) tablets 
Development Phase of Study: 
Phase IV 
Sponsor Contact: 
 
Contract Research Organization: 
N/A 
Sponsor: 
US WorldMeds, LLC 
4441 Springdale Road 
Louisville, KY 40241 
 
 
 
Protocol Date: 
12 October 2018 (Amendment 2; Final) 
01 November 2017 (Amendment 1; Final) 
28 August 2017 (Final) 
 
Confidentiality Statement: The information in this document contains trade secrets and commercial 
information that are privileged or confidential and that may not be disclosed without the written 
consent of US WorldMeds, LLC (Sponsor). Acceptance of this document constitutes the agreement 
of the recipient that this information will not be disclosed to others, except to the extent necessary 
for Institutional Review Board procedures and to obtain written informed consent from those 
persons to whom study may be administered. 

Protocol No. USWM-SA1-4001 
12 October 2018 (Amendment 2; Final) 
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PROTOCOL AMENDMENTS 
Amendment 1 dated 01 November 2017: 

Added this Protocol Amendments section to summarize revisions.

Updated Sponsor Contact / Scientific Lead on the Title Page, Signature Page (Section
1) and Procedures in Case of Emergency (Section 2) from 

Updated Protocol Date and Version from 28 August 2017 (Original) to 01 November
2017 (Amendment 1).

Updated Appendix C to replace PDQ-39 with the version provided by license holder.
Refreshed Table of Contents (Section 4).
Amendment 2 dated 12 October 2018: 
•
Updated Protocol Amendments section to summarize revisions.
•
Refreshed Table of Contents and List of Tables (Section 4).
•
Updated List of Abbreviations and Specialist Terms (Section 5) and Reference List 
(Section 15).
•
Updated Clinical Project Manager in Table 1: 
Emergency Contact Information 
from 
•
Updated Medical Monitor / Safety Physician in Table 1: Emergency Contact 
Information from 
•
Updated SAE reporting instructions in Table 1: Emergency Contact Information.
•
Updated Protocol Date and Version from 01 November 2017 (Amendment 1) to 
October 2018 (Amendment 2).
•
Updated Signature Page for an observational non-registration study and identified 
responsibility for ensuring regulatory requirements are met.
•
Changed the planned date for last patient completed from November 2019 to April 
2020.
•
Modified language to refer to Patients rather than Subjects, and to identify study 
timepoints by Study Day rather than Week for clarity.
•
Removed the separate statements of primary and secondary objectives, and restated 
them in one Study Objective: “gathering observational data from the following 
assessments in individuals in the US with Parkinson’s disease during XADAGO 
treatment: MDS-UPDRS, PDQ-39, MoCA, TSQM-9, CGI-C, and PGI-C.”
•
Deleted the secondary objective of evaluating the Care Partner’s assessment of the 
patient’s non-motor symptoms and overall health. 

Protocol No. USWM-SA1-4001 
12 October 2018 (Amendment 2; Final) 
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
Removed the assessments NMSS, GRID-HAMD-17, LARS, LARSi, PFS-16,
SCOPA-SLEEP, SCOPA-COG and mCGI-C from the study.

Added the assessments MoCA and MDS-UPDRS Parts I, II, and IV to the study.

Modified the Primary Outcome Analysis to an examination of changes in MDS-
UPDRS, PDQ-39, and MoCA from the Baseline Assessment Visit to the Primary
Endpoint (Study Day 60).

Changed the Main Study duration from 6 months to 2 months/3 Study Visits; changed
the optional extension study duration from 6 months to 4 months/3 Study Visits.

Modified the Study Visits/Schedule of Assessments, and updated the list of Study
Assessments in Section 8.1:
 Clarified that Screening and Baseline Assessments may occur at the same clinic 
visit. 
 Changed Visit 2 to a Telephone Follow-up on Study Day 30 
 Changed Visit 3 to the Primary Endpoint Visit on Study Day 60 
 Changed Visit 4 to a Follow-up Clinic Visit on Study Day 90 
 Changed Visit 5 to include a PRO Assessment only on Study Day 120 
 Changed Visit 6 to a Follow-up Clinic Visit on Study Day 180 (there is no End-
of-Study Visit) 
 Added MoCA to Study Visits 1, 3, and 6 

Increased number of planned enrolled patients to up to 540.

Clarified Inclusion Criterion 3, stating that patient age requirement applies to age at
initial screening assessment.

Removed Inclusion Criterion 5, which required patients to be on XADAGO for less
than 2 weeks; patient must be newly prescribed XADAGO at entry into this study.

Removed Inclusion Criterion 8, which described optional Care Partner participation
in the study. A Care Partner may still assist patient with visits and procedures as
necessary.

Modified the 2 study cohorts in Amendment 1 to the 3 cohorts below:
Cohort A – Patients that have switched to XADAGO from a dopamine agonist 
Cohort B – Patients that have switched to XADAGO from a monoamine oxidase-
B (MAO-B) inhibitor 
Cohort C – Patients that are MAO-B inhibitor naïve 

Clarified that Health Care Professional taking part in the study must be certified.

Clarified that interim data analyses will be performed periodically to provide study
updates and to support potential presentation of interim results.

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12 October 2018 (Amendment 2; Final) 
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 Removed eSAE forms from procedures; only paper SAE forms will be used. 
 Clarified the method by which study drug XADAGO will be made available to 
patients for treatment, XADAGO labeling and storage conditions, and accountability 
procedures. 
 Removed 1 Per-Protocol Population and renamed the other as the “Evaluable 
Population”, redefined to include patients in the safety population who complete at 
least the MDS-UPDRS assessment at the Study Day 60 visit. The previous definition 
specified completion of any 1 assessment. 
 Deleted Adjustment for Multiplicity section. 

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2.
PROCEDURES IN CASE OF EMERGENCY
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Clinical Project 
Manager 
 
US WorldMeds, LLC 
4441 Springdale Road 
Louisville, KY 40241 
Sponsor Contact /  
Scientific Lead 
 
US WorldMeds, LLC 
4441 Springdale Road 
Louisville, KY 40241 
Medical Monitor /  
Safety Physician 
 
US WorldMeds, LLC 
4441 Springdale Road 
Louisville, KY 40241 
 
 
 
SAE Reporting 
 
 
  
 
 

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12 October 2018 (Amendment 2; Final) 
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3. 
SYNOPSIS 
Name of Sponsor/Company: 
US WorldMeds, LLC 
4441 Springdale Road 
Louisville, KY 40241 
Name of Marketed Drug Product: 
XADAGO® (safinamide) tablets 
Name of Active Ingredient: 
Safinamide mesylate 
Title of Study:  
A Prospective, Observational Study to Evaluate Changes in Non-Motor Symptoms and other 
Clinical Outcome Assessments of Parkinson’s Disease Patients Treated with XADAGO 
(safinamide) Tablets 
Study Sites:  
Approximately 50 investigative sites; US only 
Study Duration:  
Planned date first patient enrolled to planned date last 
patient completed: November 2017 – April 2020 
Phase of Development:  
Phase IV (Prospective, 
Observational) 
Study Objective:  
The objective of this prospective observational study is to gather real-world observational 
data from the following assessments in individuals in the United States (US) with 
Parkinson’s disease (PD) during XADAGO treatment: the Movement Disorders Society – 
Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Parkinson’s Disease 
Questionnaire (PDQ-39), the Montreal Cognitive Assessment (MoCA), the Treatment 
Satisfaction Questionnaire for Medication (TSQM-9), the Clinical Global Impression of 
Change (CGI-C), and the Patient Global Impression of Change (PGI-C). 
Methodology:  
This is a multisite, prospective, observational study to evaluate clinician-reported outcomes 
(ClinRO) and patient-reported outcomes (PRO) related to motor and non-motor symptoms, 
health status/QoL, and treatment satisfaction in PD patients who have been newly prescribed 
XADAGO according to Package Insert indication (Appendix A). Eligible study participants 
will be consented, enrolled, and prospectively followed for 2 months, with potential to 
participate in a 4-month study extension. ClinRO measures will be completed by the 
Principal Investigator (PI) or certified health care professional (HCP) designee (i.e., MD, 
DO, PA, NP, or RN), depending on the specific assessment scale. Investigative sites will be 

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12 October 2018 (Amendment 2; Final) 
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provided secure access to a 21 CFR Part 11-compliant electronic Case Report Form (eCRF) 
and electronic Clinical Outcome Assessment (eCOA) system for collecting all patient data. 
As shown in Table 3: Schedule of Assessments, the Main Study will include: 

Baseline Assessment Visit at the PI’s clinic, including electronic completion of
ClinRO measures by the PI/certified HCP designee and PRO measures by the
patient (by use of a smartphone, tablet, or desktop, based on site and patient
electronic capabilities) (Study Day 1)

Telephone follow-up with the patient by the PI/certified HCP designee (Study
Day 30)

Primary Endpoint Assessment Study Visit at the PI’s clinic including electronic
completion of ClinROs by the PI/ certified HCP designee and PROs by the patient
(Study Day 60)
Eligible patients who compliantly complete the Main Study may participate in the 4-
month Extension Study (Table 3: Schedule of Assessments), which will include:  

Two follow-up Study Visits at the PI’s clinic, including electronic completion of
ClinROs by the PI/certified HCP designee and PROs by the patient (Study Days
90 and 180)

One scheduled PRO assessment to be completed electronically by the patient on
Study Day 120
If an enrolled patient discontinues XADAGO treatment for any reason at any point in the 
study (i.e., prior to Study Day 60 for the Main Study or Study Day 180 for the Extension 
Study), the patient is permitted to remain on study and complete the full schedule of 
assessments per protocol, as long as the patient is otherwise eligible and is able and willing to 
continue participation and complete the Main Study (through Study Day 60) or the Extension 
Study (through Study Day 180). 
Number of Patients (planned):  
Up to 540 patients enrolled 
Inclusion Criteria: 
1. Patient (and Care Partner, if required per Inclusion Criterion 7) is able to understand
and provide signed informed consent and HIPAA authorization in English
2. Patient with diagnosis of idiopathic PD (all stages)
3. Male or female, 30 to 80 years of age, inclusive, at initial screening assessment
4. Independent of the study, clinician’s and patient’s choice of treatment is XADAGO in
accordance with the Package Insert indication (Appendix A)
5. Patient is willing and able to participate in the study and complete study-related
assessments for 2 months and, if eligible, continue for a 4-month study extension
6. Patient has access to an electronic device for the interim completion of PROs

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7. Patient has an available Care Partner who is able and willing to assist with clinic
attendance and completion of study assessments (e.g., PROs, health outcomes, etc.),
if in the PI’s opinion, assistance is needed to comply with all study visits and
procedures
Exclusion Criteria: 
1. Any of the warnings, precautions, or contraindications listed in the Package Insert
(Appendix A) that in the opinion of the PI would prevent appropriate treatment with
XADAGO or impair study participation (e.g., pregnancy, lactation, severe hepatic
impairment, etc.)
2. Participation in any other clinical trial of an investigational drug or device within
4 weeks prior to the Baseline Visit or at any time during the study
3. Patient is currently receiving chemotherapy or radiation for any form of cancer (if
history of cancer, must be in clinical remission at study entry) or currently receiving
immunotherapy
4. Patients with conditions that are likely to prevent them from accurately and reliably
completing study assessments, including evidence of moderate or severe dementia as
determined by the clinician (not to include mild cognitive impairment [MCI]); major
psychiatric illness (specifically diagnosis of schizophrenia, bipolar disorder or a
history of attempted suicide); and/or severe and progressive medical illness (including
terminal cancer, end-stage renal disease +/- undergoing dialysis)
5. Severe or unpredictable dyskinesia at the time of the Baseline Visit
6. Previous participation in this study; a patient may not re-enroll after prior
discontinuation or completion
Medicinal Product, Dosage and Mode of Administration:  
XADAGO (safinamide) tablets, 50 mg and 100 mg, oral. 
Duration of Patient Participation:  
Planned patient participation will be 2 months for patients in the Main Study, including 
Baseline Assessment and Primary Endpoint Visits at the PI’s clinic, and a telephone Follow-
up Visit. A window of ± 7 days is allowed for the Baseline Assessment Visit. 
Eligible patients participating in the Extension Study (if applicable) will be in the study for a 
total of 6 months. A window of ± 14 days is allowed for the Clinic Visit on Study Day 180. 
Criteria for Evaluation: 
The assessments listed below will be performed at the Baseline Assessment Visit and at 
subsequent visits according to the Schedule of Assessments (Table 3). If patient is unable to 
self-complete the assessments, the Care Partner may record patient-directed responses to the 
questions in the assessments. The Care Partner may not answer the questions in the 
assessments from the Care Partner perspective. 

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 MDS-UPDRS (Movement Disorders Society – Unified Parkinson’s Disease 
Rating Scale) (Appendix D) administered by the PI/certified HCP designee 
 PDQ-39 (Parkinson’s Disease Questionnaire; health status/quality of life) 
(Appendix B) to be completed by the patient 
 MoCA (Montreal Cognitive Assessment) (Appendix C) administered by the 
PI/certified HCP designee 
 TSQM-9 (Treatment Satisfaction Questionnaire for Medication) (Appendix E) to 
be completed by the patient  
 CGI-C (Clinical Global Impression of Change in health) (Appendix F) 
administered by the PI/certified HCP designee 
 PGI-C (Patient Global Impression of Change in health) (Appendix G) to be 
completed by the patient 
Safety Management: 
The use of XADAGO in this study is not experimental, study procedures (questionnaires) are 
not associated with greater than minimal risk, and safety is not the principal objective of this 
protocol. However, in keeping with the Sponsor’s requirement to review and report all 
information relevant to the safety of the marketed drug XADAGO, about which the Sponsor 
becomes aware through notification by the investigator and study patients, all adverse events 
(AEs) spontaneously reported by the patient and/or in response to an open question from the 
site personnel or revealed by observation will be recorded at the investigational site and in 
the CRF for each study patient during active participation in the study. 
Statistical Methods: 
A Statistical Analysis Plan (SAP) describing all analyses will be developed for this study. 
Eligible, consented, and enrolled study participants will be analyzed for the following 
subgroups: 
Cohort A – Patients that have switched to XADAGO from a dopamine agonist 
Cohort B – Patients that have switched to XADAGO from a monoamine oxidase-B 
(MAO-B) inhibitor 
Cohort C – Patients that are MAO-B inhibitor naïve 

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4.
TABLE OF CONTENTS AND LIST OF TABLES
TABLE OF CONTENTS 
PROTOCOL AMENDMENTS .......................................................................................................2 
1.
SIGNATURE PAGE ....................................................................................................5 
2.
PROCEDURES IN CASE OF EMERGENCY ............................................................6 
3.
SYNOPSIS ...................................................................................................................7 
4.
TABLE OF CONTENTS AND LIST OF TABLES ..................................................11 
5.
ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................14 
6.
INTRODUCTION ......................................................................................................16 
6.1. 
Parkinson’s Disease ....................................................................................................16 
6.2. 
XADAGO® ................................................................................................................16 
6.3. 
Study Rationale ...........................................................................................................17 
7.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................19 
7.1. 
Study Objective ..........................................................................................................19 
7.2. 
Study Endpoints ..........................................................................................................19 
7.2.1. 
Motor Symptoms and Non-Motor Symptoms ............................................................19 
7.2.2. 
General Health Status/Quality of Life ........................................................................19 
7.2.3. 
Treatment Satisfaction ................................................................................................20 
7.2.4. 
Global Impression .......................................................................................................20 
8.
CLINICAL INVESTIGATION PLAN ......................................................................21 
8.1. 
Study Design and Schedule of Assessments ..............................................................21 
8.1.1. 
Screening / Baseline Assessments (Visit 1, Study Day 1) ..........................................21 
8.1.2. 
Telephone Follow-up with Patient by Study Site Staff (Visit 2, Study Day 
30) ...............................................................................................................................22
8.1.3. 
Primary Endpoint Assessments (Visit 3, Study Day 60) ............................................22 
8.1.4. 
Follow-Up Study Assessments (Visit 4 [Study Day 90], Visit 6 [Study Day 
180]) ............................................................................................................................22 
8.1.5. 
PRO Assessment Timepoints (Visit 5 ]Study Day 120]) ...........................................23 
8.2. 
Number of Patients .....................................................................................................23 
8.3. 
Criteria for Study Termination ...................................................................................25 
9.
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................26 
9.1. 
Inclusion Criteria ........................................................................................................26 
9.2. 
Exclusion Criteria .......................................................................................................26 

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9.3. 
Screening or Enrollment Failures ...............................................................................26 
9.4. 
Patient Withdrawal Criteria ........................................................................................27 
10. 
XADAGO AND OTHER MEDICATIONS ..............................................................28 
10.1. 
XADAGO ...................................................................................................................28 
10.1.1. 
XADAGO Study Supplies ..........................................................................................28 
10.1.2. 
XADAGO Drug Storage .............................................................................................28 
10.1.3. 
XADAGO Accountability ..........................................................................................29 
10.1.3.1. 
Site Accountability .....................................................................................................29 
10.1.3.2. 
Patient/Care Partner Accountability ...........................................................................29 
10.1.4. 
XADAGO Discontinuation ........................................................................................29 
10.2. 
Parkinson’s Disease Medications and Other Medications ..........................................29 
11. 
SAFETY MANAGEMENT .......................................................................................30 
11.1. 
Safety Assessments .....................................................................................................30 
11.2. 
Definition of Adverse Events .....................................................................................30 
11.2.1. 
Adverse Event (AE) ....................................................................................................30 
11.2.2. 
Serious Adverse Event (SAE) ....................................................................................30 
11.3. 
Relationship to XADAGO ..........................................................................................30 
11.4. 
Recording Adverse Events .........................................................................................31 
11.4.1. 
Non-Serious Adverse Event (AE) ..............................................................................32 
11.4.2. 
Serious Adverse Event (SAE) ....................................................................................32 
11.4.3. 
Pregnancy and Lactation .............................................................................................32 
12. 
STATISTICAL METHODS .......................................................................................33 
12.1. 
General Statistical Considerations ..............................................................................33 
12.2. 
Analysis Populations ..................................................................................................33 
12.3. 
Sample Size and Decision Rules ................................................................................33 
12.4. 
Handling of Missing Values .......................................................................................33 
12.5. 
Subgroups and Covariate Adjustment ........................................................................34 
12.6. 
Interim Analysis ..........................................................................................................34 
12.7. 
Population and Patient Disposition .............................................................................34 
12.8. 
Demographic and Baseline Characteristics ................................................................34 
12.9. 
Analysis ......................................................................................................................34 
12.9.1. 
Primary Outcome Analysis (Observational Assessments) .........................................34 
12.9.2. 
Safety Analysis ...........................................................................................................34 

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13.
STUDY MONITORING AND QUALITY CONTROL ............................................35 
13.1. 
Study Monitoring ........................................................................................................35 
13.2. 
Inspection of Records .................................................................................................35 
13.3. 
Site Audits ..................................................................................................................35 
13.4. 
Quality Control ...........................................................................................................36 
14.
ETHICS ......................................................................................................................37 
14.1. 
Ethics Review .............................................................................................................37 
14.2. 
Ethical Conduct of the Study and Institutional Review Board (IRB) 
Approval .....................................................................................................................37 
14.3. 
Written Informed Consent and HIPAA Authorization ...............................................38 
14.4. 
Investigator Obligations ..............................................................................................38 
15.
DATA MANAGEMENT ...........................................................................................39 
15.1. 
Data Capture ...............................................................................................................39 
15.2. 
Retention of Patient and Administrative Records ......................................................39 
16.
CONFIDENTIAL INFORMATION ..........................................................................41 
16.1. 
Confidentiality of Study Data .....................................................................................41 
16.2. 
Confidentiality of Patient Records ..............................................................................41 
17.
PUBLICATION POLICY ..........................................................................................42 
18.
REFERENCES ...........................................................................................................43 
19.
APPENDICES ............................................................................................................45 
APPENDIX A.  XADAGO PACKAGE INSERT .......................................................................46 
APPENDIX B.  PDQ-39 (PARKINSON’S DISEASE QUESTIONNAIRE) .............................62 
APPENDIX C.  MOCA (MONTREAL COGNITIVE ASSESSMENT) ....................................67 
APPENDIX D.  MDS-UPDRS (MOVEMENT DISORDERS SOCIETY-UNIFIED 
PARKINSON’S DISEASE RATING SCALE) .........................................................72 
APPENDIX E.  TSQM-9 (TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION) ........................................................................................................104 
APPENDIX F.  CGI-C (CLINICAL GLOBAL IMPRESSION - CHANGE) ...........................107 
APPENDIX G.  PGI-C (PATIENT GLOBAL IMPRESSION – CHANGE) ............................108 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................6 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................14 
Table 3: 
Schedule of Assessments ............................................................................................24 

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5.
ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or 
Specialist Term 
Explanation 
AE 
Adverse Event 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
ClinRO 
Clinician-Reported Outcome 
COMT 
Catechol-O-methyl transferase 
DO 
Doctor of Osteopathic Medicine 
eCOA 
Electronic Clinical Outcome Assessment 
eCRF 
Electronic Case Report Forms 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practices 
HCP 
Health Care Professional 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
MAO-B 
Monoamine oxidase B 
MCI 
Mild Cognitive Impairment 
MD 
Doctor of Medicine 
MDS-UPDRS 
Movement Disorders Society - Unified Parkinson’s Disease Rating Scale 
MoCA 
Montreal Cognitive Assessment 
NMS 
Non-Motor Symptoms 
NP 
Nurse Practitioner 
PA 
Physician Assistant 
PD 
Parkinson’s Disease 
PDQ-39 
Parkinson’s Disease Questionnaire; health status/quality of life 

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Table 2: 
Abbreviations and Specialist Terms  (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
PGI-C 
Patient Global Impression of Change 
PI 
Principal Investigator 
The investigator who leads the study conduct at an individual study site. Every 
study site has a Principal Investigator. 
PRO 
Patient-Reported Outcome 
QoL 
Quality of Life 
RN 
Registered Nurse 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication 
US 
United States 
USWM 
US WorldMeds, LLC 

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6. 
INTRODUCTION 
6.1. 
Parkinson’s Disease 
Parkinson’s disease (PD), a chronic neurodegenerative disorder, affects approximately 1-2% of 
people over the age of 60 years, and approximately 4% of patients older than 80 years (Dorsey, 
2007). PD is second only to Alzheimer’s disease in frequency. With the aging of the population, 
the number of PD patients is expected to increase dramatically (de Lau, 2006; Olanow, 2009). 
The symptoms of PD can be highly variable at disease onset, as well as throughout the 
progression of disease. As a result of the heterogeneity of PD, and the variation in response to 
treatment, each patient requires individualized care and a personalized treatment plan. 
For decades, PD treatment has focused on management of motor symptoms. The progressive loss 
of nigrostriatal dopaminergic neurons leads to the well-known set of PD motor symptoms 
characteristic of the disease. Although PD is generally considered to be a movement disorder, 
there is a growing recognition of the non-motor symptoms, which have a major impact on the 
quality of life of patients and their families (Olanow, 2009; Weintraub, 2008). Non-motor 
symptoms are frequently observed in PD prior to the occurrence of any motor symptoms, a 
finding that implicates not only dysregulation of the dopaminergic system but also other 
neurotransmitter involvement in different areas of the brain (Chaudhuri, 2009; Barone, 2010). 
The understanding that PD is a syndrome of dopamine deficiency led to the introduction of the 
clinical use of levodopa, a precursor of dopamine that crosses the blood brain barrier, in addition 
to the use of other dopaminergic agents, including selective inhibitors of monoamine oxidase B 
(MAO-B), the major dopamine-metabolizing enzyme in humans. 
Levodopa remains the most effective single pharmacotherapy for PD. Unfortunately, oral 
levodopa use is often limited by the development of incapacitating motor complications, related 
in part to the daily dosage used (Obeso, 2000; Olanow, 2013). Approximately 40% of PD 
patients develop motor fluctuations after 4 to 6 years of levodopa treatment (Ahlskog, 2001). 
These effects can be managed by modifying the dose or frequency of oral levodopa 
administration, changing the formulation of levodopa, or using add-on therapy, but such 
strategies may increase the risk of dyskinesia (Ferreira, 2013). Increasingly, non-dopaminergic 
agents are being studied to determine their potential to supplement or delay the use of established 
dopaminergic therapies (Fox, 2008). 
6.2. 
XADAGO® 
XADAGO (safinamide) is one of the newest treatments recently approved by the Food and Drug 
Administration (FDA) in the United States (US) as an add-on therapy to levodopa/carbidopa in 
patients with PD experiencing off episodes as described in the XADAGO Package Insert, May 
2017 (Appendix A). XADAGO is an orally active, water-soluble, α-aminoamide derivative. It is 
a potent, selective, and reversible MAO-B inhibitor. In addition, the molecule safinamide has 
been shown in animal studies to exhibit state-dependent blockade of voltage-gated sodium 
channels, modulation of calcium channels, and subsequent inhibition of stimulated release of 
glutamate (Caccia, 2006; Caccia, 2007; Chazot, 2007; Pevarello, 1998; Stocchi, 2006) which 
may be implicated in the development of dyskinesia (Chase, 2003; Gregoire, 2013). The clinical 
implication of the activity is not known. 

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XADAGO was evaluated in two double-blind, placebo-controlled, multinational, 24-week 
studies. In both studies, change in on time without dyskinesia plus on time with non-troublesome 
dyskinesia, as determined by patient diary, was the primary endpoint. Secondary endpoints 
included change in off time and clinician-rated change in Movement Disorders Society - Unified 
Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III scores. The trials were conducted in 
patients with PD who had at least 1.5 hours of daily off time, despite optimized treatment 
regimens of levodopa/carbidopa. Patients could also be taking dopamine agonists, catechol-O-
methyl transferase (COMT) inhibitors, anticholinergics, and amantadine. In Study 1, patients 
were randomized to placebo, 50 mg/day or 100 mg/day of XADAGO. In Study 2, patients were 
randomized to placebo or a treatment group in which all patients were started on 50 mg/day for 2 
weeks, then increased to 100 mg/day thereafter (Borgohain, 2014a; Schapira, 2017). Both studies 
showed significant improvements in on time without troublesome dyskinesia as compared to 
placebo, as well as significant decreases in off time and improvement in UPDRS Part III scores 
(Borgohain, 2014a; Schapira, 2017). The improvements in on time and off time seen at 6 months 
were maintained out to 2 years in an 18-month extension of Study 1 (Borgohain, 2014b). Both 
the 50 mg/day and 100 mg/day doses of XADAGO were well tolerated by patients and had 
safety profiles similar to that of placebo. The most commonly reported adverse event (AE) was 
dyskinesia, which was significantly higher in the treatment groups versus placebo. Of the 
patients who discontinued due to an AE, 1% of patients in the treatment group discontinued due 
to dyskinesia and 0% in the placebo group. In addition to the clinical benefits seen in motor 
function, there were also improvements noted in measures of activities of daily living, depressive 
symptoms, patients’ clinical status, and aspects of quality of life such as emotional well-being, 
communication, and bodily discomfort (Borgohain, 2014a; Borgohain, 2014b; Schapira, 2017). 
These improvements in non-motor symptoms were seen for the 100 mg/day group in secondary 
measures, specifically the Parkinson’s Disease Questionnaire; health status/quality of life (PDQ-
39) and the Clinical Global Impression of Change in health (CGI-C) outcomes. 
6.3. 
Study Rationale 
The objective of this prospective, observational, post-marketing study is to obtain further data on 
the effect of XADAGO on motor and non-motor symptoms in patients newly prescribed 
XADAGO. Although the cardinal symptoms of PD are motor, there is increasing appreciation of 
the non-motor symptoms, which at times may be a greater burden to the patient than the motor 
symptoms (Olanow, 2009; Weintraub, 2008). Along with the greater recognition, there is also an 
evolving science into the etiology of non-motor symptoms in PD. XADAGO as a treatment 
option is unique in that the molecule has a dual mechanism of action: 1) MAO-B inhibition 
improves motor symptoms, and 2) the second mechanism of action, sodium channel inhibition 
and subsequent modulation of glutamate, may have a role in improving non-motor symptoms. 
Secondary and post-hoc analyses of XADAGO clinical trial data described above find signals for 
improvement with endpoints in pain, quality of life, and mood that suggest possible clinical 
effects of the drug through this second mechanism of action. 
The focus of this study will be on measurement of changes in real-world outcomes (motor and 
non-motor symptoms, health status, and general quality of life) in the near term; therefore, the 
primary endpoint is set at 2 months, with an optional additional 4 months of treatment. 

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This study also will gather “real world” data from a PD population in the US regarding their 
overall experience and degree of satisfaction with the use of XADAGO as an add-on treatment to 
their L-dopa regimen. Treatment experience will be captured using patient self-rating 
assessments as well as clinician ratings on assessments. 

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7.
STUDY OBJECTIVES AND ENDPOINTS
7.1. 
Study Objective
The objective of this prospective, observational study is to gather real-world observational data 
from the following assessments in individuals in the United States (US) with Parkinson’s disease 
(PD) during XADAGO treatment: the Movement Disorders Society – Unified Parkinson’s 
Disease Rating Scale (MDS-UPDRS), the Parkinson’s Disease Questionnaire (PDQ-39), the 
Montreal Cognitive Assessment (MoCA), the Treatment Satisfaction Questionnaire for 
Medication (TSQM-9), the Clinical Global Impression of Change (CGI-C), and the Patient 
Global Impression of Change (PGI-C). 
7.2. 
Study Endpoints 
Study endpoints are the changes from the Baseline Visit to Visit 3 (Study Day 60, Primary 
Endpoint) in motor and non-motor symptoms, general health status/quality of life, treatment 
satisfaction, and global impression (Section 8.1 and Table 3) as measured by MDS-
UPDRS, PDQ-39 and MoCA, TSQM-9, and CGI-C/PGI-C, respectively. 
7.2.1. 
Motor Symptoms and Non-Motor Symptoms 
MDS-UPDRS (Appendix D) provides an assessment of the effects of PD on multiple aspects of 
a patient’s life. The assessment is administered by the Principal Investigator (PI) or certified 
Health Care Professional (HCP) designee and consists of 4 parts: 

Part I focuses on non-motor experiences of daily living, such as mood, sleeping
habits, pain, and fatigue. In IA, the investigator assesses various behaviors using
information from the patient and caregiver; in IB, the assessments are completed by
the patient without input from the investigator. Difficulties are rated on a 5-point
scale, from 0=no problems to 4=severe problems.

Part II is an evaluation of motor experiences of daily living, such as speech, eating,
hygiene, and movement, and is completed by the patient. Difficulties are rated using
the same 5-point scale as Part I.

Part III assesses the severity of the cardinal motor findings (e.g., tremor, rigidity,
bradykinesia, and postural instability). It includes 33 scores based on 18 items, and
difficulties are rated using the same 5-point scale as Part I.

Part IV is made up of questions on motor complications, and difficulties are rated
using the same 5-point scale as Part I. This section integrates patient-derived
information with the investigator’s clinical observations and judgments and is
completed by the rater (Goetz, 2008). It will be scored by the Investigator.
7.2.2. 
General Health Status/Quality of Life
PDQ-39 (Parkinson’s Disease Questionnaire) (Appendix B) is a disease-specific, health-related 
quality-of-life assessment. It is a self-completed, patient-reported outcome (PRO) designed to 
address aspects of functioning and well-being for those affected by PD. Each of the 39 items is 
rated using a 5-point Likert scale, with 0 for never having difficulties/problems and 4 for always 

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having difficulties/problems. The sum score of the 39 items will be calculated and used for 
analysis, with the maximum score of 156 (Peto, 1998). 
MoCA (Montreal Cognitive Assessment) (Appendix C) is a validated, 30-point, 1-page test 
administered by the PI or certified HCP designee and designed to assess several cognitive 
domains, including visuospatial abilities (5 points), naming (3 points), attention (6 points), 
language (3 points), abstraction (2 points), delayed recall (5 points), and orientation to time and 
place (6 points).  
7.2.3. 
Treatment Satisfaction 
TSQM-9 (Treatment Satisfaction Questionnaire for Medication) (Appendix E) is the abbreviated 
version of the original questionnaire (TSQM 1.4), a reliable and valid instrument with 
14 questions to assess patients’ satisfaction with medication. This PRO provides scores on four 
scales: side effects, effectiveness, convenience, and global satisfaction. Because questions 
relative to side effects could potentially interfere with patient care in a naturalistic setting, the 
9 questions on effectiveness, convenience, and global satisfaction are often used without the 5 on 
side effects (Bharmal, 2009). 
7.2.4. 
Global Impression 
CGI-C (Clinical Global Impression – Change) (Appendix F) is a rating of the patient’s overall 
improvement, based on a 7-point scale, using a range of responses from 1 (very much improved) 
through to 7 (very much worse) (Guy, 1976). The patient’s improvement is rated by the 
PI/certified HCP designee. 
PGI-C (Patient Global Impression – Change) (Appendix G) is a 7-point scale depicting a 
patient's rating of overall improvement. A patient reports his/her own change as “very much 
improved,” “much improved,” “minimally improved,” “no change,” “minimally worse,” “much 
worse,” or “very much worse” (Hurst, 2004). 

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8.
CLINICAL INVESTIGATION PLAN
8.1. 
Study Design and Schedule of Assessments 
This is a multisite, prospective, observational study to evaluate clinician-reported outcomes 
(ClinROs) and patient-reported outcomes (PROs) related to motor and non-motor symptoms, 
health status/QoL, and treatment satisfaction in a “real world” PD population in the US newly 
prescribed XADAGO in accordance with the Package Insert indication (Appendix A). The 
decision to prescribe XADAGO by clinician and patient must be made before site study staff 
discuss the study with the patient. If the patient is interested in participating in the study, an 
informed consent form (ICF) will be provided to the patient for review, contents of the ICF will 
be discussed, and patient’s signature will be obtained. Enrolled patients will be prospectively 
followed for 2 months, with the potential to participate in a 4-month Extension Study. 
The Schedule of Assessments (Table 3) presents all the study activities that will occur at each 
study interaction with patients during clinic visits, by telephone at protocol-specified time points, 
and by PRO via the electronic Clinical Outcome Assessment (eCOA) system. Investigative sites 
will be provided secure access to 21 CFR Part 11-compliant electronic Case Report Forms 
(eCRF), and sites and patients will have access to the eCOA system(s) for collecting all patient 
data. 
8.1.1. 
Screening / Baseline Assessments (Visit 1, Study Day 1) 
The Screening Visit and the Baseline Assessment Visit may occur on the same day. During the 
Screening Visit, patients who provide written consent to participate in the study and HIPAA 
authorization to use their personal health information will be screened for inclusion in the study 
according to the following procedures: 
•
Assessment of eligibility criteria (i.e., Inclusion [Section 9.1] and Exclusion
[Section 9.2] Criteria)
•
Collection of demographics and medical history information, including history of PD 
and other neurological conditions 
For patients determined to be eligible for the study, Baseline Assessments should be conducted 
at the same visit that Screening occurs. If the patient requires a separate Baseline Assessment 
Visit, it should occur no more than 7 days after the Screening Visit. 
Patients will arrive at the Investigator’s clinic in an “on” motor state. The following activities 
and outcome assessments (Baseline Assessments) will be completed at the clinic Baseline Visit: 

Presentation of study instructions relative to XADAGO administration, concomitant
medications, reporting of safety events, patient and Care Partner (if applicable),
completion of CROs and PROs, downloading and training on the eCOA system, and
documentation of other study data

Registration and training on the eCOA system (in which the patient will report PRO
results)

Assessment of concomitant medications

MDS-UPDRS by the PI/certified HCP designee

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 PDQ-39 by the patient 
 MoCA by the PI/certified HCP designee 
 Study Day 1 administration of XADAGO 
8.1.2. 
Telephone Follow-up with Patient by Study Site Staff (Visit 2, Study Day 30) 
All patients will be contacted by telephone on Study Day 30. If the patient is scheduled for a 
routine clinic visit within ±5 days of the Study Day 30 visit, the study assessments may be 
performed in person with the patient during the routine clinic visit. 
The following assessments will be completed: 
 Review of patient information relevant to XADAGO administration and concomitant 
medication administration 
 Daily record (e.g., electronic diary or log) will be available for the patient to enter 
information relevant to XADAGO and concomitant medications taken if patient 
decides to utilize 
 PRO assessment: 
 TSQM-9 
8.1.3. 
Primary Endpoint Assessments (Visit 3, Study Day 60) 
Patients will come to the study clinic for Primary Endpoint Assessments at Study Day 60. 
The following assessments will be completed: 
 Review of patient information relevant to XADAGO administration and concomitant 
medications administration 
 Assessment of AEs 
 Review of PRO completion compliance 
 Clinical outcome assessments administered by the PI/certified HCP designee:  
 MDS-UPDRS 
 MoCA 
 CGI-C 
 PRO assessments: 
 PDQ-39 
 TSQM-9 
 PGI-C 
8.1.4. 
Follow-Up Study Assessments (Visit 4 [Study Day 90], Visit 6 [Study Day 180]) 
Patients will come to the study clinic on Study Days 90 and 180.  
The following assessments will be completed: 

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 Review of patient information relevant to XADAGO administration and concomitant 
medications administration 
 Assessment of AEs 
 Review of PRO completion compliance 
 Clinical outcome assessments administered by the PI/certified HCP designee:  
 MDS-UPDRS  
 MoCA (Visit 6 only) 
 CGI-C 
 PRO assessments: 
 PDQ-39 
 TSQM-9 
 PGI-C 
8.1.5. 
PRO Assessment Timepoints (Visit 5 ]Study Day 120]) 
PRO assessment: 
 TSQM-9 
8.2. 
Number of Patients 
Up to 600 patients are planned for screening. This is expected to result in a final sample size of 
up to 540 eligible and evaluable enrolled patients, distributed among approximately 
50 investigative sites in the US. 

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Table 3: 
Schedule of Assessments 
Protocol Activity 
(Visit Type, Location, and Number; 
Study Day and Month;  
Window Allowance) 
2-Month Main Study
4-Month Extension Study
Screening/Baseline
Assessment Visit a 
Follow-up 
Primary 
Endpoint Visit 
Follow-up 
PRO 
Assessment 
Only 
Follow-up 
Clinic 
Telephone 
Clinic 
Clinic 
Clinic 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day 1 
Day 30 
Day 60 
Day 90 
Day 120 
Day 180 
Month 1 
Month 2 
Month 3 
Month 4 
Month 6 
±7 days 
±2 days 
±7 days 
±7 days 
±7 days 
±14days 
Informed Consent and HIPAA Authorization 
X 
Eligibility: Inclusion/Exclusion Criteria 
X 
Medical History and Demographics 
X 
Medical History of PD, other Neurological 
Conditions 
X 
Presentation of Study Instructions to Patient 
X 
Registration and Training on eCOA System 
X 
Concomitant Medications Assessmentb 
X 
X 
X 
X 
X 
XADAGO Administration Compliance Reviewb 
X 
X 
X 
X 
PRO Compliance Reviewb
 
X 
X
 
X
Adverse Events Assessmentb
 
X 
X
 
X
MDS-UPDRSb 
X 
X 
X 
X 
PDQ-39c 
X 
X 
X 
X 
MoCAb 
X 
X 
X 
TSQM-9c 
X 
X 
X 
X 
X 
CGI-Cb
X 
X 
X 
PGI-Cc 
X 
X 
X 
a Screening will take place not more than 7 days before the Baseline Visit and may occur at the same time as the Baseline Visit. The first study dose of 
XADAGO will occur in the clinic on the Baseline Visit day, which will be designated Study Day 1. 
b Assessments to be administered by the PI/certified or HCP designee. 
c Assessments to be completed by the patient, with Care Partner assistance, if required. 

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8.3. 
Criteria for Study Termination 
US WorldMeds, LLC (USWM), the study Sponsor, has the right to terminate this study at any 
time. The PI will be notified by telephone and/or in writing if the Sponsor decides to suspend or 
discontinue the study for any reason. The written notice will provide the PI with the reason that 
the study was suspended or discontinued along with instructions on how the site should proceed 
to close down the study. 
Reasons for terminating the study may include, but are not limited to, the following: 
 Discovery (from this or other studies) of an unexpected, serious, or unacceptable 
health hazard to patients 
 A decision on the part of the Sponsor to suspend evaluation or marketing of the 
product 
 Unsatisfactory patient enrollment  
 Failure of the PI and/or investigative site to comply with pertinent FDA regulations 
 Insufficient adherence to protocol requirements or an unacceptably high rate of 
missing, erroneous, or improperly collected data that threatens the scientific integrity 
of the study 
 Evidence from the data that there are sufficient technical problems with the study to 
believe with a high degree of certainty that patients are being involved in the study 
without a realistic expectation of evaluable data 

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9.
SELECTION AND WITHDRAWAL OF PATIENTS
9.1. 
Inclusion Criteria
1. Patient (and Care Partner if required per Inclusion 7) is able to understand and provide
signed informed consent and HIPAA authorization in English
2. Diagnosis of idiopathic PD (all stages)
3. Male or female, 30 to 80 years of age, inclusive, at initial screening assessment
4. Independent of the study, clinician’s and patient’s choice of treatment is XADAGO in
accordance with the Package Insert indication (Appendix A)
5. Patient is willing and able to participate in the study and complete study-related
assessments for 2 months and, patients can continue for an optional 4-month study
extension
6. Patient has access to an electronic device for the interim completion of PROs
7. Patient has an available Care Partner who is able and willing to assist with clinic
attendance and completion of study assessments (e.g., PROs, health outcomes, etc.), if in
the PI’s opinion, assistance is needed to comply with all study visits and procedures
9.2. 
Exclusion Criteria 
1. Any of the warnings, precautions, or contraindications listed in the Package Insert
(Appendix A) that in the opinion of the PI would prevent appropriate treatment with 
XADAGO or impair study participation (e.g., pregnancy, lactation, severe hepatic 
impairment, etc.)
2. Participation in any other clinical trial of an investigational drug or device within 4 weeks 
prior to the Baseline Visit or at any time during this study
3. Patient is currently receiving chemotherapy or radiation for any form of cancer (if history 
of cancer, must be in clinical remission at study entry) or currently receiving 
immunotherapy
4. Patients with conditions that are likely to prevent them from accurately and reliably 
completing study assessments, including evidence of moderate or severe dementia as 
determined by the clinician (not to include mild cognitive impairment [MCI]); major 
psychiatric illness (specifically diagnosis of schizophrenia, bipolar disorder or a history of 
attempted suicide); and/or severe and progressive medical illness (including terminal 
cancer, end-stage renal disease +/- undergoing dialysis)
5. Severe or unpredictable dyskinesia at the time of the Baseline Visit
6. Previous participation in this study; a patient may not re-enroll after prior discontinuation 
or completion 
9.3. 
Screening or Enrollment Failures 
A screening and enrollment log for all potential study participants who are assessed, and for 
those patients who have provided written informed consent and HIPAA authorization and 

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completed Baseline Assessment Visit procedures, will be maintained at the Investigator’s site. 
 
 
Potential study participants who fail the study inclusion/exclusion criteria may be re-assessed for 
inclusion at the PI’s discretion at a minimum of 2 weeks later. Re-assessed potential participants 
must fulfill all study criteria to be considered eligible for enrollment. Per Exclusion Criterion 6, a 
patient who has completed the study may not enroll a second time. 
9.4. 
Patient Withdrawal Criteria 
Any patient not completing the study for any reason will be considered a premature 
discontinuation and the study site staff must record the reason(s) for withdrawal in the patient’s 
study records. Patients who discontinue or are withdrawn from the study may not re-enter the 
study. 
A patient is free to withdraw consent from the study at any time, regardless of his/her reasons, 
and without prejudice against further treatment. The patient (and Care Partner, if applicable) will 
be queried about the reason(s) for the decision to withdraw consent and the reasons(s) must be 
clearly documented in the patient’s study record to ensure the decision was not due to an AE. If 
withdrawal was due to an AE, including SAE, the AE should be indicated as the reason for 
discontinuation even if the PI would not have considered discontinuation from the study because 
of the AE. 
The PI or Sponsor may withdraw an individual patient from the study at any time if it is deemed 
clinically appropriate. Circumstances can include the following: 
 Patient’s safety may be compromised due to intolerable AEs or a physical or mental 
condition  
 Patient requires a medication that was prohibited on this study 
 Patient is non-compliant with required study regimens or procedures specified in this 
protocol 
 Patient is lost to follow-up 
Any patient who experiences an SAE or is removed from the study because of an intolerable AE 
must be followed until the event resolves or stabilizes. If a patient cannot be reached for the 
telephone follow-up contacts or fails to return for any study visits required by the PI, repeated 
attempts will be made to reach the patient (or Care Partner, if applicable) (defined as a minimum 
of 3 telephone calls, followed by sending a certified letter). If repeated attempts are unsuccessful, 
lost to follow-up will be recorded in the patient’s study record. The PI should always inform a 
patient that he/she has been withdrawn from participation in a study and the reasons for 
withdrawal. 

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10. 
XADAGO AND OTHER MEDICATIONS  
10.1. 
XADAGO 
XADAGO is an FDA-approved and marketed product in the US. The Sponsor will initially 
provide to each qualified and activated site a supply of XADAGO (described in Section 10.1.1) 
only for use in the study. Kits will be uniquely labeled for tracking kit assignments to each study 
patient. 
When a patient is prescribed XADAGO and the patient agrees to participate in the study, which 
includes providing informed consent, the patient will be considered an enrolled study patient. 
 
 
Patients who discontinue XADAGO treatment during the conduct of the study can remain in the 
study or discontinue early (Section 10.1.4). 
10.1.1. 
XADAGO Study Supplies 
Each site will receive a supply of XADAGO to begin the study: 
 3 patient kits, each of which will contain: 
 1 blister pack of 50-mg tablets 
 4 blister packs of 100-mg tablets 
 2 extra blister packs of 50-mg tablets 
 3 bags 
 
 
 
 
 
10.1.2. 
XADAGO Drug Storage 
XADAGO should be stored at 25°C (77°F) with excursions between 15°C to 30°C (59°F to 
86°F) permitted per Appendix A (Package Insert). 

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10.1.3. 
XADAGO Accountability 
10.1.3.1. Site Accountability 
Accurate recording of all XADAGO study supplies received by the site and dispensed to patients 
in a XADAGO Study Kit will be maintained by study site personnel. 
At the end of the study, all unused XADAGO supplies or XADAGO Study Kits returned by 
study participants should be inventoried. If any XADAGO Study Kit is lost or damaged, its 
disposition should be documented. The Sponsor will provide instructions to return the unused 
study kits to the Sponsor’s designee at the end of the study. 
10.1.3.2. Patient/Care Partner Accountability 
Patients will take XADAGO as directed by the treating physician. Patients/Care Partners will be 
responsible for obtaining and storing XADAGO medication taken during the study and 
informing site study staff of any changes. 
10.1.4. 
XADAGO Discontinuation 
If an enrolled patient discontinues XADAGO treatment for any reason at any point in the study, 
the patient is permitted to remain on study and complete the full schedule of assessments per 
protocol, as long as the patient is otherwise eligible, and is able and willing to continue study 
participation through the end of the Main Study or the Extension Study, as appropriate. Refer to 
Section 9.4 for patients who discontinue XADAGO and wish to discontinue the study. 
10.2. 
Parkinson’s Disease Medications and Other Medications 
Patients will continue taking all prescribed PD medications (e.g., levodopa / carbidopa) including 
any other prescribed medication as directed by the treating physician. Any changes to prescribed 
regimen should be reported to study clinic staff. 

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11. 
SAFETY MANAGEMENT 
11.1. 
Safety Assessments 
The use of XADAGO in this study is not experimental, study procedures are not greater than 
minimal risk, and safety is not the principal objective of this protocol. In keeping with the 
Sponsor’s requirement, however, to review and report all information relevant to the safety of the 
marketed drug, XADAGO, about which the Sponsor becomes aware through notification by the 
investigator and study patients, all AEs spontaneously reported by the patient and/or in response 
to an open question from the site study personnel or revealed by observation will be recorded at 
the investigational site for each study patient during his/her active participation in the study. 
Additional information regarding AE reporting is available from the following sections of the 
CFR from the FDA, as well as from the designated website: CFR: §314.80, 
http://www.fda.gov/medwatchlindex.html. 
Please note that the governing Institutional Review Board (IRB) may impose additional safety 
reporting requirements with which the investigator’s site must comply. 
11.2. 
Definition of Adverse Events 
11.2.1. 
Adverse Event (AE)  
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether or 
not considered related to the product. 
11.2.2. 
Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring at any dose that results in any of the following 
outcomes: 
 Death 
 Life-threatening 
 Patient hospitalization or prolongation of existing hospitalization 
 Persistent or significant disability/incapacity 
 Congenital anomaly or birth defect 
 Important medical event that, based upon appropriate medical judgment, may 
jeopardize the patient or require medical or surgical intervention to prevent one of the 
outcomes listed above 
11.3. 
Relationship to XADAGO 
For each AE, the investigator will assess the attribution of XADAGO to the AE and determine 
whether the AE is or is not related to XADGAO as defined below. When in doubt, the AE should 
be considered at least “possibly related” until further evidence becomes available to refute this 
assessment. 

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
Definitely Not Related
 Patient did not receive XADAGO, the temporal sequence of the AE onset relative
to administration of XADAGO is not reasonable, or there is another obvious 
cause of the AE. 

Possibly Related
 There is evidence of exposure to XADAGO and the temporal sequence of the AE
onset relative to administration of XADAGO is reasonable, but the AE could have 
been due to another equally likely cause. 

Probably Related
 There is evidence of exposure to XADAGO, the temporal sequence of the AE
onset relative to administration of XADAGO is reasonable, and the AE is more 
likely explained by taking XADAGO than by any other cause. 

Definitely Related
 There is evidence of exposure to XADAGO, the temporal sequence of the AE
onset relative to administration of XADAGO is reasonable, the AE is more likely 
explained by taking XADAGO than by any other cause, and the AE shows a 
pattern consistent with previous knowledge in the label of XADAGO or similar 
drug class. 
AEs determined by the investigator to be “possibly” or “probably” related will be documented as 
related to XADAGO for the purposes of expedited regulatory reporting and clinical reporting. 
11.4. 
Recording Adverse Events 
AEs spontaneously reported by the patient and/or in response to an open question from the study 
personnel or revealed by observation will be recorded during the study at the investigational site. 
Information about AEs (and SAEs) will be collected from the time the patient signs the informed 
consent for this study and takes the first study dose of XADAGO until the patient’s last follow-
up visit. The AE term should be reported in standard medical terminology when possible. For 
each AE, the investigator will evaluate and report the onset date, resolution date, intensity, 
causality, action taken, serious outcome (if applicable), and whether or not it caused the patient 
to discontinue the study. 
Intensity will be assessed according to the following scale: 

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria under Section 11.2.2. An AE of severe 
intensity may not be considered serious. 

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11.4.1. 
Non-Serious Adverse Event (AE) 
If a non-serious AE occurs for any patient after signing an informed consent for this study and 
having taken XADAGO, the site should record the AE in the patient’s source medical record and 
eCRF in as real time as possible, but no later than 5 business days of observation or notification 
that such an event has occurred. The patient’s medical record and eCRF should be completed 
with as much information as is available at that time and the Sponsor will contact the site if 
additional information is required regarding the non-serious AE. Additional instruction for 
entering non-serious AE data in the eCRF is provided in the investigator site file (study binder). 
11.4.2. 
Serious Adverse Event (SAE) 
All SAEs (related and unrelated) that occur for any patient after signing an informed consent for 
this study and having taken XADAGO must be recorded by the investigator and reported. The 
site should record the SAE in the patient’s source medical record within 24 hours of observation 
or notification that such an event has occurred. The patient’s medical record should be completed 
with as much information as is available at that time with the knowledge that full clinical details 
may not be immediately available. The Sponsor will contact the site if additional information is 
required regarding the SAE. In addition, an SAE form located in the ISF binder must be 
completed and submitted to 
 (see Table 1 for details). 
All SAEs must be followed until they resolve or stabilize (i.e., a new baseline has been 
established). The PI must provide the Sponsor with all relevant follow-up information necessary 
to facilitate a thorough understanding of the experience and judgment regarding the relationship 
to XADAGO. Patients who discontinue because of an SAE before study completion will be 
contacted 7 days (±3 days) after discontinuation to determine if the SAE has resolved, continues 
unabated, or has reached a new baseline. 
 
. 
 
 
Reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
11.4.3. 
Pregnancy and Lactation 
Pregnancy is not considered an AE. According to the XADAGO Package Insert, XADAGO is 
classified as Pregnancy Category C. There are no adequate and well-controlled studies of 
XADAGO in pregnant women. XADAGO should be used during pregnancy only if the potential 
benefit justifies the potential risk to the fetus. 
It is not known whether this drug is present in human milk. Because many drugs are excreted in 
human milk and because of the potential for serious adverse reactions in nursing infants from 
safinamide, a decision should be made whether to discontinue nursing or to discontinue drug, 
taking into account the importance of the drug to the mother. 

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12. 
STATISTICAL METHODS 
12.1. 
General Statistical Considerations 
All assessments will be summarized at specified time points. Continuous variables will be 
summarized using the number of patients, mean, standard deviation (SD), and minimum, 
median, and maximum values. Categorical variables will be summarized using the number and 
percentage. All data will be summarized according to cohort and overall. 
Endpoints are defined at Study Day 60 (primary endpoint). Descriptive statistics will be provided 
for all data collected. All tests of significance, unless otherwise stated, will be performed using a 
two-sided alpha at 0.05. 
All analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Inc., Cary, 
North Carolina, USA). 
12.2. 
Analysis Populations 
The 2 analysis populations are defined in the study’s Statistical Analysis Plan (SAP) as follows: 
 Safety Population: All patients who sign informed consent for the study, complete 
baseline assessments, and receive at least 1 dose of XADAGO. 
 Evaluable Population: All patients in the safety population who complete at least the 
MDS-UPDRS assessment at the Study Day 60 visit. 
The principal analysis of the primary endpoint will be conducted for the evaluable population. 
Sensitivity analysis of the primary endpoint will be carried out for the safety population. Safety 
summaries will be provided for the safety population.  
Eligible, consented, and enrolled study participants will be analyzed based on concomitant PD 
medication regimen change at Baseline: 
Cohort A – Patients that have switched to XADAGO from a Dopamine Agonist 
Cohort B – Patients that have switched to XADAGO from an MAO-B inhibitor 
Cohort C – Patients that are MAO-B inhibitor naïve 
12.3. 
Sample Size and Decision Rules 
This is an observational study that will not assign treatment to patients. Patients will be analyzed 
collectively and in one of 3 cohorts based on the study entry criteria. A sample size of up to 
540 patients was selected to ensure a meaningful representation in each of the 3 cohorts. 
12.4. 
Handling of Missing Values 
PROs will handle missing values per the recommended process for that instrument. In general, 
missing item values for PRO instruments will not be imputed. Missing values will usually result 
in non-computational item scores for the patient. 
Missing visit information will usually be handled by analyzing using last-observation-carried-
forward (LOCF) imputations. 

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12.5. 
Subgroups and Covariate Adjustment 
Age, sex, and disease duration will be included in any subgrouping and/or covariate modeling. 
When variables are used in modeling, the inclusion in model will only stay if the p-value < 0.10 
for those situations. 
12.6. 
Interim Analysis 
Interim data analyses will be performed periodically to provide study updates and to support 
potential presentation of interim results via posters, publications, and other data dissemination 
vehicles. Since this study is observational only and treatments are not assigned to specific 
patient/treatment groups, these interim analyses will have no statistical implications. 
12.7. 
Population and Patient Disposition 
Frequency of patients enrolled, safety population, and evaluable patients will be displayed. 
Populations will be reported by cohort, site. 
Patient disposition will be summarized in each cohort along with reason of discontinuation. 
Frequency and percentages of patients completing and discontinuing the study prior to the 
primary endpoint (Study Day 60) and prior to the last study visit (Study Day 180) will be 
analyzed. 
12.8. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will include age, sex, weight, height, body mass index 
(BMI), race, and vital signs. Baseline characteristics will be detailed for all PROs and will be 
analyzed descriptively. 
12.9. 
Analysis 
12.9.1. 
Primary Outcome Analysis (Observational Assessments)  
The change in MDS-UPDRS, PDQ-39, and MoCA from the Baseline Assessment Visit to the 
Primary Endpoint (Study Day 60) will be analyzed and described in detail in the SAP. 
For the endpoints of CGI-C and PGI-C, the data will be dichotomized to have two categories, 
with ‘very much improved’ and ‘much improved’ into one category and the remaining levels into 
the other. 
12.9.2. 
Safety Analysis 
Serious and non-serious AEs will be collected as part of this study and reported for each cohort 
and overall. 

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13. 
STUDY MONITORING AND QUALITY CONTROL  
13.1. 
Study Monitoring 
The Sponsor is responsible for monitoring the progress of this study and overseeing data quality. 
 
 
 
 
 
 
 
 
13.2. 
Inspection of Records 
The Sponsor, designated representatives, the IRB, and any applicable regulatory agency will be 
provided with direct access to all information in original source documents and/or certified 
copies of original records of clinical findings, observations, or other activities in the clinical 
study necessary for the reconstruction and evaluation of the study. 
 
 
 
 
 
 
 
13.3. 
Site Audits 
It may be necessary for the Sponsor, designated representatives, and/or a regulatory agency to 
audit an investigative site. The purpose of an audit is to assess the accuracy, adequacy, and 
consistency of the study records and patient data, as well as to assess the site’s adherence to the 
procedures described in the study protocol. Direct access must be provided to all information in 
original source documents (if applicable) and/or certified copies of original records of clinical 
findings, observations, or other activities in the clinical study necessary for the reconstruction 
and evaluation of the study. 
 
 
 
 

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13.4. 
Quality Control 
 
 
 
 

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14. 
ETHICS 
This study will be conducted according to US CFRs dealing with Protection of Human Subjects 
(US 21 CFR Part 50) and IRBs (US 21 CFR Part 56); the Nuremberg Code; and the Declaration 
of Helsinki, revised version of Fortaleza, Brazil, October 2013 (in compliance with FDA 
guidance).  
14.1. 
Ethics Review 
The US FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to regulations and guidance issued by the FDA and are included in the 
following parts of the US CFR and guideline document: 
 21 CFR Part 50 - Protection of Human Subjects 
 21 CFR Part 56 - Institutional Review Boards  
 21 CFR Part 314.80 - Post-marketing reporting of adverse drug experiences 
Copies of these materials can be downloaded from the FDA’s website at www.fda/gov. 
The purpose of these regulations, legal obligations, and guidelines is to define the standards and 
principles for the proper conduct of clinical trials that have been developed by the medical, 
scientific, and regulatory communities. They are not intended to impede or restrict clinical 
research. 
14.2. 
Ethical Conduct of the Study and Institutional Review Board (IRB) 
Approval  
The Sponsor of this study is responsible for selecting qualified investigators, providing 
investigators with the information needed to properly conduct a study, properly monitoring the 
study, and ensuring that the FDA and all participating investigators are properly informed of 
significant new information regarding post-marketing adverse drug experiences or risks 
associated with the marketed drug XADAGO. 
Before the study can be initiated, the PI must obtain written IRB approval from the IRB of the 
PI’s institution and/or a central IRB (whichever is applicable) that complies with the 
requirements relating to IRBs. The final study protocol and final version of the Informed 
Consent Form (ICF) must be approved or given a favorable opinion in writing by an IRB as 
appropriate. The PI must submit written approval to the Sponsor (or designee) before he/she can 
enroll any patient into the study. 
If an amendment(s) to the study protocol becomes necessary, the Sponsor will provide the 
protocol amendment(s) and the PI will submit the written amendment(s) to his or her IRB for 
approval before amendment implementation. In addition, the PI’s IRB must approve all site-
specific advertising used to recruit patients for the study. Re-approval by the IRB must be 
obtained annually, if the study is more than 1 year in duration. 
Progress reports will be submitted to the IRB annually or at a frequency requested by the IRB. 
The PI is also responsible for providing the IRB with reports of all unanticipated problems 
involving risk to human patients or others, including serious and non-serious AEs. 

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14.3. 
Written Informed Consent and HIPAA Authorization 
The PI at each research site will ensure that each patient is given full and adequate oral and 
written information about the nature, purpose, and possible risks and benefits of the study. 
Attention is directed to the basic elements that are required in the informed consent and process 
under US CFR for Protection of Human Subjects (21 CFR 50.25 and/or ICH E6 4.8.10). Patients 
must be told that they may withdraw from the study at any time. The patient should have ample 
opportunity to ask questions and should be allowed time to consider the information provided. 
The patient’s signed and dated informed consent must be obtained before any study procedures 
are conducted. Patients may require Care Partner support to be considered eligible for the study 
(e.g., needs help in physically completing assessments or requires assistance with transportation 
to clinic visits), but must be cognitively capable of communicating and providing responses to 
questions. Care Partners, if willing, may also need to sign the informed consent form indicating 
their willingness to assist the patient as necessary. Patients who refuse to participate or who 
withdraw from the study will be provided care and treated without prejudice. 
The PI must maintain the original, signed, and dated ICF. A copy of the fully executed ICF must 
be given to the patient. 
Each patient must also sign a HIPAA Authorization form before his/her participation in the 
study. A signed copy must be provided to the patient and a signed original shall be maintained in 
the patient’s clinical file. 
14.4. 
Investigator Obligations 
The following is a list of key PI responsibilities during the study. A more detailed discussion of 
investigator obligations may be found in the US 21 CFR Part 50. 
 The PI must ensure that the study is conducted according to the protocol as written 
and must protect the rights, safety, and welfare of study patients in their care. Only 
the Sponsor may modify the protocol. If a protocol amendment (and perhaps a new 
ICF) is needed, the Sponsor will prepare the documents and guide all investigators 
through the amendment process. 
 The PI is required to maintain complete and accurate study documentation in 
compliance with current good documentation standards and make such 
documentation available as requested in the event of an inspection, review, or audit of 
the clinical research facility by the Sponsor, its representatives, and/or any 
appropriate regulatory agencies. 
 In accordance with FDA reporting requirements, the PI and site personnel are 
required to collect, document, and report all SAEs and noteworthy AEs during the 
study and, under special circumstances, thereafter (as described in Section 9.4 and 
Section 11.4.2 of this protocol). 

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15. 
DATA MANAGEMENT 
All data collected in the context of this study will be stored and evaluated in accordance with 
regulatory requirements and applicable guidance for electronic records. 
15.1. 
Data Capture 
Investigative sites will be provided secure access to a 21 CFR Part 11-compliant eCRF and 
eCOA system(s) for collecting patient data. All information recorded in the eCRF must be 
supported by source documentation in the patient’s medical file unless the electronic entry is the 
original entry (e.g., assessments completed through electronic device). The patient’s source file 
must include (but is not limited to) the following: 
 An entry documenting that the patient signed and dated an ICF and HIPAA 
authorization form before entry into and participation in the study 
 Patient study identification number and protocol number 
 Medical diagnosis and entries for all treatment and medications 
 Summaries of all clinic visits including those for study purposes 
 Documentation of all SAEs and noteworthy AEs 
15.2. 
Retention of Patient and Administrative Records 
The Sponsor (or designee) will be allowed to conduct site visits to study facilities for the purpose 
of monitoring and auditing any aspect of the study. The PI must also allow the IRB and any 
applicable regulatory agency direct access to all study-related facilities and materials, including 
original source documents and/or certified copies of original records of clinical findings, 
observations, or other activities relevant to the study and necessary for the reconstruction and 
evaluation of study conduct. 
The study site must provide the Sponsor with the following essential documents prior to study 
initiation and retain a copy in its study files: 
 Current curriculum vitae for the PI  
 Sponsor-approved protocol and protocol amendments signed and dated by the PI 
 Written IRB approval of the protocol and protocol amendments 
 IRB membership roster or assurance number 
 ICF and HIPAA authorization form approved by the IRB and accepted by the 
Sponsor 
 Fully executed Clinical Trial Agreement between the Sponsor and the site 
In addition to the documents listed above, the site must also retain the following items: 
 All original ICFs/HIPAA authorizations fully signed and dated 
 All IRB approvals and correspondence (e.g. informed consent [including any 
approved revisions], protocol, AEs [including SAEs] advertisements, newsletters) 

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 Copies of all correspondence (emails, faxes, postal mail) pertaining to the study from 
the Sponsor and IRB and other relevant parties 
 Copies of all safety-related information 
 Study personnel signature and delegation of authority log for the site 
 A separate file containing the Clinical Trial Agreement and related financial 
correspondence between the Sponsor and the site 
The PI and/or study site must retain copies of all pertinent study information, essential 
documents, and study data records (e.g., eCRFs, eCOAs, original data, patient identification lists, 
etc.) for a minimum period of 2 years after the study database lock and closure or until notified, 
in writing, by the Sponsor that these documents/copies are not needed. 
If record retention at the investigative site is no longer possible, or if the investigative site or 
study records are relocated, the Sponsor must be notified immediately in writing with the address 
of the new storage location. 

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16. 
CONFIDENTIAL INFORMATION 
16.1. 
Confidentiality of Study Data 
Confidential information refers to any information provided to your site by the Sponsor or its 
agents that has not been previously published. This includes, but is not limited to, the study 
protocol (and protocol amendments, if any), eCRFs (if applicable), assay methods, and basic 
scientific data. Any data collected at the site during the study are also considered confidential. 
All confidential information remains the sole property of the Sponsor, may not be disclosed to 
others without prior written consent from the Sponsor, and may not be used except in the 
performance of this study. The PI is required to provide the Sponsor with complete test results 
and all data obtained during this study. At the discretion of the Sponsor, the information from 
this study may be made available to any applicable regulatory agency and/or other physicians 
who are conducting similar studies. 
16.2. 
Confidentiality of Patient Records 
To maintain patient confidentiality, all laboratory results (if applicable), eCRFs (if applicable), 
reports, and other records will be coded using patient identification numbers. Only research staff 
and Sponsor officials will have access to the records. Patient information will not be released 
without written permission, except as necessary for monitoring by the Sponsor or a regulatory 
agency. 
By participating in this protocol, the PI and research site agree that within local regulatory 
restrictions and ethical considerations, the Sponsor or any regulatory agency may consult and/or 
copy study documents to verify eCRF data. 
Patient confidentiality will be maintained in any publications or presentations that result from 
this study. 

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17. 
PUBLICATION POLICY 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages publication of such data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study are described in the Clinical Trial Agreement 
between the Sponsor and the PI or his/her institution. 

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18. 
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